A shift in the understanding of the cerebellum has taken place over the past 25 years. The majority of the human cerebellum is associated with cerebral networks involved in cognition, which is an astonishing finding given that, until quite recently, the cerebellum was thought to contribute primarily to the planning and execution of movements (). The focus on motor function arose early in the 19century following careful observations in animal models of cerebellar damage (). The cerebellum’s anatomical positioning atop the spinal cord and deficits observed in neurological patients led Charlesto refer to the cerebellum as the “head ganglion of the proprioceptive system.” Despite sporadic findings supporting a more general role of the cerebellum in nonmotor functions, often conducted by eminent neurophysiologists (), the overwhelming emphasis of the literature did not waiver from focus on motor control. The motor emphasis was partly driven by a peculiar feature of cerebrocerebellar circuitry that has prevented traditional anatomical techniques from discovering the cerebellum’s full organizational properties ( Figure 1 ).

The cerebellum possesses complex connectivity with multiple subcortical structures including vestibular nuclei and the basal ganglia. The focus of this review is on circuits connecting the cerebellum to the cerebral cortex. A schematic diagram depicts the major input and output cerebrocerebellar circuits. Input projections from the cerebral cortex first synapse on the ipsilateral pons and then cross to the contralateral cerebellar cortex. Output projections first synapse on the dentate then cross to synapse in the contralateral thalamus and finally project to the cerebral cortex. Because there are no monosynaptic connections between the cerebral cortex and the cerebellum, conventional tract tracing techniques have been unable to map the relationship between the cortex and its projection zones in the cerebellum.

The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy.

The cerebellum is interconnected with the contralateral cerebrum primarily through two polysynaptic circuits—an input channel that synapses in the pons and then crosses to the cerebellum and an output channel that projects first to the deep cerebellar nuclei, then to the thalamus, and finally to the cerebral cortex (). This polysynaptic circuitry is a major contributor to the controversy surrounding the organization of the cerebellum. Because there are no monosynaptic projections between the cerebral cortex and the cerebellum, the organization of the cerebellum could not be unraveled using conventional anterograde and retrograde tracing techniques that do not cross the synapse. Foundational questions including whether portions of the cerebellum map to domains of the cortex involved in nonmotor function were left unanswered. In the absence of clear anatomical evidence that the cerebellum projects to nonmotor structures and the emphasis on motor deficits in clinical settings, early influential models of the cerebellum focused exclusively on motor function (e.g.,). The past 25 years have witnessed a major revision in our understanding of the cerebellum.

Anchoring from this initial observation, a number of studies soon found that the “cognitive” cerebellar response could be attenuated by keeping the motor response demands constant but automating the task () and modified by making features of the cognitive demands easier (). An early high-resolution fMRI study further revealed that the dentate, the output nucleus of the cerebellum, could be activated by cognitive processing—in this case, completion of a puzzle (). Directly motivated by the neuroimaging findings,conducted a detailed assessment of the cognitive capabilities of a patient with cerebellar damage and found evidence of deficits further fueling interest. The nature of the tasks used in these initial studies—in particular the requirement to generate action verbs to presented nouns—lent the findings to alternative interpretations, including the possibility that motor imagery was a critical component of the tasks. However, the growing availability of human functional neuroimaging using fMRI quickly produced a large number of cerebellar activations to many domains of cognitive tasks, leaving little doubt that the origins of the responses were nonmotor. Two recent meta-analyses capture the current state of the field, so I will not recount the results here (; see also). It is sufficient to note that, without setting out to do so, the vast community of researchers conducting functional human neuroimaging studies generated compelling evidence that the human cerebellum responds to cognitive task demands.

In 1988, Petersen and colleagues published a landmark paper on the functional anatomy of single-word processing (; see also). Their strategy was simple: measure brain function using PET while people viewed words and engaged in progressively more elaborate tasks. At the most basic task level, participants passively viewed the words (e.g., nouns like cake, dog, and tree). A second-level task evoked motor control demands by asking the participants to read the words aloud. At the most demanding level, the participants generated action verbs that were meaningfully related to the words (e.g., eat, walk, and climb). It was this last condition that yielded an extraordinary result. When participants generated words, a robust response was observed in the right lateral cerebellum ( Figure 2 ). The response was distinct from the expected motor response present in the anterior lobe of the cerebellum, leading the authors to conclude that “The different response locale from cerebellar motor activation and the presence of the activation to the generate use subtractions argue for a ‘cognitive,’ rather than a sensory or motor computation being related to this activation” (). The right lateralization in the cerebellum was consistent with strong responses in the left cerebral association regions presumably activated by the controlled semantic processing demands of the task.

(B) A summary diagram from the original publication highlights the “cognitive” cerebellar response (shown by red squares). The location of the cognitive cerebellar response was anatomically distinct from the motor zones (shown by blue circles). Adapted with permission from

(A) A transverse section displays a robust PET activation of the right lateral cerebellum (arrow) while subjects generated verbs to nouns in one of the first human neuroimaging studies of cognition. The response was present when the motor demands of the task, evoked by simple word reading, were subtracted.

Human neuroimaging techniques emerged in the mid-1980s as a revolutionary tool to indirectly map brain function in humans (). Early studies were conducted using positron emission tomography (PET). fMRI first appeared in the early 1990s () and became widely available within a few years. PET and fMRI both measure brain activity indirectly through the coupling of neuronal activity to increases in blood flow, often called the hemodynamic response. The approaches are frustratingly indirect, causing uncertainty about the neuronal origins of the recorded signals (). Despite this limitation, the approaches are powerful because brain activity can be surveyed in living individuals performing cognitive tasks. Critically, many studies broadly survey activity across the full brain (or nearly so) including the cerebellum because the field of view is large compared to other invasive physiological techniques. The ability of neuroimaging to survey regional responses in the cerebellum led to an unexpected discovery when human neuroimaging was first directed toward the study of cognition.

What we can do and what we cannot do with fMRI.

Discoveries beginning in the 1980s set the stage for reframing the role of the cerebellum in cognition. The initial impetus was an incisive review by the interdisciplinary team of Henrietta Leiner, Alan Leiner, and Robert Dow.(see also) summarized extensive evidence to suggest that the human cerebellum contains regions linked to cerebral association areas. Their review, which initially met resistance (), was based on the observation that the lateral output nucleus of the cerebellum (the dentate) is expanded in apes and humans relative to other species. The expansion is accounted for by preferential of the newer ventrolateral portion of the dentate and, by their estimates, occurred in parallel with expansion of prefrontal cortex. By comparing the topography of the dentatothalamic and thalamocortical projections, they deduced that the output channel from the cerebellum contains substantial projections to cerebral association areas including those within the prefrontal cortex. Foreshadowing research to appear over the next several decades, they further suggested that human neuroimaging methods could be used to confirm their hypothesis.

These collective observations reveal an anatomical substrate for contributions of the cerebellum to cognition. Despite earlier assumptions, the cerebellum receives and sends information to nonmotor cortical regions including prefrontal areas involved in higher cognition. The topographic relationship between the cerebellar motor zones and the newly discovered association zones provides an interesting clue to the broader organization of the cerebellum. The cerebellar association zones in Crus I/II fall between motor zones of the anterior and posterior lobes that possess mirrored motor maps. The cerebellum’s motor topography was first described by British physiologist Edgar Adrian, who stimulated the cerebral motor areas and recorded cerebellar discharges (). He discovered an inverted somatomotor representation in the anterior lobe of the cerebellum ( Figure 4 A). The hind-limb (foot) was represented within the central lobule (HIII) and the fore-limb (hand) in adjacent lobule HIV.made a similar observation in the cat but additionally observed a second, upright body map in the posterior lobe. The transneuronal viral tracing results of Strick and colleagues suggest that the cerebellar regions connected to association cortex fall between the mirrored motor representations. An open question is whether there are multiple cerebellar representations of cerebral association areas within the in-between zone and, if so, whether they possess a mirrored topography that parallels the motor representations. Comprehensive mapping of the human cerebellum using neuroimaging approaches answered this question and revealed a simple topography that connects the long-known motor representations to the newly discovered cerebellar association zones.

(C) Cerebellar locations of the foot (F), hand (H), and tongue (T) representations from fcMRI are shown in a sagittal section. This view demonstrates the anterior lobe (top) and posterior lobe (bottom) somatomotor representations. Note that they are mirror images of one another—the anterior lobe representation is inverted, while the posterior lobe representation is upright. In addition to informing motor topography, these findings illustrate that the human cerebellum can be mapped using functional connectivity. Further details of these data are illustrated in Figures 5 and 6 , which comprehensively map association zones of the cerebellum. Adapted from

(B) Cerebellar locations of the foot, hand, and tongue representation in the human measured by fMRI. In the left cerebellar hemisphere, labeled fcMRI, results based on intrinsic functional connectivity are displayed. In the right cerebellar hemisphere, labeled Task, results based on actual foot (green), hand (red), and tongue (blue) movements are displayed.

(A) The cerebral (right) and cerebellar (left) locations of the foot (green), hand (red), and face (blue) representation are shown for the monkey. Adapted from. Note that the body representation in the cerebellum is inverted (meaning the feet are anterior and the face is posterior).

Strick and colleagues resolved the issue by using transneuronal tracing to observe both input and output projections between the cerebellum and cerebral association cortex (; seefor review). Transneuronal tracing techniques use viruses that spread across synapses to map polysynaptic circuits, thereby overcoming the limitations of traditional tracing techniques.) first used transneuronal retrograde tracing to show that prefrontal areas receive projections from the dentate (output) nucleus. Further advances in viral tracing techniques provided a means to explore how cerebellar input and output is organized (e.g.,). Critically, they discovered that a large region near Crus I and Crus II both sends and receives projections from prefrontal cortex area 46, forming a closed-loop circuit ( Figure 3 ). The cerebellar region participating in prefrontal circuitry was nonoverlapping with distinct cerebellar regions that formed motor circuits.

(Right) Granule cells that receive input from prefrontal area 46 are displayed. These neurons were labeled using anterograde transport of a HSV1 virus strain injected into area 46. The shaded green region illustrates the zone of Crus I/II that forms a closed-loop circuit with prefrontal cortex. The topography of the projections is specific and distinct from the motor zones. Adapted with permission from

(Left) Purkinje cells that send output to prefrontal area 46 are displayed. These neurons were labeled using retrograde transport of a modified rabies virus injected into area 46.

Two bodies of anatomical work in the monkey met this challenge—one body of work from Jeremy Schmahmann and colleagues and the other from Peter Strick and colleagues. The development of sensitive anterograde tracing methods made it possible to inject specific cerebral areas and determine whether their projections terminate in the pons. The presence of pontine-labeled neurons indicates that cerebrocerebellar input to the cerebellum exists without specifying where the projections terminate within the cerebellar cortex. Using anterograde tracing techniques,) demonstrated that specific regions of prefrontal cortex linked to cognitive networks project to the cerebellum. Prior studies using retrograde tracers had noted widespread cerebral input but relatively modest involvement of prefrontal areas typically associated with cognitive function (e.g.,). However, the clear observation of anatomic input to the cerebellum from multiple prefrontal regions left open the possibility that cerebrocerebellar circuits form a type of anatomical siphon: the cerebellum might integrate incoming information from widespread cortical regions via the pons but then project exclusively to motor areas.

Corticopontine projection in the macaque: the distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei.

Projections to the basis pontis from the superior temporal sulcus and superior temporal region in the rhesus monkey.

The recurring observation that the cerebellum is active during cognitive tasks remained an enigma for many years because there was still widespread belief that the cerebellum predominantly influenced motor areas. Recall that cerebrocerebellar circuits are polysynaptic and therefore cannot be delineated with conventional tract tracing techniques. The seminal review ofsuggesting a role for the cerebellum in cognition was based on indirect arguments and therefore open to alternative interpretations. What was required to solidify a revision in thinking about the cerebellum’s contribution to nonmotor function was direct anatomical evidence.

A final interesting property of cerebellar organization that has been revealed by human neuroimaging concerns its asymmetry. Asymmetry here refers to the relative dominance of one hemisphere over the other hemisphere for a specific network or function, not simply that the cerebrum projects preferentially to the contralateral cerebellum. As noted above, the “cognitive” response first noted bywas right lateralized in the cerebellum consistent with the left dominance of language. Meta-analysis of task responses in the cerebellum indicates strong asymmetry as expected from notions of cerebral lateralization (e.g.,). In a recent exploration of functional coupling,reported that the asymmetrically organized networks in the cerebral cortex, meaning functional coupling on one side of the brain is stronger than the other, show a parallel but reversed asymmetry in the cerebellum. These functional asymmetries were preferential for association as compared to sensorimotor networks and varied across individuals in a predictable manner. Those individuals displaying the strongest cerebral functional asymmetries also possessed the strongest cerebellar asymmetries. By all measures the cerebellum appears to possess a roughly homotopic map of the cerebral cortex including its asymmetrical functional organization.

Viewing the organization of the cerebellum in the sagittal (side view) plane suggests one possible broad organizing principle ( Figure 6 ). The anterior lobe motor representation, which is inverted with respect to body orientation (foot, hand, tongue), is sequentially followed by representations of premotor networks, association networks related to executive control, and then finally the limbic-association network, sometimes called the default network. At Crus I/II the entire sequential ordering reverses and progresses through the cerebellum with a flipped representation ending with the upright body map (tongue, hand, foot). Thus, the major cerebellar representation of the cerebral cortex may comprise two maps (and possibly a smaller third map) of the cortical mantle oriented as mirror images of each another. The established body maps in the anterior and posterior lobes may be continuous with cortical association maps.

The topographic ordering of cerebellar zones is illustrated on a sagittal view of the left hemisphere. The colors represent the networks displayed in Figure 5 . Note that the regular ordering of zones is repeated between primary and secondary maps of the cerebral mantle. The primary map begins with the inverted foot, hand, and tongue somatomotor map (labeled F, H, T) and then progresses through a hierarchy of association zones labeled 1 through 4. Near the boundary of Crus I/II, the map flips and progresses through the full representation in reverse order (4 through 1 then T,H,F). The white line demarcates the approximate boundary between the two large maps. What appears initially as a complex pattern may be explained by the tentative hypothesis that the major portion of the cerebellum contains two mirrored representations of the cerebral cortex. A smaller tertiary map may also be present in the posterior lobe.

First, the majority of the human cerebellum falling between the anterior and posterior motor representations maps to cerebral association networks ( Figure 5 ). Second, with a few notable exceptions, the proportion of the cerebellum dedicated to a cerebral network was about as large as the extent of that network in the cerebrum. That is, cerebral networks that are large display coupling to correspondingly large cerebellar territories. Thus, the cerebellum, at least insofar as representation of the cerebrum is concerned, displays a roughly homotopic representation of the full cerebral mantle. The few notable exceptions include the primary visual and auditory cortex, which are not represented within the cerebellum of the human. Finally, cerebral association networks displayed multiple anterior and posterior representations in the cerebellum paralleling the long-established double representation of the body motor map. This last finding is particularly revealing as it suggests that there may be parsimony to the overall organization of the cerebellum.

Multiple coronal sections are displayed through various levels of the cerebellum. The colored parcellation of the cerebellum represents the most strongly functionally coupled networks of the cerebral cortex (illustrated on right). The blue cerebellar region corresponds to cerebral somatomotor cortex. Note that the cerebellum possesses regions in the anterior and posterior lobes strongly coupled to the somatomotor cortex as expected (see Figure 4 ). However, most of the human cerebellum is linked to cerebral association networks including an executive control network (shown in orange) and the default network (shown in red). Also note that the association networks each have multiple representations in the cerebellum. Similar maps have been converged upon by multiple, independent studies.

What maps to the extensive zones between the cerebral motor representations in the human? Three independent studies examining coupling with cerebral association cortex, including prefrontal regions, all demonstrated that extensive portions of the cerebellum map to association cortex (). For example,showed that major portions of Crus I/II are linked to association networks involved with executive control. Given that association cortex is disproportionately expanded in humans relative to monkeys and apes (), it is possible that a majority of the human cerebellum is connected to association cortex. To explore this possibility in greater detail,used an approach to comprehensively map the cerebellum. In a group of 1,000 individuals, each voxel within the cerebellum, which represents 2 blurred cubic mm of tissue volume, was mapped to its most strongly associated cortical network. Three findings resulted from this winner-take-all approach.

The usefulness of the approach can be appreciated by examining motor topography in the cerebellum, which, as described above, is well established from studies in the cat and monkey () and also from neuroimaging studies of active movements in the human (). In a particularly detailed exploration of human motor topography using actual motor movements,found that the body maps in the human cerebellum converge closely with the monkey in both the anterior and posterior lobes (see also). Critically, studies using intrinsic functional coupling also detect both the inverted body representation in the anterior lobe and the upright body representation in the posterior lobe ( Figures 4 B and 4C). The responses are strongly lateralized as expected with the left cerebrum preferentially coupled to the right cerebellum and can be detected in individual participants as well as group-averaged data (). Demonstrating that the functional coupling depends on intact anatomical connectivity, patients with focal infarcts to the hemipons, which disconnect the cerebrum from the contralateral cerebellum, display selectively disrupted functional coupling between the cerebrum and contralateral cerebellum (). These results suggest that measures of intrinsic functional coupling reveal details of cerebellar organization with a high degree of precision.

When individuals are imaged at rest in an MRI scanner there is a tremendous amount of spontaneous activity that exhibits spatial and temporal structure. Marcus Raichle notes that the brain’s energy budget is directed more toward these spontaneous activity events than toward activity changes transiently evoked by the immediate task at hand (). The precise physiological origin of the slow fluctuations is presently unclear but several lines of evidence suggest that, while there are multiple determinants of the spontaneous activity fluctuations, regions that show monosynaptic or polysynaptic connections tend to fluctuate together (). This means that anatomically connected regions can be inferred, with many caveats, by measuring correlations among brain regions (for discussion of caveats as they pertain to mapping the cerebellum, see). In a seminal proof-of-concept,demonstrated that fluctuations in primary motor cortex measured while subjects rested were correlated with the contralateral motor cortex and midline motor regions. While this initial study surveyed only a small portion of the brain that did not include the cerebellum, later work subsequently showed that correlated fluctuations can be detected between the cerebral cortex and the cerebellum with preferential coupling to the contralateral cerebellum ().

The anatomical work reviewed above demonstrates that major portions of the cerebellum are connected to cerebral association regions. The transneuronal viral tracing results further reveal that extensive cerebellar association zones fall in between the primary and secondary motor maps. But how are the association zones and motor zones related? And is there a parsimonious principle that explains the global topography of cerebrocerebellar circuits? A surprisingly powerful approach able to comprehensively map the organization of cerebellar cortex in the human has recently provided insight into these two questions. The approach derives from the observation that brain organization can be inferred by measuring spontaneous low-frequency fluctuations in intrinsic activity (; for review see).

The Unsolved Mysteries of Origin and Function

Ito, 1984 Ito M. The Cerebellum and Neural Control. Ramnani, 2006 Ramnani N. The primate cortico-cerebellar system: anatomy and function. Schmahmann [1991] Schmahmann J.D. An emerging concept. The cerebellar contribution to higher function. A striking feature of the cerebellum is the beautifully regular and simple cellular organization that is repeated across its cortex (). The progress in mapping the topography of the cerebellum suggests that the cerebellum is functionally heterogeneous because the repeating cerebellar modules (microcomplexes) process distinct information dependent upon the location of the cortical input. The prevailing view, based partly on the uniformity of the cerebellar cortex, is that the processing contribution the cerebellum performs on inputs from motor areas generalizes to inputs from association cortex (seefor an early articulation of this idea).

Ito (2008) Ito M. Control of mental activities by internal models in the cerebellum. Ito, 1984 Ito M. The Cerebellum and Neural Control. Thach, 1998 Thach W.T. What is the role of the cerebellum in motor learning and cognition?. Thach, 2007 Thach W.T. On the mechanism of cerebellar contributions to cognition. For example,suggested that the cerebellum’s contribution to cognitive function parallels its role in the control of movement (). Within this theory, the cerebellum forms an internal model through repeated performance and feedback. As a movement is repeated, the cerebellum allows the movement to be executed skillfully without dynamic feedback. Analogous processes are postulated to support the skillful execution of mental acts. Prefrontal control of cognitive objects—the mental models that represent imagined scenes and constructed thoughts—are operated upon by feedback mechanisms and internal models supported by the cerebellum. A similar evolution of ideas is present in the proposal of), who suggested that a postulated role of the cerebellum in coordinating and temporally synchronizing multimuscled movements might find a parallel whereby the cerebellum links cognitive units of thought.

Schmahmann, 1991 Schmahmann J.D. An emerging concept. The cerebellar contribution to higher function. Schmahmann and Sherman, 1998 Schmahmann J.D.

Sherman J.C. The cerebellar cognitive affective syndrome. Tavano et al., 2007 Tavano A.

Grasso R.

Gagliardi C.

Triulzi F.

Bresolin N.

Fabbro F.

Borgatti R. Disorders of cognitive and affective development in cerebellar malformations. Schmahmann, 2010 Schmahmann J.D. The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Andreasen et al., 1998 Andreasen N.C.

Paradiso S.

O’Leary D.S. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry?. Motivated by behavioral disturbances in patients with cerebellar abnormalities, Jeremy Schmahmann was among the earliest modern proponents for a role of the cerebellum in nonmotor functions including neuropsychiatric illness (e.g.,). He hypothesized, “It may also transpire that in the same way as the cerebellum regulates the rate, force, rhythm, and accuracy of movements, so may it regulate the speed, capacity, consistency, and appropriateness of mental or cognitive processes,” further noting “the overshoot and inability in the motor system to check parameters of movement may thus be equated, in the cognitive realm, with a mismatch between reality and perceived reality, and the erratic attempts to correct the errors of thought or behavior. Hence, perhaps, a dysmetria of thought.” The concept of dysmetria of thought has been expanded considerably in recent years with observations of patients with cerebellar abnormalities (e.g.,) and psychosis (e.g.,).

Fiez et al., 1992 Fiez J.A.

Petersen S.E.

Cheney M.K.

Raichle M.E. Impaired non-motor learning and error detection associated with cerebellar damage. A single case study. Grafman et al., 1992 Grafman J.

Litvan I.

Massaquoi S.

Stewart M.

Sirigu A.

Hallett M. Cognitive planning deficit in patients with cerebellar atrophy. Courchesne et al., 1994 Courchesne E.

Townsend J.

Akshoomoff N.A.

Saitoh O.

Yeung-Courchesne R.

Lincoln A.J.

James H.E.

Haas R.H.

Schreibman L.

Lau L. Impairment in shifting attention in autistic and cerebellar patients. Stoodley and Schmahmann, 2009b Stoodley C.J.

Schmahmann J.D. The cerebellum and language: evidence from patients with cerebellar degeneration. Tomlinson et al., 2013 Tomlinson S.P.

Davis N.J.

Bracewell R.M. Brain stimulation studies of non-motor cerebellar function: a systematic review. Helmuth et al., 1997 Helmuth L.L.

Ivry R.B.

Shimizu N. Preserved performance by cerebellar patients on tests of word generation, discrimination learning, and attention. Despite these ideas and other examples of cognitive impairments in patients with cerebellar lesions (e.g.,; see also), there remains a general belief among neurologists that cerebellar lesions do not typically produce marked cognitive impairment, at least as contrasted to the severe motor disturbances that are obvious. It is difficult to know where the gap lies between clinical impressions and the impairments that have now been documented in several studies. One possibility is that clinicians are not testing appropriately for cognitive and affective disturbances in patients with cerebellar damage. Another possibility is that, in the end, the cognitive deficits are relatively subtle even in many cases of large cerebellar lesions. Several explorations of deficits in patients with cerebellar lesions have found minimal cognitive impairment (e.g.,). This raises an interesting paradox: how can the majority of the human cerebellum be linked to cerebral association networks important to cognition yet the deficits following cerebellar damage be so subtle as to be missed by many clinicians and traditional tests of function?

The resolution to this paradox is presently unclear. Details of how deficits are tested are likely a large contributor. That said, I will end this review by offering an alternative thought—not because it is likely to be correct, but because it emphasizes a dimension to the complexity of the problem that has received little consideration to date. The thought is this: what if the increased size of the cerebellum and the extensive projections to association cortex are a spandrel or an unavoidable byproduct of coordinated evolution?

Holmes, 1939 Holmes G. The cerebellum of man. Glickstein, 2007 Glickstein M. What does the cerebellum really do?. Leiner et al., 1986 Leiner H.C.

Leiner A.L.

Dow R.S. Does the cerebellum contribute to mental skills?. Evolution of brain structures is powerfully limited by rules of embryonic development, birth orders of neurons, and size scaling relations among brain regions. In considering the large size of the cerebellum in primates and humans, adaptive arguments have been put forward in the context of motor function leaning on the dexterous hands of primates and consequences of full bipedalism in humans (e.g.,) or, in the context of cognitive function, the extraordinary mental abilities of apes and humans (). These notions assume that there has been direct selection for an increase in the size of the cerebellum. An alternative is that the selection has been for an overall increase in brain size and the cerebellum comes along as a byproduct.

Finlay and Darlington, 1995 Finlay B.L.

Darlington R.B. Linked regularities in the development and evolution of mammalian brains. Barton and Harvey, 2000 Barton R.A.

Harvey P.H. Mosaic evolution of brain structure in mammals. Finlay and Darlington, 1995 Finlay B.L.

Darlington R.B. Linked regularities in the development and evolution of mammalian brains. Finlay and Darlington, 1995 Finlay B.L.

Darlington R.B. Linked regularities in the development and evolution of mammalian brains. Herculano-Houzel, 2012 Herculano-Houzel S. The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost. As overall brain size enlarges across diverse mammalian species, the sizes of component brain structures scale predictably but at different rates (). The relation is far from perfect in that exceptions can occur (e.g.,) but the overall trend is nonetheless compelling. For example, the cerebral cortex scales with the largest rate of growth as overall brain size increases between species (). Mammals with big brains will have very big cerebrums. One likely reason for this regularity is constraints of embryonic development. The progenitor pool that gives rise to the cerebral cortex is large as the process of neurogenesis begins relatively late. Thus, as brain size is enlarged, the cerebral cortex disproportionately scales in relation to other structures such as the brain stem, which emerge relatively early in the developmental sequence. Mosaic evolutionary events are not needed to drive relative overexpansion of the cerebral cortex—in fact, an exceptional evolutionary event shifting neuronal birth order, progenitor pool size, or a related factor would be required to modify the rate of scaling. Relevant here is that the next fastest scaling brain structure is the cerebellum (). As brain size increases from a mouse to a monkey to a human, the cerebellum’s size scales at a rate second only to that of the cerebral cortex. Moreover, recent neuronal counting studies using modern techniques demonstrate that there is a relatively fixed ratio between the numbers of neurons in the cerebellum and cerebrum across species ().


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INTRODUCTION
============

Excessive daytime sleepiness (EDS) is a recurrent uncontrollable compulsion to sleep when intending to stay awake.[@B1][@B2] Sleepiness lowers the ability of an individual to perform various daytime functions, and is a risk factor for traffic accidents and occupational injuries.[@B3][@B4][@B5] Sleepiness also has negative effects on general health, social engagement, and quality of life,[@B6][@B7][@B8] and has been associated with cardiovascular disease and metabolic abnormality.[@B9][@B10][@B11][@B12][@B13][@B14] These findings have led to daytime sleepiness receiving increasing attention as an important public health issue.[@B15]

The prevalence of EDS has ranged widely in many studies worldwide, from 2.5% to 26%.[@B2][@B9][@B12][@B13][@B15][@B16][@B17][@B18][@B19][@B20][@B21][@B22][@B23][@B24][@B25][@B26][@B27] This high variability is mainly due to the use of different tools to measure sleepiness and the different definitions of EDS. In population-based studies using the Epworth Sleepiness Scale (ESS), which is a well-validated survey instrument used to quantify daytime sleepiness, the prevalence of EDS is estimated to range between 9% and 26%.

Several studies performed in Western countries have determined the prevalence of EDS, but there have been few reports on the nationwide prevalence of EDS in Korea. Most previous epidemiologic studies have investigated the possible determinants of EDS in relation to sleep duration or insufficient sleep separately. Since the sleep need differs between individuals, the same duration of sleep will lead to sleep insufficiency in some individuals but not others.[@B28] For example, self-reported short sleepers may include individuals with no sleep insufficiency and others with sleep insufficiency who purposefully curtail their sleep even if they need more sleep. This makes it necessary to differentiate the effects of short sleep duration and unmet sleep need on EDS. However, few studies have evaluated the effects of both sleep duration and unmet sleep need on EDS.

The aim of this study was to determine the prevalence of EDS in Korean adults and identify the separate and combined associations of both habitual sleep duration and unmet sleep need with EDS.

METHODS
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Study population and survey method
----------------------------------

The participants in this study comprised adults aged 19 years and older who resided in South Korea. Detailed information regarding the study population and survey method is available elsewhere.[@B29] Briefly, the survey was conducted by Gallup Korea in 2010 using multistage clustered sampling and involved participants from 15 administrative districts (metropolitan and provincial areas); all administrative districts except Jeju Island (a province) were included. All administrative divisions were further divided into si, gun, or gu, which are the basic units of administrative districts in South Korea. Using the proportionate quota sampling method according to the population distributions of sex and age, Gallup Korea approached 7,615 individuals, of which 2,836 subjects completed this survey. Seventy-six trained interviewers conducted the face-to-face interviews. All of the respondents provided informed consent before the survey. We excluded 67 participants with missing questionnaire responses on smoking, alcohol consumption, exercise, education level, body mass index (BMI), occupation, Insomnia Severity Index (ISI), ESS score, and sleep habits; data from 2,769 participants were therefore used in the analyses. This study was approved by the Institutional Review Board of the Soonchunhyang University Cheonan Hospital.

Measurement of excessive daytime sleepiness
-------------------------------------------

Daytime sleepiness was assessed using the ESS, which is a well-validated questionnaire consisting of eight items that quantify the likelihood of dozing in eight different situations.[@B1] The total ESS score ranges from 0 to 24, and daytime sleepiness was considered excessive in this study if the score was \>10.

Sleep questionnaire
-------------------

The main independent variables for this study were habitual sleep duration and unmet sleep need. The weekday and weekend average sleep durations of the participants over the previous month were recorded from their answers to a specific question in the questionnaire. Habitual sleep duration was defined as \[(weekday sleep duration×5)+(weekend sleep duration×2)\]/7. For sleep need, participants were asked \"How much sleep do you need to be at your best during the day?\" Unmet sleep need was calculated as the sleep need minus the habitual sleep duration. We used the ISI to measure the intensity of insomnia. The ISI is a brief self-report instrument consisting of seven items rated on a numeric scale from 0 to 4. Scores on the ISI may range from 0 to 28, and insomnia severity was classified as follows: 0--7, no clinically significant insomnia; 8--14, subthreshold insomnia; and 15--28, clinical insomnia.[@B30]

Other measures
--------------

Information on age, sex, height, weight, education level, physical activity, smoking, alcohol consumption, occupation, and snoring was self-reported. BMI was calculated by dividing the weight in kilograms by the square of the height in meters.

Statistical analysis
--------------------

All of the statistical analyses were performed using STATA (version 11.0, StataCorp., College Station, TX, USA). Unadjusted differences in continuous and categorical variables between the EDS and non-EDS groups were assessed for significance using the *t*-test or the χ^2^ test, as appropriate. We used logistic regression analyses to examine odds ratios (ORs) and 95% confidence intervals (CIs) of EDS scores associated with habitual sleep duration and unmet sleep need, separately and then together; this also included adjustment for relevant covariates. The statistical models were progressively adjusted. The covariates included in the model were age (continuous), sex, BMI (\<18.5, 18.5--25, or ≥25 kg/m^2^), smoking (yes or no), alcohol consumption (yes or no), physical activity (none, 1 or 2, or ≥3 times/week), education level (lower than high school, high school, or higher than high school), and ISI (normal, subthreshold insomnia, or clinical insomnia), and snoring (none, 1--3, or ≥4 days/week). A probability level of *p*\<0.05 was considered statistically significant.

RESULTS
=======

The sociodemographic and sleep-related characteristics in the participants with and without EDS are compared in [Table 1](#T1){ref-type="table"}. The overall prevalence of EDS in the study population was 11.9% (95% CI, 10.7--13.2). Participants with EDS were older, more likely to have less than a high-school education, and had a higher BMI than those without EDS. The distributions of sex, smoking, alcohol consumption, and physical activity did not differ between those with and without EDS. In terms of sleep-related factors, participants with EDS had shorter sleep durations and a longer unmet sleep need compared with those without EDS. The prevalence of insomnia and frequent snoring was higher among participants with EDS than among those without EDS.

The prevalence rates of EDS according to sociodemographic and sleep-related characteristics are presented in [Table 2](#T2){ref-type="table"}. Of all the subjects, 883 (31.9%) reported not getting at least 7 hours of sleep. An unmet sleep need of \>0 hours was present in 835 (30.2%) of the participants. The prevalence of EDS increased with age, and was significantly higher in those aged 60--69 years (15.5%) than in those aged 19--29 years (9.7%). The prevalence rates of EDS were 15.9% and 16.3% in the underweight and overweight groups, respectively, and these were both significantly higher than that in the normal-weight group (10.2%). The prevalence of EDS among those with less than a high-school education was 15.2%, which was significantly higher than those in the groups with a high-school and a higher level of education. The prevalence of EDS was 33.6% in the clinical insomnia group and 22.4% in the subclinical insomnia group; these were significantly higher than that in the normal group (9.1%). The prevalence of EDS was 18.1% in habitual snorers (snoring ≥4 days/week), which was significantly higher than in those who did not snore (10.6%). The prevalence of EDS was 15.8% in the group with sleep durations of \<6 hours and 14.4% in the group with sleep durations of 6 to 7 hours, which was significantly higher than that in the group with sleep durations of ≥8 hours (9.4%). The prevalence of EDS was 19.6% in the group with an unmet sleep need of ≥2 hours, and 15.4% in the group with an unmet sleep need of 0.01 to 2 hours; these were significantly higher than that in the group with a sufficient sleep duration (9.5%).

Logistic regression analyses were performed to assess the associations of sleep duration and unmet sleep need with EDS, separately and then together, while adjusting for age, sex, BMI, smoking status, alcohol consumption, physical activity, and education level. Additionally, we progressively adjusted for insomnia and snoring ([Table 3](#T3){ref-type="table"}). The adjusted OR for EDS was significantly higher in subjects with a sleep duration of \<6 hours a night (OR, 1.79; 95% CI, 1.21--2.64) and subjects with a sleep duration of 6 to 7 hours a night (OR, 1.62; 95% CI, 1.17--2.23) than in those with a sleep duration of ≥8 hours a night. The adjusted OR for EDS was significantly higher in subjects with an unmet sleep need of ≥2 hours (OR, 2.41; 95% CI, 1.80--3.23) and subjects with an unmet sleep need of 0.01 to 2 hours (OR, 1.87; 95% CI, 1.37--2.55) than in those with no unmet sleep need. The combination effect of sleep duration and unmet sleep need was then evaluated, which resulted in the association between sleep duration and EDS no longer being statistically significant. In contrast, there was a significantly higher risk of EDS in the groups with unmet sleep needs of ≥2 hours (OR, 2.32; 95% CI, 1.66--3.23) and 0.01 to 2 hours (OR, 1.79; 95% CI, 1.30--2.47). This trend persisted after also adjusting for insomnia and snoring, although the ORs for EDS were reduced to 1.80 (95% CI, 1.27--2.54) and 1.42 (95% CI, 1.02--1.98), respectively.

DISCUSSION
==========

This study investigated the prevalence of EDS (defined as an ESS score of \>10) according to sociodemographic factors, and evaluated the association between sleep duration and/or unmet sleep need and EDS in a population of Korean adults. We found that the prevalence of EDS was 11.9% among both male and female Korean adults. Several studies have estimated the prevalence of EDS using the ESS in general populations. Studies involving Australian adults found that the prevalence of EDS ranged from 11.7% to 15.3%.[@B2][@B12][@B25] In French adults, 12.0% of men and 6.0% of women reportedly had EDS.[@B24] A previous Korean study using data from the Korean Genome Epidemiology Study found that the prevalence of EDS was 12.2%.[@B26] Another study found that the prevalence of EDS in Norwegian adults was 17.7%.[@B23] In the Sleep Heart Health Study, 29.7% of men and 20.8% of women had an ESS score of \>10.[@B20] In the MONICA Study, 26.1% of a Polish population suffered from EDS.[@B18] The overall prevalence of EDS in the present study is similar to those found in Australia, New Zealand, and France, but lower than those in the US and Poland. These differences between studies may be caused by various factors, including differences in study methodologies and in the sociocultural and other characteristics of the included populations.

We found that the prevalence of EDS did not differ between the sexes. Although sex-based differences have been found in community-based studies,[@B20][@B31] several populationbased studies produced conflicting findings.[@B13][@B32] This inconsistency may be due to differences in sampling methods leading to different sex ratios in the populations included in the different studies, or in the questionnaires used to measure daytime sleepiness, since men and women can interpret questions differently. Unadjusted analysis showed that the factors associated with EDS in the present study were older age, higher BMI, lower level of education, frequent snoring, and insomnia. Older people (aged 60--69 years) had a higher prevalence of EDS compared with younger people (aged 19--29 years) in our study, which may be attributed to the presence of underlying medical or sleep disorders and the different lifestyle of the elderly. Many older adults are not able to get sufficient sleep for various reasons, including conditions associated with depression, poor general health, physical inactivity, medical illness, and the use of numerous medications.[@B33][@B34] The prevalence of certain primary sleep disorders (e.g., sleep-disordered breathing, restless legs syndrome, and REM behavior disorder) increases with age and interferes with sleep, leading to daytime sleepiness. Obesity is known to be a risk factor for obstructive sleep apnea (OSA)[@B35][@B36] and a significant predictor of EDS, independent of underlying OSA.37 Previous studies have found lower socioeconomic status (including the education level) to be associated with worse sleeping patterns.[@B38][@B39] The present study found that EDS was associated with a lower level of education, which tends to be present in older Koreans, like in many other societies. A better characterization of the factors associated with a higher prevalence of EDS among people with lower levels of education is needed. EDS is the most frequent presenting symptom in subjects with OSA syndrome.[@B40][@B41] Although we did not perform polysomnography, the presence of snoring as a symptom of OSA might be correlated with EDS. Insomnia is a subjective symptom of insufficient or nonrestorative sleep despite there being an adequate opportunity to sleep, resulting in sleepiness during the daytime. We used the ISI but could not define primary insomnia and could not exclude co-morbidities of insomnia; nevertheless, it is well known that EDS is caused by insufficient sleep, and various types of sleep problems are linked to poor sleep quality, insomnia, misalignments of circadian rhythm (e.g., jet lag or shift work) and sleep-enhancing drugs.[@B17][@B19][@B27][@B42][@B43]

Unmet sleep need, insomnia, and snoring were significantly associated with an increased risk of EDS in the present study after adjusting for sociodemographic factors. These results are similar to those of previous studies.[@B16][@B17][@B18][@B19][@B21][@B22][@B24][@B25][@B26][@B27][@B44] We attempted to elucidate whether EDS is directly linked to sleep duration or unmet sleep need. When sleep duration and unmet sleep need were examined separately, significant associations were found with EDS, but when sleep duration and unmet sleep need were examined together, unmet sleep need alone accounted for the risk of EDS, with the association between sleep duration and EDS disappearing. This result did not change after performing additional adjustments for insomnia and snoring. In short, unmet sleep need is independently associated with EDS, suggesting that sleep duration is not directly linked to the risk of EDS. These results suggest that measuring unmet sleep need would be a more direct way of detecting EDS than measuring the habitual sleep duration, since the basal sleep requirement for preventing daytime sleepiness may differ between natural short sleepers and natural long sleepers, and it is necessary to differentiate between short-duration sleepers with a decreased basal sleep need and those experiencing insufficient sleep.[@B28][@B45]

Our study had several limitations that should be noted. First, the information on sleep duration was self-reported by the participants. However, previous studies have found adequate agreement between self-reported sleep durations and data obtained using actigraphic monitoring.[@B46][@B47] Thus, although self-administered questionnaires are not as accurate as actigraphy or polysomnography, they are widely used in population-based studies due to the method being rapid and simple to apply. Second, insufficient sleep may be influenced by subjectively perceived normative standards. For example, socioeconomic status and other factors may affect how subjects answer questions, thereby potentially introducing information bias.[@B48] Third, due to a survey limitation, we could not evaluate the presence of underlying primary sleep disorders such as OSA. Finally, this study had a cross-sectional design, and so causal relationships could not be elucidated.

Our study has revealed the prevalence of EDS using ESS in a general population of Korean adults. According to our results, 11.9% of Korean adults have EDS. When sleep duration and unmet sleep need were examined together, only the effect of unmet sleep need was associated with EDS. EDS was associated with unmet sleep need, insomnia, snoring, and BMI after adjusting for sociodemographic factors. We suggest that the unmet sleep need of an individual is more important than the habitual sleep duration in terms of the relationship with EDS.

This work was supported by a grant from Soonchunhyang University Cheonan Hospital Research Fund.

**Conflicts of Interest:** The authors have no financial conflicts of interest.

###### Baseline characteristics of study participants

![](jcn-12-194-i001)

                                      EDS          Non-EDS       *p*-value^\*^
  ----------------------------------- ------------ ------------- ---------------
  Number of subjects (%)              330 (11.9)   2439 (88.1)
  Age (years)                         46.7±15.4    44.1±15.0     0.003
  Sex, women (%)                      50.0         50.1          0.983
  Body mass index (kg/m^2^)           23.7±3.3     22.9±2.9      \<0.001
  Smoking (%)                         26.7         27.0          0.905
  Drinking (%)                        62.4         65.5          0.275
  Physical activity (times/week, %)                              0.131
   None                               57.9         52.1
   1-2                                19.1         20.8
   ≥3                                 23.0         27.1
  Education leves (%)                                            0.043
   Lower than high school             23.0         17.4
   High school                        41.5         44.0
   Higher than high school            35.5         38.6
  ESS score                           13.1±2.3     4.6±3.0       \<0.001
  Sleep duration (hours/day)          7.1±1.5      7.3±1.2       0.004
  Unmet sleep need (hours/day)        1.0±1.4      0.5±1.0       \<0.001
  Insomnia (%)                                                   \<0.001
   Normal                             63.3         85.4
   Subthreshold insomnia              23.7         11.1
   Clinical insomnia                  13.0         3.5
  Snoring                                                        \<0.001
   None                               54.5         62.1
   1-3 days/wk                        17.3         20.7
   ≥4 days/wk                         28.2         17.2

Data are presented as mean±standard deviation or percentage.

^\*^Significance tests for the difference between 2 groups are based on the χ^2^ test for categorical variables and on the *t*-test for continuous variables.

EDS: excessive daytime sleepiness, ESS: Epworth Sleepiness Scale.

###### Prevalence and unadjusted odds ratios (95% CI) of excessive daytime sleepiness according to socio-demographic and sleep-related variables

![](jcn-12-194-i002)

  Variables                        Categories      *n*                Prevalence % (95% CI)   Unadjusted OR (95% CI)
  -------------------------------- --------------- ------------------ ----------------------- ------------------------
  Age (years)                      19-29           536                9.7 (7.3-12.5)          1.00 (reference)
  30-39                            593             11.8 (9.3-14.7)    1.25 (0.85-1.82)
  40-49                            593             9.9 (7.7-12.6)     1.03 (0.69-1.52)
  50-59                            514             12.8 (10.1-16.0)   1.37 (0.93-2.02)
  60-69                            459             15.5 (12.3-19.1)   1.70 (1.16-2.50)
  ≥70                              74              16.2 (8.7-26.6)    1.80 (0.91-3.56)
  Sex                              Female          1386               11.9 (10.2-13.7)        1.00 (reference)
  Male                             1383            11.9 (10.3-13.8)   1.00 (0.80-1.26)
  Body mass index (kg/m^2^)        \<18.5          126                15.9 (10.0-23.4)        1.65 (1.01-2.72)
  18.5-25                          1991            10.2 (8.9-11.7)    1.00 (reference)
  ≥25                              652             16.3 (13.5-19.3)   1.70 (1.32-2.19)
  Smoking                          No              2023               12.0 (10.6-13.5)        1.00 (reference)
  Yes                              746             11.8 (9.6-14.3)    0.98 (0.76-1.28)
  Drinking                         No              966                12.8 (10.8-15.1)        1.00 (reference)
  Yes                              1803            11.4 (10.0-13.0)   0.88 (0.69-1.11)
  Physical activity (times/week)   None            1462               13.1 (11.4-14.9)        1.00 (reference)
                                   1-2             569                11.1 (8.6-13.9)         0.83 (0.61-1.12)
                                   ≥3              738                10.3 (8.2-12.7)         0.76 (0.58-1.01)
  Education levels                 \<High school   500                15.2 (12.2-18.7)        1.00 (reference)
  =High school                     1210            11.3 (9.6-13.2)    0.71 (0.53-0.96)
  \>High school                    1059            11.0 (9.2-13.1)    0.69 (0.51-0.95)
  Insomnia                         Normal          2293               9.1 (8.0-10.4)          1.00 (reference)
  Subthreshold insomnia            348             22.4 (18.1-27.2)   2.88 (2.16-3.85)
  Clinical insomnia                128             33.6 (25.5-42.5)   5.04 (3.40-7.48)
  Snoring (days/week)              None            1695               10.6 (9.2-12.2)         1.00 (reference)
  1-3                              561             10.2 (7.8-13.0)    0.95 (0.70-1.30)
  ≥4                               513             18.1 (14.9-21.7)   1.86 (1.42-2.45)
  Sleep duration (hours/day)       \<6             291                15.8 (11.8-20.5)        1.80 (1.23-2.64)
  6 to \<7                         592             14.4 (11.6-17.4)   1.61 (1.17-2.21)
  7 to \<8                         965             11.6 (9.7-13.8)    1.26 (0.94-1.69)
  ≥8                               921             9.4 (7.6-11.5)     1.00 (reference)
  Unmet sleep need (hours/day)     0               1934               9.5 (8.2-10.9)          1.00 (reference)
  0.01 to \<2                      421             15.4 (12.1-19.3)   1.74 (1.28-2.36)
  ≥2                               414             19.6 (15.9-23.7)   2.31 (1.74-3.08)

###### Odds ratios (95% confidence intervals) for excessive daytime sleepiness (ESS \>10)

![](jcn-12-194-i003)

  Characteristics                          Model 1a^\*^       Model 2^\*^         Model 3^†^          Model 4^‡^
  ---------------------------------------- ------------------ ------------------- ------------------- ------------------
  Sleep duration (hours/day)
   \<6                                     1.79 (1.21-2.64)                       1.12 (0.72-1.73)    0.89 (0.56-1.40)
   6 to \<7                                1.62 (1.17-2.23)                       1.22 (0.87-1.72)    1.21 (0.85-1.72)
   7 to \<8                                1.32 (0.98-1.77)                       1.19 (0.88-1.61)    1.23 (0.91-1.68)
   ≥8                                      1.00 (reference)                       1.00 (reference)    1.00 (reference)
  Unmet sleep need (hours/day, vs. none)                      1.00 (reference)    1.00 (reference)    1.00 (reference)
   0.01-1.99                                                  1.87 (1.37, 2.55)   1.79 (1.30, 2.47)   1.42 (1.02-1.98)
   ≥2                                                         2.41 (1.80, 3.23)   2.32 (1.66, 3.23)   1.80 (1.27-2.54)
  Insomnia (vs. normal)                                                                               1.00 (reference)
   Subthreshold insomnia                                                                              2.61 (1.93-3.55)
   Clinical insomnia                                                                                3.88 (2.52-5.96)
  Snoring (days/wk, vs. none)                                                                         1.00 (reference)
   1-3                                                                                0.89 (0.64-1.24)
   ≥4                                                                                1.45 (1.08-1.96)

^\*^Model 1 & 2, adjusted for age, sex, BMI, smoking status, drinking, physical activity and education level, ^†^Model 3, adjusted for the variables in model 1 plus unmet sleep need, ^‡^Model 4, adjusted for the variables in model 3 plus insomnia and snoring.

BMI: body mass index, ESS: Epworth Sleepiness Scale.


John Randall, Baron Randall of Uxbridge

Alexander John Randall, Baron Randall of Uxbridge  (born 5 August 1955) is a British politician who served as the Member of Parliament (MP) for Uxbridge from 1997 to 2010 and for Uxbridge and South Ruislip until 2015, before being awarded a life peerage. A member of the Conservative Party, he was Deputy Chief Whip between May 2010 and October 2013, as well as Environment Advisor to Theresa May until July 2019.

Lord Randall is a trustee and Vice-Chair of the Human Trafficking Foundation and in February 2016 was appointed Special Envoy on modern slavery to the Mayor of London, alongside Anthony Steen.

Early life

Randall's family have lived in Uxbridge for many years. The family owned the major local department store Randalls of Uxbridge on Vine Street, which was founded by his great-grandfather Philip Randall in 1891, and closed in 2015.

Born in Uxbridge, Randall was educated at Rutland House School, an independent school in Hillingdon in the west of Greater London and at Merchant Taylors' School in Moor Park, Hertfordshire. In 1979, he graduated from the School of Slavonic and East European Studies (which is now part of University College London) with an Upper Second Class Honours BA degree in Serbo-Croatian language and literature.

Randall later became managing director of Randall's and one of three shareholders in the business. In 1994, he became Honorary Treasurer of Uxbridge Conservative Association, which later elected him Chairman.

He announced in 2014 that the family store would close, citing decreased turnover and competition from online shopping as causes. Speaking about the closure, he criticised other employers for using zero-hours contracts to cut their costs.

Parliamentary career

House of Commons
Randall was elected Member of Parliament for Uxbridge in a by-election following the death of Sir Michael Shersby in the wake of the Labour Party's 1997 landslide election victory. Randall had been an election agent for Shersby throughout the 1997 General Election campaign. He became the first Conservative candidate to win a parliamentary by-election since the party’s recently elected leader William Hague's victory in Richmond in 1989.

During his political career he has sat on the Environment, Transport and Regional Affairs Select Committee and its Environment Sub-Committee. He is strongly against the expansion of Heathrow Airport.

In 1999 he was appointed as an Opposition Whip, but, due to his opposition to Britain's involvement in the Iraq War, he resigned as a matter of conscience in March 2003. He was later reappointed as a Whip in 2003. At the end of 2005 he was promoted to Conservative Assistant Chief Whip. In 2010 he was appointed the joint Deputy Chief Whip and Treasurer of Her Majesty's Household in the Coalition Government.

He was appointed as a Privy Counsellor on 9 June 2010.

He resigned from the government with praise to David Cameron on 6 October 2013, amid a cabinet reshuffle. On 21 October 2013 it was announced that he was to receive a knighthood, having the accolade bestowed by The Prince of Wales on 12 February 2014. On 10 July 2014, Randall announced that he would not be standing as a parliamentary candidate for the seat at the 2015 general election.

House of Lords
On 18 May 2018, it was announced he would be elevated to the House of Lords. On 25 June, he was created a life peer as Baron Randall of Uxbridge, of Uxbridge in the London Borough of Hillingdon.

Outside Parliament
In February 2016 he was appointed Special Envoy on Modern Slavery to the Mayor of London, alongside Anthony Steen CBE.

Personal life
Lord Randall married Katherine Frances Gray in 1986; the couple have two sons and a daughter. Randall is a keen supporter of Uxbridge Football Club and Saracens Rugby Club, and a keen birdwatcher.

References

External links
 John Randall MP Official website
  Biography- House of Lords
 John Randall General Election 2010 Campaign site for Uxbridge and South Ruislip Constituency
 Guardian Unlimited Politics – Ask Aristotle: John Randall MP
 TheyWorkForYou.com – John Randall MP

Category:1955 births
Category:Living people
Category:Conservative Party (UK) life peers
Category:Peers nominated by Theresa May
Category:Conservative Party (UK) MPs for English constituencies
Category:UK MPs 1997–2001
Category:UK MPs 2001–2005
Category:UK MPs 2005–2010
Category:People educated at Merchant Taylors' School, Northwood
Category:Alumni of University College London
Category:Alumni of the UCL School of Slavonic and East European Studies
Category:Alumni of the University of London
Category:UK MPs 2010–2015
Category:Knights Bachelor
Category:Members of the Privy Council of the United Kingdom


Syrian Rebels Massacred Civilians, Says Human Rights Watch

Rebel forces in Syria killed as many as 190 civilians and seized more than 200 hostages during a military offensive in August.

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Kochava Rozenbaum , 11/10/13 14:22

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Human Rights Watch (HRW) reported Friday that groups of Syrian rebel forces executed at least 190 civilians and seized over 200 as hostages during a military offensive on August 4.

According to the report, a majority of the massacres took place in the city of Latakia, predominantly inhabited by members of Bashar al-Assad's minority Alawite sect.

“These abuses were not the actions of rogue fighters,” said Joe Stork, Acting Middle East Director at Human Rights Watch. “This operation was a coordinated, planned attack on the civilian population in these Alawite villages.”

Human Rights Watch says it conducted an on-site investigation and interviewed more than 35 people, including survivors and fighters from both sides of the offensive.

A 105-page report says that in the early hours of August 4, opposition fighters overran government positions in the Latakia countryside and occupied more than ten Alawite villages. HRW says it appears the civilians were killed on the first day of the operation.

The report says the high civilian death toll and the nature of the recorded wounds "indicate that opposition forces either intentionally or indiscriminately killed most of the remaining victims."

"The evidence strongly suggests that the killings, hostage taking, and other abuses committed by opposition forces on and after August 4 rise to the level of crimes against humanity," the report said.

HRW says Islamist rebel groups - which include foreign fighters - are financed by individuals in Kuwait and other Gulf states. It calls on the UN to impose an arms embargo on all groups credibly accused of war crimes.

Human rights organizations also accuse Syrian government forces of killing civilians during the country's 31-month long conflict, most recently in a poison gas attack near Damascus on August 21 in which hundreds died. President Bashar al-Assad denied the allegations saying it was rebel fighters who were responsible.

In a separate case of war crimes during the fighting in Syria, a group of Hezbollah fighters filmed themselves rejoicing and celebrating as they dragged injured Syrian civilians from a van and executed them.

Hezbollah has been fighting alongside Syrian army forces loyal to the regime of Bashar al-Assad, and have provided key support in a number of strategically important operations against rebel forces.


Bezos' rise to No. 1 followed a surge in Amazon.com shares Thursday ahead of the online retailer's earnings report due out later in the day. The company's shares have been on a tear over the past year, passing the $1,000 mark and hitting $1,082 around noon on Thursday, propelling Bezos, 53, to $90.6 billion compared with Gates's $90.1 billion. Gates, 61, who built his fortune through Microsoft, has long been among the world's richest and had held the top spot since May 2013.

By midday, however, Amazon shares gave up much of the gain, and Gates reclaimed the top spot on Forbes magazine's real-time measure of the fortunes of the world's wealthiest people.

Amazon shares were down about 3 percent in after-hours trading Thursday after the retail giant reported that second-quarter profits fell short of expectations. The company posted $197 million in profit, or about 40 cents per share. That is down from $857 million a year ago, or $1.78 per share in profit. Analysts were expecting $.1.42 a share.

Revenue continues to soar, coming in at $38 billion. That was better than Wall Street's estimates of $37.2 billion, and far outstrips $30.4 billion in second quarter revenue a year ago.

Amazon's share price has gained about 40 percent, year to date.

"We can chalk the miss up to more fulfillment center and technology spending," said R.J. Hottovy, consumer equity strategist at Morningstar. "The technology is where a lot of spending is going, such as Amazon Web Services and Echo and other new products."

Amazon's market cap, which is the total value of all its shares, also broke the $500 billion mark recently, joining other exclusive members of the $500-billion-plus club such as Alphabet, Microsoft and Apple.

Often referred to as the "Everything Store," it has built on its online retail empire and pushed more heavily into groceries and apparel in recent quarters. Amazon Web Services, its cloud-computing unit with large government contracts, also accounts for a sizable portion of its profits.

A cornerstone of its success is its Prime membership program, in which shoppers pay $99 a year for unlimited two-day shipping on many purchase. Amazon does not disclose its number of Prime shoppers, but analysts estimate it is about 50 million. In February, Bezos said that "tens of millions of new paid members" had joined Prime in the past year.

Amazon's surprise announcement in June that it would buy Whole Foods, the purveyor of organics and healthy fare, for $13.7 billion is already rattling the grocery sector, with competitors' share prices dropping on the news.Ads by ZINC

Amazon's move to buy Whole Foods has raised the specter of antitrust issues. The United Food and Commercial Workers International Union has filed a complaint with the Federal Trade Commission arguing that the deal would trigger store closings, job losses and eventually wipe out competition and customer choice.

Michael A. Carrier, professor at Rutgers Law School specializing in antitrust, said Amazon "should be between worried and complacent" when it comes to anti-trust action.

"Typically, the antitrust authorities do not worry about mergers when the companies are not direct competitors," he said, referring to Amazon and Whole Foods.

"The complicating factor, however, is that Amazon is a large company that has increasing tentacles into many markets," Carrier said. "There's a sense that they are having more and more control over our lives. The reason their level of concern should be above complacency is that Washington has noticed that Amazon is getting big. Politicians from the president on down have observed Amazon is large and maybe this merger deserves a closer look."

Hottovy said the company's proposed acquisition of Whole Foods would not make it even one of the top five brick-and-mortar grocers in the United States. Beyond antitrust, Hottovy said, he is more concerned about a tax that might be levied against the internet retail giant.

"My biggest worry is more stringent taxes," he said. He notes that the company relies heavily on the U.S. Postal Service.

The vast majority of Bezos' wealth is composed of his Amazon.com shares. He owns just shy of 17 percent of the company. He also owns space rocket company Blue Origin.

"Mae West said, 'Too much of a good thing can be wonderful,' " said Michael Farr, who runs a Washington investment firm. "We presume Mr. Bezos agrees. The power and value of technology can't be overestimated. We believe Mr. Bezos will continue to set records."


There are a variety of hydrocarbon conversion processes, and these processes utilize different catalysts.
Alkylation is typically used to combine light olefins, for example mixtures of alkenes such as propylene and butylene, with isobutane to produce a relatively high-octane branched-chain paraffinic hydrocarbon fuel, including isoheptane and isooctane. Similarly, an alkylation reaction can be performed using an aromatic compound such as benzene in place of the isobutane. When using benzene, the product resulting from the alkylation reaction is an alkylbenzene (e.g. ethylbenzene, cumene, dodecylbenzene, etc.).
The alkylation of paraffins with olefins for the production of alkylate for gasoline can use a variety of catalysts. The choice of catalyst depends on the end product a producer desires. Typical alkylation catalysts include concentrated sulfuric acid or hydrofluoric acid. However, sulfuric acid and hydrofluoric acid are hazardous and corrosive, and their use in industrial processes requires a variety of environmental controls.
Solid catalysts are also used for alkylation. However, solid catalysts are very water sensitive and are generally rapidly deactivated by oligomerization of feed olefins to coke, which may block the pores, leading to short active life and the need for expensive regeneration processes.
Acidic ionic liquids can be used as an alternative to the commonly used strong acid catalysts in alkylation processes. Ionic liquids are salts comprised of cations and anions which typically melt below about 100° C. Ionic liquids are described in U.S. Pat. Nos. 4,764,440, 5,104,840, and 5,824,832. The properties vary extensively for different ionic liquids, and the use of ionic liquids depends on the properties of a given ionic liquid. Depending on the organic cation of the ionic liquid and the anion, the ionic liquid can have very different properties.
Ionic liquids provide advantages over other catalysts, including being less corrosive than catalysts like HF, and being non-volatile.
Although ionic liquid catalysts can be very active, alkylation reactions need to be run at low temperatures, typically between −10° C. to 30° C., to maximize the alkylate quality. This requires cooling the reactor and reactor feeds, which adds substantial cost to an alkylation process utilizing ionic liquids in the form of additional equipment and energy. The most common ionic liquid catalysts for alkylation include imidazolium, or pyridinium-based cations coupled with the chloroaluminate anion (Al2Cl7−).
In addition, the use of ionic liquids for alkylation requires the use of HCl or an HCl precursor as a co-activator/co-catalyst. The HCl can be introduced into the process in several ways, such as the direct vapor phase injection of HCl to the ionic liquid using anhydrous HCl, or the introduction of a liquid organic chloride. Although the vapor phase method is effective, stringent governmental regulations covering the use of HCl gas may make it impractical. The liquid phase method is less effective because the organic chloride does not readily breakdown to HCl and paraffin in the absence of a catalyst.
Products from the alkylation reactor may contain excess HCl and organic chloride byproducts formed by the reaction of HCl with olefins in the feed, which must be removed from the products to meet specifications and avoid downstream corrosion.
A number of processes have been developed to handle the HCl and organic chlorides in alkylation processes. For example, U.S. Pat. No. 7,538,256 describes an alkylation process using an acidic ionic liquid catalyst and an organic halide promoter. The alkylate formed in the reaction is contacted with a hydrotreating catalyst and hydrogen to reduce the concentration of the organic halide.
U.S. Pat. No. 8,237,004 discusses a process in which the alkylation reactor effluent is sent to a stripper to separate it into a first fraction having an increased amount of hydrogen halide and a bottoms stream having less than 25 ppm hydrogen halide. The first fraction can be recycled to the reactor. The bottoms stream is then sent to a distillation column to be separated into one or more product streams such as an alkylate product stream and isoparaffin streams which can be recycled to the alkylation reactor. The equipment used for recovery is made from materials having poor corrosion resistance to HCl which is said to reduce equipment costs and upstream removal of HCl helps to protect this equipment.
Therefore, there is a need for an integrated system of subprocesses and equipment for more complete handling and control of organic chlorides and HCl in ionic liquid alkylation systems.


How to use Alcortin A topical

Use this medication on the skin only. Clean and thoroughly dry the area to be treated. Apply a thin layer of the medication to the affected area and gently rub in, usually 3 to 4 times daily or as directed by your doctor. Wash your hands after using unless you are using this medication to treat the hands.

Do not wrap, cover, or bandage the area unless directed to do so by your doctor. Do not use tight-fitting diapers or plastic pants on children being treated in the diaper area.

Do not apply the medication in the eyes, nose, mouth, or inside the vagina. If you do get the medication in those areas, flush with plenty of water.

Do not apply more often or use longer than prescribed. Doing so may increase the risk of side effects.

Use this medication regularly to get the most benefit from it. To help you remember, use it at the same times each day.

Continue to use this medication until the full prescribed amount is finished, even if symptoms disappear after a few days. Stopping the medication too early may result in a return of the infection.

Side Effects

Dry skin may occur. If this effect persists or worsens, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Precautions

Before using this medication, tell your doctor or pharmacist if you are allergic to iodoquinol or hydrocortisone; or to other 8-hydroxyquinolines (e.g., clioquinol); or to other corticosteroids (e.g., triamcinolone); or to iodine; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Interactions

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that weaken the immune system (e.g., cyclosporine), other corticosteroid products (e.g., prednisone).

This medication may interfere with certain laboratory tests (including certain thyroid function tests and certain test for phenylketonuria), possibly causing false test results. Make sure laboratory personnel and all your doctors know that you use this drug or have used this drug in the past month.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

Overdose

This medicine may be harmful if swallowed. If swallowing or overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

Notes

Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another skin condition unless told to do so by your doctor. A different medication may be necessary in that case.

Missed Dose

If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

Storage

Store at room temperature between 59-86 degrees F (15-30 degrees C) away from heat. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised December 2013. Copyright(c) 2013 First Databank, Inc.

Treatment by Condition Related to Alcortin A topical

Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, expect as may be authorized by the applicable terms of use.

CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

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Deep Pocket

A range of two flute cutters with extra length shanks for deep grooving and mortising. These long cutters need to be used with considerable care to avoid breakage. Take many small passes when slotting. When mortising, plunge down all over the area of the mortice, then clean out in stages down to the full depth.All cutters have reduced necks for clearance, except T2125½ and T2126½, which do not need it.N.B. It is very important that the shank of these long cutters is inserted fully into the collet. The cutters may extend through the base of the routing machine even in the fully up position.


1998 Paris–Tours

The 1998 Paris–Tours was the 92nd edition of the Paris–Tours cycle race and was held on 4 October 1998. The race started in Saint-Arnoult-en-Yvelines and finished in Tours. The race was won by Jacky Durand of the Casino team.

General classification

References

Category:1998 in French sport
1998


1. Field
Some example embodiments relate to a logic device and/or an operating method thereof.
2. Description of the Related Art
Recently, configurable or re-configurable logic devices, such as programmable logic devices (PLDs), which may be designed by users, have been widely used. Users may control connection between signal lines included in the logic device to configure or re-configure the logic device to thereby implement a desired function.


Painted directly on the wall or on fitted, removable panels, murals are distinguished from smaller canvases not only by their size but also in the way that they complement and relate to a room’s existing architecture. Depending on their scale and style, murals can subtly enhance already elegant features, or can transform the plainest room into a fantasy setting.

Murals can be painted from afar on canvas, then mounted on-site. I encourage clients to include personal objects, beloved pets, or family members in their murals.


More Thoughts on Sarah Palin

A few days have passed since Sarah Palin announced she’s leaving the governorship, more pundits have thrown in their two cents: Mark Steyn seems to think she’s really out of politics for good, while Victor Davis Hanson advances the 2016 theory. I’d like to expand upon my initial reaction with a closer look at each theory, as well as the pros and cons of what she’s done so far.

Theory: She’s leaving politics behind for a permanent return to private life

Steyn floats this theory on the basis that Palin entered public life in a very different, less cutthroat political culture than the one she found at the national level:

In states far from the national spotlight, politics still attracts normal people. You’re a mayor or a state senator or even the governor, but you lead a normal life. The local media are tough on you, but they know you, they live where you live, they’re tough on the real you, not on some caricature cooked up by a malign alliance of late-night comics who’d never heard of you a week earlier and media grandees supposedly on your own side who pronounce you a “cancer.”

Then suddenly you get the call from Washington. You know it’ll mean Secret Service, and speechwriters, and minders vetting your wardrobe. But nobody said it would mean a mainstream network comedy host doing statutory rape gags about your 14-year old daughter. You’ve got a special-needs kid and a son in Iraq and a daughter who’s given you your first grandchild in less than ideal circumstances. That would be enough for most of us. But the special-needs kid and the daughter and most everyone else you love are a national joke, and the PC enforcers are entirely cool with it.

It’s a possibility we certainly can’t dismiss—she’s got a family to care for, and heaven knows she’s been put through hell by the Left—but then how do you account for the fact that her explanation (which, sorry, had a lot of room for improvement) is chock-full of references to taking her fight in new directions and such? If you believe she’s permanently retiring, then you also have to believe she’s misleading a whole bunch of people whom she knows adore her, and will be crushed to see her disappear.

I’ll have to see more before I accept that. Sarah Palin’s planning something. But what?

Theory: She is not interested in the presidency, but believes she can better fight for the country in some other, as-yet unspecified way

Possible, but unless she’s got something very specific in mind, most of the usual non-office routes she could take (book deals, speaking tours, etc.) seem to me a waste of her star power if that’s the extent of her long-term plans. That sort of thing is good for building goodwill and keeping your image out there, but honestly, I don’t know if its audience would include more than a handful of new converts. In other words, they can be means to an end, but if Palin intends them as the end, I’m afraid her efforts will yield less than she hopes. A Senate run? Maybe, but I don’t think an early leave for one Alaska office is exactly the best foundation for seeking another one…

Whatever she has in mind, I think it’s vital that she reveals it sooner rather than later. If she wants to be a Republican or conservative leader, she can’t leave her followers in the dark as to her intentions. They can’t be left waiting in the wings for a cause that’s never going to materialize, and if they’ll need to look elsewhere for leadership, they need to know.

Theory: She plans to run for president

I still think this is the most likely. But when? Hanson says:

In the long run, she can lecture, earn a good income through speaking, develop a coterie of advisers and supporters, take care of her family, not have the constant political warring on all flanks, and invest time in reflecting and studying issues, visit the country, meet leaders, etc. She’s not looking at 2012; but in eight years by 2016 she will be far more savvy, still young, and far more experienced. It matters not all that the Left writes her off as daffy, since they were going to do that whatever she did; the key is whether she convinces conservatives in eight years of travel and reflection that she’s a charismatic Margaret Thatcher-type heavyweight.

I don’t think so. Getting a head start on the next race is one thing, but eight years is overkill—she can still do a lot towards building her credentials and her ally list in three and a half. Hanson’s comments do highlight the fact that she’ll have ample opportunities even if the upcoming election doesn’t pan out. But I think that the stars are aligning for 2012, if she wants it. The Right is clamoring for a true leader to stand up to Obama’s disastrous agenda, and none of the other would-be names in the field are distinguishing themselves (though, for reasons I may elaborate on in a later post, I think Mike Huckabee could be surprisingly formidable). With the numbers looking worse still for Obamanomics, a charismatic, passionate voice that can unite the opposition and articulate conservative alternatives is The One’s worst nightmare. Sarah Palin has a gift for communication that could give her just the edge she needs to take him down.

Yes, she’ll need to work on her policy expertise in areas in which she’s had less experience, chiefly foreign affairs and the judiciary. But that’s certainly doable, as is surrounding herself with high-caliber advisors. She’ll have to be careful who she listens to—just because some conservatives have constructive criticism to offer doesn’t mean they have sinister ulterior motives (the last thing we need is a repeat of the Fredhead fiasco). And again, she’s got to make her intentions clear soon. Forget the conventional wisdom—if you’re running for president, say so.

There’s a lot we don’t know, and it’s too early to crown her the new queen of the conservative movement. But if Sarah Palin’s willing to put in the effort, Barack Obama’s reign of error could come crashing down sooner than he thinks.

"We have counted the cost of this contest, and find nothing so dreadful as voluntary slavery. Honor, justice, and humanity forbid us tamely to surrender that freedom which we received from our gallant ancestors, and which our innocent posterity have a right to receive from us."
- Thomas Jefferson, 1775

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The views expressed on this weblog are strictly my own, and do not necessarily reflect those of the David Horowitz Freedom Center, NewsRealBlog, Front Page Magazine, or any other websites, blogs, campaigns, publications, or organizations where I have been employed and/or my work has been featured, nor do they necessarily reflect the views of any individuals employed by or otherwise affiliated with the aforementioned groups.


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SURVIV analysis of breast cancer isoforms. Blue isoforms are associated with longer survival times, and magenta isoforms with shorter survival times. Credit: Yi Xing

People with cancer are often told by their doctors approximately how long they have to live, and how well they will respond to treatments, but what if there were a way to improve the accuracy of doctors' predictions?

A new method developed by UCLA scientists could eventually lead to a way to do just that, using data about patients' genetic sequences to produce more reliable projections for survival time and how they might respond to possible treatments. The technique is an innovative way of using biomedical big data—which gleans patterns and trends from massive amounts of patient information—to achieve precision medicine—giving doctors the ability to better tailor their care for each individual patient.

The approach is likely to enable doctors to give more accurate predictions for people with many types of cancers. In this research, the UCLA scientists studied cancers of the breast, brain (glioblastoma multiforme, a highly malignant and aggressive form; and lower grade glioma, a less aggressive version), lung, ovary and kidney.

In addition, it may allow scientists to analyze people's genetic sequences and determine which are lethal and which are harmless.

The new method analyzes various gene isoforms—combinations of genetic sequences that can produce an enormous variety of RNAs and proteins from a single gene—using data from RNA molecules in cancer specimens. That process, called RNA sequencing, or RNA-seq, reveals the presence and quantity of RNA molecules in a biological sample. In the method developed at UCLA, scientists analyzed the ratios of slightly different genetic sequences within the isoforms, enabling them to detect important but subtle differences in the genetic sequences. In contrast, the conventional analysis aggregates all of the isoforms together, meaning that the technique misses important differences within the isoforms.

SURVIV (for "survival analysis of mRNA isoform variation") is the first statistical method for conducting survival analysis on isoforms using RNA-seq data, said senior author Yi Xing, a UCLA associate professor of microbiology, immunology and molecular genetics. The research is published today in the journal Nature Communications.

The researchers report having identified some 200 isoforms that are associated with survival time for people with breast cancer; some predict longer survival times, others are linked to shorter times. Armed with that knowledge, scientists might eventually be able to target the isoforms associated with shorter survival times in order to suppress them and fight disease, Xing said.

The researchers evaluated the performance of survival predictors using a metric called C-index and found that across the six different types of cancer they analyzed, their isoform-based predictions performed consistently better than the conventional gene-based predictions.

The result was surprising because it suggests, contrary to conventional wisdom, that isoform ratios provide a more robust molecular signature of cancer patients than overall gene abundance, said Xing, director of UCLA's bioinformatics doctoral program and a member of the UCLA Institute for Quantitative and Computational Biosciences.

"Our finding suggests that isoform ratios provide a more robust molecular signature of cancer patients in large-scale RNA-seq datasets," he said.

The researchers studied tissues from 2,684 people with cancer whose samples were part of the National Institutes of Health's Cancer Genome Atlas, and they spent more than two years developing the algorithm for SURVIV.

According to Xing, a human gene typically produces seven to 10 isoforms.

"In cancer, sometimes a single gene produces two isoforms, one of which promotes metastasis and one of which represses metastasis," he said, adding that understanding the differences between the two is extremely important in combatting cancer.

"We have just scratched the surface," Xing said. "We will apply the method to much larger data sets, and we expect to learn a lot more."

Explore further Scientists develop gene test to accurately classify brain tumors


Improvement of the Immunogenicity of Porcine Circovirus Type 2 DNA Vaccine by Recombinant ORF2 Gene and CpG Motifs.
Nowadays, adjuvant is still important for boosting immunity and improving resistance in animals. In order to boost the immunity of porcine circovirus type 2 (PCV2) DNA vaccine, CpG motifs were inserted. In this study, the dose-effect was studied, and the immunity of PCV2 DNA vaccines by recombinant open reading frame 2 (ORF2) gene and CpG motifs was evaluated. Three-week-old Changbai piglets were inoculated intramuscularly with 200 μg, 400 μg, and 800 μg DNA vaccines containing 14 and 18 CpG motifs, respectively. Average gain and rectum temperature were recorded everyday during the experiments. Blood was collected from the piglets after vaccination to detect the changes of specific antibodies, interleukin-2, and immune cells every week. Tissues were collected for histopathology and polymerase chain reaction. The results indicated that compared to those of the control piglets, all concentrations of two DNA vaccines could induce PCV2-specific antibodies. A cellular immunity test showed that PCV2-specific lymphocytes proliferated the number of TH, TC, and CD3+ positive T-cells raised in the blood of DNA vaccine immune groups. There was no distinct pathological damage and viremia occurring in pigs that were inoculated with DNA vaccines, but there was some minor pathological damage in the control group. The results demonstrated that CpG motifs as an adjuvant could boost the humoral and cellular immunity of pigs to PCV2, especially in terms of cellular immunity. Comparing two DNA vaccines that were constructed, the one containing 18 CpG motifs was more effective. This is the first report that CpG motifs as an adjuvant insert to the PCV2 DNA vaccine could boost immunity.


Copyright (c) Microsoft Corporation. All rights reserved.

Licensed under the Source EULA. See License.txt in the project root for license information.

Do not edit this file. It is machine generated.

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