miladalsh/processed_scinews_dataset · Datasets at Hugging Face

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Compared to females, males experience a range of health inequities including higher rates of diabetes and cardiovascular disease. Although sitting time is emerging as a distinct risk factor for chronic disease, research on the association of sitting time and chronic disease in middle-aged Australian males is limited. Methods A sample of 63,048 males aged 45-64 years was drawn from the baseline dataset of the 45 and Up Study – a longitudinal cohort study on healthy ageing with 267,153 participants from across New South Wales, Australia’s most populous state. Baseline data on self-reported chronic disease (heart disease, cancer, diabetes, high blood pressure, combined chronic diseases), sitting time, physical activity (Active Australia Survey), and a range of covariates were used for cross-sectional analyses. Crude (OR), partially and fully adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated using binary logistic regression. Results Compared to those sitting <4 hours/day, participants reporting 4 to <6, 6 to <8, and ≥8 hours were significantly more likely to report ever having any chronic disease (AOR 1.06, 95% CI 1.00 – 1.12, p = 0.050; AOR 1.10, 95% CI 1.03 – 1.16, p = 0.003; AOR 1.09, 95% CI 1.03 – 1.15, p = 0.002, respectively). Participants who reported 6 to <8 hours and ≥8 hours of sitting were also significantly more likely to report ever having diabetes than those reporting <4 hours/day (AOR 1.15, 95% CI 1.03 – 1.28, p = 0.016; AOR 1.21, 95% CI 1.09 – 1.33, p <0.001, respectively). Conclusions Our findings suggest that higher volumes of sitting time are significantly associated with diabetes and overall chronic disease, independent of physical activity and other potentially confounding factors. Prospective studies using valid and reliable measures into domain-specific sitting time in middle-aged males are required to understand and explain the direction of these relationships. Background Research into the area of male health is gaining momentum in countries across the world, and has been highlighted by the release of a range of male-specific health reports and policies [ 1 – 4 ]. Australian males experience higher rates of a range of chronic diseases, such as diabetes and cardiovascular disease (CVD), in comparison to their female counterparts [ 1 ]. Australian data from 2007 showed that cancer and other tumours were the leading cause of death in both males and females aged between 45 and 64 years, while CVD, including both coronary heart disease (CHD) and stroke, was the second highest cause of death in this age group [ 5 ]. It has been well established that participation in regular physical activity has the potential to reduce a person’s risk of developing various chronic diseases [ 6 , 7 ]. Among middle-aged and older males, specifically, physical activity has been found to be inversely associated with CHD risk [ 8 , 9 ], hypertension [ 8 ], cancer mortality [ 10 ], and CVD mortality [ 11 ]. Further, greater leisure time physical activity (LTPA), has been associated with reduced diabetes risk [ 12 ], while high lifetime occupational physical activity has been shown to be protective against colon and prostate cancer in adult males [ 13 ]. Researchers have established that physical (in)activity and sedentary behaviour are two distinct risk factors that can independently affect health. Sedentary behaviour is characterised by activities such as sitting or lying down, involving energy expenditure of 1.0-1.5 metabolic equivalents [ 14 ]. Independent of LTPA, higher levels of daily sitting time have been found to increase the risk of both CVD [ 15 ] and all-cause mortality in adults [ 15 , 16 ]. Specific (presumably) sedentary behaviours such as television viewing have also been associated with higher CVD mortality risk in males [ 11 ], increased likelihood of having the metabolic syndrome [ 17 ] and increased diabetes risk [ 12 ]. Time spent in sedentary behaviours has also been associated with clustered metabolic risk, independent of physical activity [ 18 ]. In addition to these findings that have demonstrated associations between sedentary time and health outcomes, other prospective studies have provided evidence of reverse causality, whereby specific health indicators such as body mass index (BMI) have been shown to predict sedentary time [ 19 , 20 ]. Current literature highlights the importance of participating in regular physical activity and limiting sedentary time for positive health outcomes. A number of studies have focused on specific domains of sedentary behaviour (e.g. television viewing), however, it has been demonstrated that television viewing time is not necessarily representative of overall sedentary time [ 21 , 22 ]. Furthermore, although several studies have examined the association between sedentary time and specific chronic diseases, few have examined overall time spent sitting on the association with a range of chronic diseases, particularly in middle-aged males. The aim of this study was to build upon an existing and growing body of literature on sitting time – and the association of this modifiable lifestyle behaviour – with a range of chronic diseases. This study utilised a large sample of middle-aged Australian males – a relatively understudied population group – and statistically controlled for a range of associated covariates, including age, BMI, and functional limitation. Methods The 45 and Up Study The 45 and Up Study has been described in detail elsewhere [ 23 ]. Briefly, the 45 and Up Study is a large-scale Australian cohort study of 267,153 individuals from across New South Wales (NSW), the most populous state in Australia. Data derived from the 45 and Up Study baseline questionnaire [ 24 ] provide insight into an extensive range of health conditions and underlying determinants of health. Participants were randomly sampled from the Medicare Australia (national health insurance) database between February 2006 and December 2008. All adults who were aged 45 years and over and who were currently residing in NSW at the time of recruitment were eligible for inclusion in the Study. Participants were included in the Study if they completed a mailed baseline questionnaire and provided their signed consent for", "role": "user" }, { "content": "The more you sit, the higher your risk of chronic diseases. Kansas State University researcher Richard Rosenkranz, assistant professor of human nutrition, examined the associations of sitting time and chronic diseases in middle-aged Australian males in a study that is published in the International Journal of Behavioral Nutrition and Physical Activity. Collaborators include University of Western Sydney researchers Emma George and Gregory Kolt. The study's sample included 63,048 males ages 45-65 from the Australian state of New South Wales. Study participants reported the presence or absence of various chronic diseases, along with their daily sitting time: categorized as less than four hours, four to six hours, six to eight hours, or more than eight hours. Compared with those who reported sitting four hours or less per day, those who sat for more than four hours per day were significantly more likely to report having a chronic disease such as cancer, diabetes, heart disease and high blood pressure. The reporting of chronic diseases rose as participants indicated they sat more. Those sitting for at least six hours were significantly more likely to report having diabetes. \"We saw a steady stair-step increase in risk of chronic diseases the more participants sat,\" Rosenkranz said. \"The group sitting more than eight hours clearly had the highest risk.\" The study is relevant to office workers sitting at desks and those sitting for long periods of time such as truck drivers, he said. \"We know that with very high confidence that more physically active people do better with regard to chronic disease compared with less physically active people, but we should also be looking at reducing sitting,\" Rosenkranz said. \"A lot of office jobs that require long periods of sitting may be hazardous to your health because of inactivity and the low levels of energy expenditure.\" Researchers discovered consistent findings in those who had a similar physical activity level, age, income, education, weight and height. Participants who sat more reported more chronic diseases—even if they had a similar body mass index compared with those who sat less. In general, people should get more physical activity and sit less, Rosenkranz said. \"It's not just that people aren't getting enough physical activity, but it's that they're also sitting too much,\" he said. \"And on top of that, the more you sit, the less time you have for physical activity.\" The study focused on males, because they have higher rates of diabetes and heart disease, but it is probably applicable in adults across gender, race and ethnicity, Rosenkranz said. Little is known about children and sitting with regard to chronic disease. The research is part of the 45 and Up Study, the largest long-term study of aging in Australia, involving more than 267,000 people. Researchers said that although most of the current evidence is suggestive of a causal connection, they cannot be certain in this study whether volumes of sitting time led to the development of chronic diseases or whether the chronic diseases influenced sitting time. \"It's a classic case of, 'Which came first: the chicken or the egg?'\" Rosenkranz said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Compared to females, males experience a range of health inequities including higher rates of diabetes and cardiovascular disease. Although sitting time is emerging as a distinct risk factor for chronic disease, research on the association of sitting time and chronic disease in middle-aged Australian males is limited. Methods A sample of 63,048 males aged 45-64 years was drawn from the baseline dataset of the 45 and Up Study – a longitudinal cohort study on healthy ageing with 267,153 participants from across New South Wales, Australia’s most populous state. Baseline data on self-reported chronic disease (heart disease, cancer, diabetes, high blood pressure, combined chronic diseases), sitting time, physical activity (Active Australia Survey), and a range of covariates were used for cross-sectional analyses. Crude (OR), partially and fully adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated using binary logistic regression. Results Compared to those sitting <4 hours/day, participants reporting 4 to <6, 6 to <8, and ≥8 hours were significantly more likely to report ever having any chronic disease (AOR 1.06, 95% CI 1.00 – 1.12, p = 0.050; AOR 1.10, 95% CI 1.03 – 1.16, p = 0.003; AOR 1.09, 95% CI 1.03 – 1.15, p = 0.002, respectively). Participants who reported 6 to <8 hours and ≥8 hours of sitting were also significantly more likely to report ever having diabetes than those reporting <4 hours/day (AOR 1.15, 95% CI 1.03 – 1.28, p = 0.016; AOR 1.21, 95% CI 1.09 – 1.33, p <0.001, respectively). Conclusions Our findings suggest that higher volumes of sitting time are significantly associated with diabetes and overall chronic disease, independent of physical activity and other potentially confounding factors. Prospective studies using valid and reliable measures into domain-specific sitting time in middle-aged males are required to understand and explain the direction of these relationships. Background Research into the area of male health is gaining momentum in countries across the world, and has been highlighted by the release of a range of male-specific health reports and policies [ 1 – 4 ]. Australian males experience higher rates of a range of chronic diseases, such as diabetes and cardiovascular disease (CVD), in comparison to their female counterparts [ 1 ]. Australian data from 2007 showed that cancer and other tumours were the leading cause of death in both males and females aged between 45 and 64 years, while CVD, including both coronary heart disease (CHD) and stroke, was the second highest cause of death in this age group [ 5 ]. It has been well established that participation in regular physical activity has the potential to reduce a person’s risk of developing various chronic diseases [ 6 , 7 ]. Among middle-aged and older males, specifically, physical activity has been found to be inversely associated with CHD risk [ 8 , 9 ], hypertension [ 8 ], cancer mortality [ 10 ], and CVD mortality [ 11 ]. Further, greater leisure time physical activity (LTPA), has been associated with reduced diabetes risk [ 12 ], while high lifetime occupational physical activity has been shown to be protective against colon and prostate cancer in adult males [ 13 ]. Researchers have established that physical (in)activity and sedentary behaviour are two distinct risk factors that can independently affect health. Sedentary behaviour is characterised by activities such as sitting or lying down, involving energy expenditure of 1.0-1.5 metabolic equivalents [ 14 ]. Independent of LTPA, higher levels of daily sitting time have been found to increase the risk of both CVD [ 15 ] and all-cause mortality in adults [ 15 , 16 ]. Specific (presumably) sedentary behaviours such as television viewing have also been associated with higher CVD mortality risk in males [ 11 ], increased likelihood of having the metabolic syndrome [ 17 ] and increased diabetes risk [ 12 ]. Time spent in sedentary behaviours has also been associated with clustered metabolic risk, independent of physical activity [ 18 ]. In addition to these findings that have demonstrated associations between sedentary time and health outcomes, other prospective studies have provided evidence of reverse causality, whereby specific health indicators such as body mass index (BMI) have been shown to predict sedentary time [ 19 , 20 ]. Current literature highlights the importance of participating in regular physical activity and limiting sedentary time for positive health outcomes. A number of studies have focused on specific domains of sedentary behaviour (e.g. television viewing), however, it has been demonstrated that television viewing time is not necessarily representative of overall sedentary time [ 21 , 22 ]. Furthermore, although several studies have examined the association between sedentary time and specific chronic diseases, few have examined overall time spent sitting on the association with a range of chronic diseases, particularly in middle-aged males. The aim of this study was to build upon an existing and growing body of literature on sitting time – and the association of this modifiable lifestyle behaviour – with a range of chronic diseases. This study utilised a large sample of middle-aged Australian males – a relatively understudied population group – and statistically controlled for a range of associated covariates, including age, BMI, and functional limitation. Methods The 45 and Up Study The 45 and Up Study has been described in detail elsewhere [ 23 ]. Briefly, the 45 and Up Study is a large-scale Australian cohort study of 267,153 individuals from across New South Wales (NSW), the most populous state in Australia. Data derived from the 45 and Up Study baseline questionnaire [ 24 ] provide insight into an extensive range of health conditions and underlying determinants of health. Participants were randomly sampled from the Medicare Australia (national health insurance) database between February 2006 and December 2008. All adults who were aged 45 years and over and who were currently residing in NSW at the time of recruitment were eligible for inclusion in the Study. Participants were included in the Study if they completed a mailed baseline questionnaire and provided their signed consent for<|im_end|> <|im_start|>assistant The more you sit, the higher your risk of chronic diseases. Kansas State University researcher Richard Rosenkranz, assistant professor of human nutrition, examined the associations of sitting time and chronic diseases in middle-aged Australian males in a study that is published in the International Journal of Behavioral Nutrition and Physical Activity. Collaborators include University of Western Sydney researchers Emma George and Gregory Kolt. The study's sample included 63,048 males ages 45-65 from the Australian state of New South Wales. Study participants reported the presence or absence of various chronic diseases, along with their daily sitting time: categorized as less than four hours, four to six hours, six to eight hours, or more than eight hours. Compared with those who reported sitting four hours or less per day, those who sat for more than four hours per day were significantly more likely to report having a chronic disease such as cancer, diabetes, heart disease and high blood pressure. The reporting of chronic diseases rose as participants indicated they sat more. Those sitting for at least six hours were significantly more likely to report having diabetes. "We saw a steady stair-step increase in risk of chronic diseases the more participants sat," Rosenkranz said. "The group sitting more than eight hours clearly had the highest risk." The study is relevant to office workers sitting at desks and those sitting for long periods of time such as truck drivers, he said. "We know that with very high confidence that more physically active people do better with regard to chronic disease compared with less physically active people, but we should also be looking at reducing sitting," Rosenkranz said. "A lot of office jobs that require long periods of sitting may be hazardous to your health because of inactivity and the low levels of energy expenditure." Researchers discovered consistent findings in those who had a similar physical activity level, age, income, education, weight and height. Participants who sat more reported more chronic diseases—even if they had a similar body mass index compared with those who sat less. In general, people should get more physical activity and sit less, Rosenkranz said. "It's not just that people aren't getting enough physical activity, but it's that they're also sitting too much," he said. "And on top of that, the more you sit, the less time you have for physical activity." The study focused on males, because they have higher rates of diabetes and heart disease, but it is probably applicable in adults across gender, race and ethnicity, Rosenkranz said. Little is known about children and sitting with regard to chronic disease. The research is part of the 45 and Up Study, the largest long-term study of aging in Australia, involving more than 267,000 people. Researchers said that although most of the current evidence is suggestive of a causal connection, they cannot be certain in this study whether volumes of sitting time led to the development of chronic diseases or whether the chronic diseases influenced sitting time. "It's a classic case of, 'Which came first: the chicken or the egg?'" Rosenkranz said. <|im_end|>

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1,978

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract According to the theory of embodied cognition, semantic processing is closely coupled with body movements. For example, constraining hand movements inhibits memory for objects that can be manipulated with the hands. However, it has not been confirmed whether body constraint reduces brain activity related to semantics. We measured the effect of hand constraint on semantic processing in the parietal lobe using functional near-infrared spectroscopy. A pair of words representing the names of hand-manipulable (e.g., cup or pencil) or nonmanipulable (e.g., windmill or fountain) objects were presented, and participants were asked to identify which object was larger. The reaction time (RT) in the judgment task and the activation of the left intraparietal sulcus (LIPS) and left inferior parietal lobule (LIPL), including the supramarginal gyrus and angular gyrus, were analyzed. We found that constraint of hand movement suppressed brain activity in the LIPS toward hand-manipulable objects and affected RT in the size judgment task. These results indicate that body constraint reduces the activity of brain regions involved in semantics. Hand constraint might inhibit motor simulation, which, in turn, would inhibit body-related semantic processing. Introduction Our knowledge of an object, such as a pencil, depends on what we implicitly know about body movements—in this case, how to grip the pencil and how to move our hands and fingers in a coordinated manner to write. At least part of our knowledge is embedded in the interactions between the body and objects and between the body and the environment. Based on this framework of embodied cognition, many studies have explored the relationship between word meanings and body motions 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . It is becoming clear, through behavioral and neuroscientific studies, that word semantics are closely related to motor simulations. For example, several researchers measured reaction time (RT) after participants learned to map specific gestures to objects or words denoting the objects 9 , 10 . Faster responses were found when the mapped gestures were congruent with the gestures typically associated with the objects. This suggests that the actions compatible with the objects are automatically activated not only by the visual information of the objects but also by the semantic information of the words. Moreover, action verbs (e.g., “grasp”) followed by an object name elicit the formation of a “motor prototype” of the object 11 , 12 . These findings seem to imply that semantic processing related to object manipulation is embodied. However, others have poisted that these results can be explained by the view that conceptual and motor systems do not share processing resources 13 . Chatterjee 14 pointed out that abstract semantic processing requires disembodiment. An alternative perspective is that these results are not due to embodiment but rather encoding of the object's size 15 . To ascertain whether conceptual and motor systems share at least some processing resources, studies have employed physical constraints that prevent body movements. For example, hand immobilization was found to decrease the proactivity of gaze behavior when observing others grasping an object. Specifically, gaze shifts became slower when participants’ hands were tied behind their back 16 . Dutriaux and Gyselinck 17 confirmed that conceptual knowledge of words is closely related to somatosensory and motor systems. The authors asked participants to learn lists of words for manipulable or nonmanipulable objects; then, the authors compared data from a condition in which participants had their hands behind their back while memorizing words with data from a condition in which their hands were unrestrained on the desk. In a later free recall task, performance on words denoting objects that can be manipulated with one’s hands was reduced by restraining the hands. They speculated that information about the impossibility of hand movement might have suppressed activity in brain areas involved in motor simulation, as a possible reason why hand restraint suppressed memory for objects that could be manipulated with one’s hand. However, under their experimental conditions, hand position and hand visibility were not controlled, so Onishi & Makioka 18 examined the effect of posture and visibility in more detail. The authors found that only suppression of hand movements degraded the memory of words denoting manipulable objects, not the visibility or position of the hand (whether the hand was placed on a desk or folded behind the back). It has been shown that the activity of corticospinal tracts while participants were imagining a specific movement with their hand was influenced by their hand posture 19 . Corticospinal excitability was enhanced when the actual hand posture was congruent with the imagined movement. The relationship between hand immobilization and brain activity has been investigated using a variety of methodologies: motor evoked potential 20 , 21 , 22 , resting motor threshold 23 , local blood flow and event-related desynchronization 24 . However, it remains unclear whether constraining the hands during semantic tasks affects the activity of brain regions involved in semantic processing. In addition, although it has been found that hand restraint reduces memory for words denoting hand-manipulable objects 17 , 18 , it is unclear at which processing stage this effect occurs. By examining the effects of hand constraints on the speed of semantic processing and brain activity, we expect to obtain a clearer understanding of semantic processing for objects that can be manipulated by hand. Previous neurological studies have repeatedly indicated that the premotor and parietal lobes involve object operations and object knowledge 25 , 26 , 27 . Patients with damage to the parietal lobe or premotor cortex show impairment in their knowledge of manipulable objects and the movements needed to manipulate those objects 28 . It is known that damage to the left parietal lobe can result in ideomotor apraxia, which is the inability to perform an action according to verbal direction, and poor use of certain tools 29 , 30 . Chao and Martin 27 found that the ventral area of the premotor cortex (BA 6) and left inferior parietal lobule (LIPL) are more strongly activated when individuals", "role": "user" }, { "content": "How do we understand words? Scientists don't fully understand what happens when a word pops into your brain. A research group led by Professor Shogo Makioka at the Graduate School of Sustainable System Sciences, Osaka Metropolitan University, wanted to test the idea of embodied cognition. Embodied cognition proposes that people understand the words for objects through how they interact with them, so the researchers devised a test to observe semantic processing of words when the ways that the participants could interact with objects were limited. Words are expressed in relation to other words; a \"cup,\" for example, can be a \"container, made of glass, used for drinking.\" However, you can only use a cup if you understand that to drink from a cup of water, you hold it in your hand and bring it to your mouth, or that if you drop the cup, it will smash on the floor. Without understanding this, it would be difficult to create a robot that can handle a real cup. In artificial intelligence research, these issues are known as symbol grounding problems, which map symbols onto the real world. How do humans achieve symbol grounding? Cognitive psychology and cognitive science propose the concept of embodied cognition, where objects are given meaning through interactions with the body and the environment. To test embodied cognition, the researchers conducted experiments to see how the participants' brains responded to words that describe objects that can be manipulated by hand, when the participants' hands could move freely compared to when they were restrained. \"It was very difficult to establish a method for measuring and analyzing brain activity. The first author, Ms. Sae Onishi, worked persistently to come up with a task, in a way that we were able to measure brain activity with sufficient accuracy,\" Professor Makioka explained. In the experiment, two words such as \"cup\" and \"broom\" were presented to participants on a screen. They were asked to compare the relative sizes of the objects those words represented and to verbally answer which object was larger—in this case, \"broom.\" Comparisons were made between the words, describing two types of objects, hand-manipulable objects, such as \"cup\" or \"broom\" and nonmanipulable objects, such as \"building\" or \"lamppost,\" to observe how each type was processed. During the tests, the participants placed their hands on a desk, where they were either free or restrained by a transparent acrylic plate. When the two words were presented on the screen, to answer which one represented a larger object, the participants needed to think of both objects and compare their sizes, forcing them to process each word's meaning. Brain activity was measured with functional near-infrared spectroscopy (fNIRS), which has the advantage of taking measurements without imposing further physical constraints. The measurements focused on the interparietal sulcus and the inferior parietal lobule (supramarginal gyrus and angular gyrus) of the left brain, which are responsible for semantic processing related to tools. The speed of the verbal response was measured to determine how quickly the participant answered after the words appeared on the screen. The results showed that the activity of the left brain in response to hand-manipulable objects was significantly reduced by hand restraints. Verbal responses were also affected by hand constraints. These results indicate that constraining hand movement affects the processing of object-meaning, which supports the idea of embodied cognition. These results suggest that the idea of embodied cognition could also be effective for artificial intelligence to learn the meaning of objects. The paper was published in Scientific Reports. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract According to the theory of embodied cognition, semantic processing is closely coupled with body movements. For example, constraining hand movements inhibits memory for objects that can be manipulated with the hands. However, it has not been confirmed whether body constraint reduces brain activity related to semantics. We measured the effect of hand constraint on semantic processing in the parietal lobe using functional near-infrared spectroscopy. A pair of words representing the names of hand-manipulable (e.g., cup or pencil) or nonmanipulable (e.g., windmill or fountain) objects were presented, and participants were asked to identify which object was larger. The reaction time (RT) in the judgment task and the activation of the left intraparietal sulcus (LIPS) and left inferior parietal lobule (LIPL), including the supramarginal gyrus and angular gyrus, were analyzed. We found that constraint of hand movement suppressed brain activity in the LIPS toward hand-manipulable objects and affected RT in the size judgment task. These results indicate that body constraint reduces the activity of brain regions involved in semantics. Hand constraint might inhibit motor simulation, which, in turn, would inhibit body-related semantic processing. Introduction Our knowledge of an object, such as a pencil, depends on what we implicitly know about body movements—in this case, how to grip the pencil and how to move our hands and fingers in a coordinated manner to write. At least part of our knowledge is embedded in the interactions between the body and objects and between the body and the environment. Based on this framework of embodied cognition, many studies have explored the relationship between word meanings and body motions 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . It is becoming clear, through behavioral and neuroscientific studies, that word semantics are closely related to motor simulations. For example, several researchers measured reaction time (RT) after participants learned to map specific gestures to objects or words denoting the objects 9 , 10 . Faster responses were found when the mapped gestures were congruent with the gestures typically associated with the objects. This suggests that the actions compatible with the objects are automatically activated not only by the visual information of the objects but also by the semantic information of the words. Moreover, action verbs (e.g., “grasp”) followed by an object name elicit the formation of a “motor prototype” of the object 11 , 12 . These findings seem to imply that semantic processing related to object manipulation is embodied. However, others have poisted that these results can be explained by the view that conceptual and motor systems do not share processing resources 13 . Chatterjee 14 pointed out that abstract semantic processing requires disembodiment. An alternative perspective is that these results are not due to embodiment but rather encoding of the object's size 15 . To ascertain whether conceptual and motor systems share at least some processing resources, studies have employed physical constraints that prevent body movements. For example, hand immobilization was found to decrease the proactivity of gaze behavior when observing others grasping an object. Specifically, gaze shifts became slower when participants’ hands were tied behind their back 16 . Dutriaux and Gyselinck 17 confirmed that conceptual knowledge of words is closely related to somatosensory and motor systems. The authors asked participants to learn lists of words for manipulable or nonmanipulable objects; then, the authors compared data from a condition in which participants had their hands behind their back while memorizing words with data from a condition in which their hands were unrestrained on the desk. In a later free recall task, performance on words denoting objects that can be manipulated with one’s hands was reduced by restraining the hands. They speculated that information about the impossibility of hand movement might have suppressed activity in brain areas involved in motor simulation, as a possible reason why hand restraint suppressed memory for objects that could be manipulated with one’s hand. However, under their experimental conditions, hand position and hand visibility were not controlled, so Onishi & Makioka 18 examined the effect of posture and visibility in more detail. The authors found that only suppression of hand movements degraded the memory of words denoting manipulable objects, not the visibility or position of the hand (whether the hand was placed on a desk or folded behind the back). It has been shown that the activity of corticospinal tracts while participants were imagining a specific movement with their hand was influenced by their hand posture 19 . Corticospinal excitability was enhanced when the actual hand posture was congruent with the imagined movement. The relationship between hand immobilization and brain activity has been investigated using a variety of methodologies: motor evoked potential 20 , 21 , 22 , resting motor threshold 23 , local blood flow and event-related desynchronization 24 . However, it remains unclear whether constraining the hands during semantic tasks affects the activity of brain regions involved in semantic processing. In addition, although it has been found that hand restraint reduces memory for words denoting hand-manipulable objects 17 , 18 , it is unclear at which processing stage this effect occurs. By examining the effects of hand constraints on the speed of semantic processing and brain activity, we expect to obtain a clearer understanding of semantic processing for objects that can be manipulated by hand. Previous neurological studies have repeatedly indicated that the premotor and parietal lobes involve object operations and object knowledge 25 , 26 , 27 . Patients with damage to the parietal lobe or premotor cortex show impairment in their knowledge of manipulable objects and the movements needed to manipulate those objects 28 . It is known that damage to the left parietal lobe can result in ideomotor apraxia, which is the inability to perform an action according to verbal direction, and poor use of certain tools 29 , 30 . Chao and Martin 27 found that the ventral area of the premotor cortex (BA 6) and left inferior parietal lobule (LIPL) are more strongly activated when individuals<|im_end|> <|im_start|>assistant How do we understand words? Scientists don't fully understand what happens when a word pops into your brain. A research group led by Professor Shogo Makioka at the Graduate School of Sustainable System Sciences, Osaka Metropolitan University, wanted to test the idea of embodied cognition. Embodied cognition proposes that people understand the words for objects through how they interact with them, so the researchers devised a test to observe semantic processing of words when the ways that the participants could interact with objects were limited. Words are expressed in relation to other words; a "cup," for example, can be a "container, made of glass, used for drinking." However, you can only use a cup if you understand that to drink from a cup of water, you hold it in your hand and bring it to your mouth, or that if you drop the cup, it will smash on the floor. Without understanding this, it would be difficult to create a robot that can handle a real cup. In artificial intelligence research, these issues are known as symbol grounding problems, which map symbols onto the real world. How do humans achieve symbol grounding? Cognitive psychology and cognitive science propose the concept of embodied cognition, where objects are given meaning through interactions with the body and the environment. To test embodied cognition, the researchers conducted experiments to see how the participants' brains responded to words that describe objects that can be manipulated by hand, when the participants' hands could move freely compared to when they were restrained. "It was very difficult to establish a method for measuring and analyzing brain activity. The first author, Ms. Sae Onishi, worked persistently to come up with a task, in a way that we were able to measure brain activity with sufficient accuracy," Professor Makioka explained. In the experiment, two words such as "cup" and "broom" were presented to participants on a screen. They were asked to compare the relative sizes of the objects those words represented and to verbally answer which object was larger—in this case, "broom." Comparisons were made between the words, describing two types of objects, hand-manipulable objects, such as "cup" or "broom" and nonmanipulable objects, such as "building" or "lamppost," to observe how each type was processed. During the tests, the participants placed their hands on a desk, where they were either free or restrained by a transparent acrylic plate. When the two words were presented on the screen, to answer which one represented a larger object, the participants needed to think of both objects and compare their sizes, forcing them to process each word's meaning. Brain activity was measured with functional near-infrared spectroscopy (fNIRS), which has the advantage of taking measurements without imposing further physical constraints. The measurements focused on the interparietal sulcus and the inferior parietal lobule (supramarginal gyrus and angular gyrus) of the left brain, which are responsible for semantic processing related to tools. The speed of the verbal response was measured to determine how quickly the participant answered after the words appeared on the screen. The results showed that the activity of the left brain in response to hand-manipulable objects was significantly reduced by hand restraints. Verbal responses were also affected by hand constraints. These results indicate that constraining hand movement affects the processing of object-meaning, which supports the idea of embodied cognition. These results suggest that the idea of embodied cognition could also be effective for artificial intelligence to learn the meaning of objects. The paper was published in Scientific Reports. <|im_end|>

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6677, 315, 4339, 374, 15499, 5552, 311, 1794, 14357, 729, 683, 323, 9048, 6067, 13, 578, 12283, 4691, 13324, 311, 4048, 11725, 315, 4339, 369, 14951, 360, 481, 477, 2536, 1543, 575, 360, 481, 6302, 26, 1243, 11, 279, 12283, 7863, 828, 505, 264, 3044, 304, 902, 13324, 1047, 872, 6206, 4920, 872, 1203, 1418, 16420, 4954, 4339, 449, 828, 505, 264, 3044, 304, 902, 872, 6206, 1051, 38223, 58827, 389, 279, 18496, 13, 763, 264, 3010, 1949, 19635, 3465, 11, 5178, 389, 4339, 3453, 11780, 6302, 430, 649, 387, 55315, 449, 832, 753, 6206, 574, 11293, 555, 84393, 279, 6206, 13, 2435, 74877, 430, 2038, 922, 279, 91182, 3225, 315, 1450, 7351, 2643, 617, 56089, 5820, 304, 8271, 5789, 6532, 304, 9048, 19576, 11, 439, 264, 3284, 2944, 3249, 1450, 59456, 56089, 5044, 369, 6302, 430, 1436, 387, 55315, 449, 832, 753, 1450, 13, 4452, 11, 1234, 872, 22772, 4787, 11, 1450, 2361, 323, 1450, 24035, 1051, 539, 14400, 11, 779, 1952, 39476, 612, 386, 14966, 31866, 220, 972, 25078, 279, 2515, 315, 48378, 323, 24035, 304, 810, 7872, 13, 578, 12283, 1766, 430, 1193, 46735, 315, 1450, 19567, 91978, 279, 5044, 315, 4339, 3453, 11780, 14951, 360, 481, 6302, 11, 539, 279, 24035, 477, 2361, 315, 279, 1450, 320, 49864, 279, 1450, 574, 9277, 389, 264, 18496, 477, 48135, 4920, 279, 1203, 570, 1102, 706, 1027, 6982, 430, 279, 5820, 315, 23100, 292, 4890, 992, 490, 11613, 1418, 13324, 1051, 77724, 264, 3230, 7351, 449, 872, 1450, 574, 28160, 555, 872, 1450, 48378, 220, 777, 662, 36775, 292, 4890, 992, 25435, 2968, 574, 24872, 994, 279, 5150, 1450, 48378, 574, 31269, 11942, 449, 279, 35706, 7351, 13, 578, 5133, 1990, 1450, 77441, 2065, 323, 8271, 5820, 706, 1027, 27313, 1701, 264, 8205, 315, 81898, 25, 9048, 3721, 11059, 4754, 220, 508, 1174, 220, 1691, 1174, 220, 1313, 1174, 41219, 9048, 12447, 220, 1419, 1174, 2254, 6680, 6530, 323, 1567, 14228, 951, 69029, 220, 1187, 662, 4452, 11, 433, 8625, 25420, 3508, 19477, 2101, 279, 6206, 2391, 42833, 9256, 22223, 279, 5820, 315, 8271, 13918, 6532, 304, 42833, 8863, 13, 763, 5369, 11, 8051, 433, 706, 1027, 1766, 430, 1450, 59456, 26338, 5044, 369, 4339, 3453, 11780, 1450, 21110, 575, 360, 481, 6302, 220, 1114, 1174, 220, 972, 1174, 433, 374, 25420, 520, 902, 8863, 6566, 420, 2515, 13980, 13, 3296, 38936, 279, 6372, 315, 1450, 17413, 389, 279, 4732, 315, 42833, 8863, 323, 8271, 5820, 11, 584, 1755, 311, 6994, 264, 49479, 8830, 315, 42833, 8863, 369, 6302, 430, 649, 387, 55315, 555, 1450, 13, 30013, 64908, 7978, 617, 19352, 16717, 430, 279, 6954, 10088, 323, 1370, 3978, 278, 41253, 288, 21736, 1665, 7677, 323, 1665, 6677, 220, 914, 1174, 220, 1627, 1174, 220, 1544, 662, 44430, 449, 5674, 311, 279, 1370, 3978, 278, 326, 15784, 477, 6954, 10088, 49370, 1501, 53317, 304, 872, 6677, 315, 14951, 360, 481, 6302, 323, 279, 19567, 4460, 311, 37735, 1884, 6302, 220, 1591, 662, 1102, 374, 3967, 430, 5674, 311, 279, 2163, 1370, 3978, 278, 326, 15784, 649, 1121, 304, 2679, 316, 10088, 21726, 710, 689, 11, 902, 374, 279, 38550, 311, 2804, 459, 1957, 4184, 311, 36870, 5216, 11, 323, 8009, 1005, 315, 3738, 7526, 220, 1682, 1174, 220, 966, 662, 921, 3524, 323, 11826, 220, 1544, 1766, 430, 279, 10594, 3545, 3158, 315, 279, 6954, 10088, 49370, 320, 7209, 220, 21, 8, 323, 2163, 38279, 1370, 3978, 278, 41253, 1130, 320, 19046, 2989, 8, 527, 810, 16917, 22756, 994, 7931, 128257, 198, 128256, 78191, 198, 4438, 656, 584, 3619, 4339, 30, 57116, 1541, 956, 7373, 3619, 1148, 8741, 994, 264, 3492, 48700, 1139, 701, 8271, 13, 362, 3495, 1912, 6197, 555, 17054, 1443, 24404, 386, 14966, 31866, 520, 279, 44825, 6150, 315, 61593, 744, 23199, 11, 88085, 45878, 3907, 11, 4934, 311, 1296, 279, 4623, 315, 78643, 75310, 13, 30227, 72206, 75310, 55725, 430, 1274, 3619, 279, 4339, 369, 6302, 1555, 1268, 814, 16681, 449, 1124, 11, 779, 279, 12074, 69120, 264, 1296, 311, 23846, 42833, 8863, 315, 4339, 994, 279, 5627, 430, 279, 13324, 1436, 16681, 449, 6302, 1051, 7347, 13, 28730, 527, 13605, 304, 12976, 311, 1023, 4339, 26, 264, 330, 37765, 1359, 369, 3187, 11, 649, 387, 264, 330, 3670, 11, 1903, 315, 9168, 11, 1511, 369, 16558, 1210, 4452, 11, 499, 649, 1193, 1005, 264, 10747, 422, 499, 3619, 430, 311, 7172, 505, 264, 10747, 315, 3090, 11, 499, 3412, 433, 304, 701, 1450, 323, 4546, 433, 311, 701, 11013, 11, 477, 430, 422, 499, 6068, 279, 10747, 11, 433, 690, 53006, 389, 279, 6558, 13, 17586, 8830, 420, 11, 433, 1053, 387, 5107, 311, 1893, 264, 12585, 430, 649, 3790, 264, 1972, 10747, 13, 763, 21075, 11478, 3495, 11, 1521, 4819, 527, 3967, 439, 7891, 95841, 5435, 11, 902, 2472, 18210, 8800, 279, 1972, 1917, 13, 2650, 656, 12966, 11322, 7891, 95841, 30, 73235, 31018, 323, 25702, 8198, 30714, 279, 7434, 315, 78643, 75310, 11, 1405, 6302, 527, 2728, 7438, 1555, 22639, 449, 279, 2547, 323, 279, 4676, 13, 2057, 1296, 78643, 75310, 11, 279, 12074, 13375, 21896, 311, 1518, 1268, 279, 13324, 6, 35202, 16846, 311, 4339, 430, 7664, 6302, 430, 649, 387, 55315, 555, 1450, 11, 994, 279, 13324, 6, 6206, 1436, 3351, 26662, 7863, 311, 994, 814, 1051, 77300, 13, 330, 2181, 574, 1633, 5107, 311, 5813, 264, 1749, 369, 30090, 323, 42118, 8271, 5820, 13, 578, 1176, 3229, 11, 16450, 13, 328, 6043, 1952, 39476, 11, 6575, 23135, 4501, 311, 2586, 709, 449, 264, 3465, 11, 304, 264, 1648, 430, 584, 1051, 3025, 311, 6767, 8271, 5820, 449, 14343, 13708, 1359, 17054, 386, 14966, 31866, 11497, 13, 763, 279, 9526, 11, 1403, 4339, 1778, 439, 330, 37765, 1, 323, 330, 65, 3039, 1, 1051, 10666, 311, 13324, 389, 264, 4264, 13, 2435, 1051, 4691, 311, 9616, 279, 8844, 12562, 315, 279, 6302, 1884, 4339, 15609, 323, 311, 85207, 4320, 902, 1665, 574, 8294, 49525, 420, 1162, 11, 330, 65, 3039, 1210, 23611, 19941, 1051, 1903, 1990, 279, 4339, 11, 23524, 1403, 4595, 315, 6302, 11, 1450, 21110, 575, 360, 481, 6302, 11, 1778, 439, 330, 37765, 1, 477, 330, 65, 3039, 1, 323, 2536, 1543, 575, 360, 481, 6302, 11, 1778, 439, 330, 24177, 1, 477, 330, 24705, 604, 537, 1359, 311, 23846, 1268, 1855, 955, 574, 15590, 13, 12220, 279, 7177, 11, 279, 13324, 9277, 872, 6206, 389, 264, 18496, 11, 1405, 814, 1051, 3060, 1949, 477, 77300, 555, 264, 18300, 59741, 12235, 13, 3277, 279, 1403, 4339, 1051, 10666, 389, 279, 4264, 11, 311, 4320, 902, 832, 15609, 264, 8294, 1665, 11, 279, 13324, 4460, 311, 1781, 315, 2225, 6302, 323, 9616, 872, 12562, 11, 25957, 1124, 311, 1920, 1855, 3492, 596, 7438, 13, 31417, 5820, 574, 17303, 449, 16003, 3221, 3502, 82482, 66425, 51856, 320, 69, 45, 91064, 705, 902, 706, 279, 9610, 315, 4737, 22323, 2085, 49941, 4726, 7106, 17413, 13, 578, 22323, 10968, 389, 279, 958, 1768, 3978, 278, 26858, 57440, 323, 279, 38279, 1370, 3978, 278, 41253, 1130, 320, 13066, 2453, 867, 992, 80605, 355, 323, 20932, 80605, 355, 8, 315, 279, 2163, 8271, 11, 902, 527, 8647, 369, 42833, 8863, 5552, 311, 7526, 13, 578, 4732, 315, 279, 36870, 2077, 574, 17303, 311, 8417, 1268, 6288, 279, 25923, 19089, 1306, 279, 4339, 9922, 389, 279, 4264, 13, 578, 3135, 8710, 430, 279, 5820, 315, 279, 2163, 8271, 304, 2077, 311, 1450, 21110, 575, 360, 481, 6302, 574, 12207, 11293, 555, 1450, 312, 7610, 13, 6383, 13616, 14847, 1051, 1101, 11754, 555, 1450, 17413, 13, 4314, 3135, 13519, 430, 19477, 2101, 1450, 7351, 22223, 279, 8863, 315, 1665, 84096, 287, 11, 902, 11815, 279, 4623, 315, 78643, 75310, 13, 4314, 3135, 4284, 430, 279, 4623, 315, 78643, 75310, 1436, 1101, 387, 7524, 369, 21075, 11478, 311, 4048, 279, 7438, 315, 6302, 13, 578, 5684, 574, 4756, 304, 38130, 29140, 13, 220, 128257, 198 ]

2,007

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The absence of strong buoyancy forces severely complicates the management of multiphase flows in microgravity. Different types of space systems, ranging from in-space propulsion to life support, are negatively impacted by this effect. Multiple approaches have been developed to achieve phase separation in microgravity, whereas they usually lack the robustness, efficiency, or stability that is desirable in most applications. Complementary to existing methods, the use of magnetic polarization has been recently proposed to passively induce phase separation in electrolytic cells and other two-phase flow devices. This article illustrates the dia- and paramagnetic phase separation mechanism on MilliQ water, an aqueous MnSO 4 solution, lysogeny broth, and olive oil using air bubbles in a series of drop tower experiments. Expressions for the magnetic terminal bubble velocity are derived and validated and several wall–bubble and multi-bubble magnetic interactions are reported. Ultimately, the analysis demonstrates the feasibility of the dia- and paramagnetic phase separation approach, providing a key advancement for the development of future space systems. Introduction Human space exploration is presented with multiple challenges, to the fore, the absence of buoyancy forces in orbit. This has severe complications for phase separation in microgravity environments, which is, however, a crucial process for a wide variety of space technologies. These include propellant management devices, heat transfer, and life support systems comprising the production of oxygen, fuels, and other chemicals as well as the removal of carbon dioxide from cabin air and the recycling of wastewater, among many others. Numerous phase separation methods have been developed for microgravity conditions. Centrifuges 1 , 2 , forced vortical flows 3 , 4 , rocket firing 5 , 6 , membranes 7 , 8 , and surface-tension-based technologies 9 , 10 , which include wedge geometries 11 , 12 , 13 , 14 , springs 15 , eccentric annuli 16 , microfluidic channels 17 , or porous substrates 18 , 19 , among others, are the most traditional solutions. As an alternative, the use of electrohydrodynamic forces has been studied since the early 1960s 20 and successfully tested for boiling 21 , 22 , 23 , two-phase flow management 24 , 25 , and conduction pumping 26 applications. Hydroacoustic forces arising from the application of ultrasonic standing waves 27 have been used to enhance a wide variety of terrestrial processes 28 and are also proposed to control bubbly flows in propellant tanks 29 , 30 and life support systems 31 . Small amplitude vibrations can also be employed to manage multiphase flows and induce phase separation in microgravity 32 by selecting viscoequilibrium configurations 33 or exploiting frozen wave instabilities 34 . These approaches present unique characteristics that affect aspects like their operational lifespan, reliability, performance, and intrusiveness 31 . Complementary to the aforementioned methods, the inherent dia- and paramagnetic properties of liquids can be employed for passive phase separation 35 . Inhomogeneous magnetic fields induce a weak volume force in continuous media 36 that, due to the differential magnetic properties between phases, results in a net buoyancy effect. This phenomenon is known as magnetic buoyancy and has been applied to terrestrial boiling experiments with ferrofluids 37 , 38 . Previous works on low-gravity magnetohydrodynamics have explored the diamagnetic manipulation of air bubbles in water 39 , 40 , the positioning of diamagnetic materials 41 , air-water separation 42 , protein crystal growth 43 , magnetic-positive positioning 44 , 45 , magnetic liquid sloshing 46 , 47 , and combustion enhancement 40 , among others. The application of Lorentz’s force on liquid electrolytes has also been studied as a way to enhance hydrogen production 48 , 49 , 50 . The use of magnetic buoyancy in phase separation under microgravity conditions remains, however, largely unexplored. The discovery of diamagnetism dates back to 1778 when A. Brugmans reported the diamagnetic effect on bismuth 51 . In 1845, M. Faraday demonstrated that magnetism is a universal property of matter and carried out the first thorough study of the phenomenon, classifying different materials as “diamagnetic” and “paramagnetic” 52 . From a macroscopic perspective, diamagnetic and paramagnetic substances are respectively repelled and attracted by magnetic dipoles by means of the Kelvin body force 53 $${{{\\bf{f}}}}={\\mu }_{0}M\\nabla H,$$ (1) where μ 0 is the magnetic permeability of free space, and M and H are the modules of the magnetization ( M ) and magnetic ( H ) fields, respectively. The volume magnetic susceptibility of a soft magnetic material, χ vol , is defined through M = χ vol H , and its sign determines whether a substance is diamagnetic or paramagnetic. The magnetic polarization force on natural liquids is so weak that its effects on Earth are usually negligible. However, in a microgravity environment this weak interaction leads to a magnetic buoyancy effect that can be exploited to induce phase separation 35 . Herein, this paper reports the first comprehensive study of magnetically induced buoyancy in microgravity environments generated for 4.7 s at the drop tower of the Center for Applied Space Technology and Microgravity (ZARM). The artificially created buoyancy force is utilized to direct air gas bubbles on specific trajectories through dia- and paramagnetic solutions. The results demonstrate that the inherent magnetic properties of these substances are sufficient to allow the collection and coalescence of gas bubbles at distinct locations of the experiment vessel, providing a proof of concept that the development of microgravity magnetic phase separators could lead to reliable and lightweight space systems. Results and discussion Overview Gas bubbles are the elemental multiphase flow unit and represent the main focus of this work. The application of dia- and paramagnetic buoyancy to bubble management in microgravity is subsequently demonstrated with liquids of technical interest. Five 4.7 s microgravity experiments, listed in Table 1 , are performed at ZARM’s drop tower. During each drop, bubbles are simultaneously injected inside three syringes filled with the same carrier liquid. The first two drops employ MilliQ water, whose properties are well-characterized. This motivates the adoption of these experiments in the validation of theoretical results. An", "role": "user" }, { "content": "A potentially better way to make oxygen for astronauts in space using magnetism has been proposed by an international team of scientists, including a University of Warwick chemist. The conclusion is from new research on magnetic phase separation in microgravity published in npj Microgravity by researchers from the University of Warwick in the United Kingdom, University of Colorado Boulder and Freie Universität Berlin in Germany. Keeping astronauts breathing aboard the International Space Station and other space vehicles is a complicated and costly process. As humans plan future missions to the Moon or Mars better technology will be needed. Lead author Álvaro Romero-Calvo, a recent Ph.D. graduate from the University of Colorado Boulder, says that \"on the International Space Station, oxygen is generated using an electrolytic cell that splits water into hydrogen and oxygen, but then you have to get those gasses out of the system. A relatively recent analysis from a researcher at NASA Ames concluded that adapting the same architecture on a trip to Mars would have such significant mass and reliability penalties that it wouldn't make any sense to use.\" Dr. Katharina Brinkert of the University of Warwick Department of Chemistry and Center for Applied Space Technology and Microgravity (ZARM) in Germany says that \"efficient phase separation in reduced gravitational environments is an obstacle for human space exploration and known since the first flights to space in the 1960s. This phenomenon is a particular challenge for the life support system onboard spacecraft and the International Space Station (ISS) as oxygen for the crew is produced in water electrolyzer systems and requires separation from the electrode and liquid electrolyte.\" The underlying issue is buoyancy. Imagine a glass of fizzy soda. On Earth, the bubbles of CO2 quickly float to the top, but in the absence of gravity, those bubbles have nowhere to go. They instead stay suspended in the liquid. NASA currently uses centrifuges to force the gasses out, but those machines are large and require significant mass, power, and maintenance. Meanwhile, the team has conducted experiments demonstrating magnets could achieve the same results in some cases. Although diamagnetic forces are well known and understood, their use by engineers in space applications have not been fully explored because gravity makes the technology difficult to demonstrate on Earth. Enter the Center for Applied Space Technology and Microgravity (ZARM) in Germany. There, Brinkert, who has ongoing research funded by the German Aerospace Center (DLR), led the team in successful experimental tests at a special drop tower facility that simulates microgravity conditions. Here, the groups have developed a procedure to detach gas bubbles from electrode surfaces in microgravity environments generated for 9.2s at the Bremen Drop Tower. This study demonstrates for the first time gas bubbles can be 'attracted to' and 'repelled from' a simple neodymium magnet in microgravity by immersing it in different types of aqueous solution. The research could open up new avenues for scientists and engineers developing oxygen systems as well as other space research involving liquid-to-gas phase changes. Dr. Brinkert says that \"these effects have tremendous consequences for the further development of phase separation systems, such as for long-term space missions, suggesting that efficient oxygen and, for example, hydrogen production in water (photo-)electrolyzer systems can be achieved even in the near-absence of the buoyant-force.\" Professor Hanspeter Schaub of University of Colorado Boulder says that \"after years of analytical and computational research, being able to use this amazing drop tower in Germany provided concrete proof that this concept will function in the zero-g space environment.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The absence of strong buoyancy forces severely complicates the management of multiphase flows in microgravity. Different types of space systems, ranging from in-space propulsion to life support, are negatively impacted by this effect. Multiple approaches have been developed to achieve phase separation in microgravity, whereas they usually lack the robustness, efficiency, or stability that is desirable in most applications. Complementary to existing methods, the use of magnetic polarization has been recently proposed to passively induce phase separation in electrolytic cells and other two-phase flow devices. This article illustrates the dia- and paramagnetic phase separation mechanism on MilliQ water, an aqueous MnSO 4 solution, lysogeny broth, and olive oil using air bubbles in a series of drop tower experiments. Expressions for the magnetic terminal bubble velocity are derived and validated and several wall–bubble and multi-bubble magnetic interactions are reported. Ultimately, the analysis demonstrates the feasibility of the dia- and paramagnetic phase separation approach, providing a key advancement for the development of future space systems. Introduction Human space exploration is presented with multiple challenges, to the fore, the absence of buoyancy forces in orbit. This has severe complications for phase separation in microgravity environments, which is, however, a crucial process for a wide variety of space technologies. These include propellant management devices, heat transfer, and life support systems comprising the production of oxygen, fuels, and other chemicals as well as the removal of carbon dioxide from cabin air and the recycling of wastewater, among many others. Numerous phase separation methods have been developed for microgravity conditions. Centrifuges 1 , 2 , forced vortical flows 3 , 4 , rocket firing 5 , 6 , membranes 7 , 8 , and surface-tension-based technologies 9 , 10 , which include wedge geometries 11 , 12 , 13 , 14 , springs 15 , eccentric annuli 16 , microfluidic channels 17 , or porous substrates 18 , 19 , among others, are the most traditional solutions. As an alternative, the use of electrohydrodynamic forces has been studied since the early 1960s 20 and successfully tested for boiling 21 , 22 , 23 , two-phase flow management 24 , 25 , and conduction pumping 26 applications. Hydroacoustic forces arising from the application of ultrasonic standing waves 27 have been used to enhance a wide variety of terrestrial processes 28 and are also proposed to control bubbly flows in propellant tanks 29 , 30 and life support systems 31 . Small amplitude vibrations can also be employed to manage multiphase flows and induce phase separation in microgravity 32 by selecting viscoequilibrium configurations 33 or exploiting frozen wave instabilities 34 . These approaches present unique characteristics that affect aspects like their operational lifespan, reliability, performance, and intrusiveness 31 . Complementary to the aforementioned methods, the inherent dia- and paramagnetic properties of liquids can be employed for passive phase separation 35 . Inhomogeneous magnetic fields induce a weak volume force in continuous media 36 that, due to the differential magnetic properties between phases, results in a net buoyancy effect. This phenomenon is known as magnetic buoyancy and has been applied to terrestrial boiling experiments with ferrofluids 37 , 38 . Previous works on low-gravity magnetohydrodynamics have explored the diamagnetic manipulation of air bubbles in water 39 , 40 , the positioning of diamagnetic materials 41 , air-water separation 42 , protein crystal growth 43 , magnetic-positive positioning 44 , 45 , magnetic liquid sloshing 46 , 47 , and combustion enhancement 40 , among others. The application of Lorentz’s force on liquid electrolytes has also been studied as a way to enhance hydrogen production 48 , 49 , 50 . The use of magnetic buoyancy in phase separation under microgravity conditions remains, however, largely unexplored. The discovery of diamagnetism dates back to 1778 when A. Brugmans reported the diamagnetic effect on bismuth 51 . In 1845, M. Faraday demonstrated that magnetism is a universal property of matter and carried out the first thorough study of the phenomenon, classifying different materials as “diamagnetic” and “paramagnetic” 52 . From a macroscopic perspective, diamagnetic and paramagnetic substances are respectively repelled and attracted by magnetic dipoles by means of the Kelvin body force 53 $${{{\bf{f}}}}={\mu }_{0}M\nabla H,$$ (1) where μ 0 is the magnetic permeability of free space, and M and H are the modules of the magnetization ( M ) and magnetic ( H ) fields, respectively. The volume magnetic susceptibility of a soft magnetic material, χ vol , is defined through M = χ vol H , and its sign determines whether a substance is diamagnetic or paramagnetic. The magnetic polarization force on natural liquids is so weak that its effects on Earth are usually negligible. However, in a microgravity environment this weak interaction leads to a magnetic buoyancy effect that can be exploited to induce phase separation 35 . Herein, this paper reports the first comprehensive study of magnetically induced buoyancy in microgravity environments generated for 4.7 s at the drop tower of the Center for Applied Space Technology and Microgravity (ZARM). The artificially created buoyancy force is utilized to direct air gas bubbles on specific trajectories through dia- and paramagnetic solutions. The results demonstrate that the inherent magnetic properties of these substances are sufficient to allow the collection and coalescence of gas bubbles at distinct locations of the experiment vessel, providing a proof of concept that the development of microgravity magnetic phase separators could lead to reliable and lightweight space systems. Results and discussion Overview Gas bubbles are the elemental multiphase flow unit and represent the main focus of this work. The application of dia- and paramagnetic buoyancy to bubble management in microgravity is subsequently demonstrated with liquids of technical interest. Five 4.7 s microgravity experiments, listed in Table 1 , are performed at ZARM’s drop tower. During each drop, bubbles are simultaneously injected inside three syringes filled with the same carrier liquid. The first two drops employ MilliQ water, whose properties are well-characterized. This motivates the adoption of these experiments in the validation of theoretical results. An<|im_end|> <|im_start|>assistant A potentially better way to make oxygen for astronauts in space using magnetism has been proposed by an international team of scientists, including a University of Warwick chemist. The conclusion is from new research on magnetic phase separation in microgravity published in npj Microgravity by researchers from the University of Warwick in the United Kingdom, University of Colorado Boulder and Freie Universität Berlin in Germany. Keeping astronauts breathing aboard the International Space Station and other space vehicles is a complicated and costly process. As humans plan future missions to the Moon or Mars better technology will be needed. Lead author Álvaro Romero-Calvo, a recent Ph.D. graduate from the University of Colorado Boulder, says that "on the International Space Station, oxygen is generated using an electrolytic cell that splits water into hydrogen and oxygen, but then you have to get those gasses out of the system. A relatively recent analysis from a researcher at NASA Ames concluded that adapting the same architecture on a trip to Mars would have such significant mass and reliability penalties that it wouldn't make any sense to use." Dr. Katharina Brinkert of the University of Warwick Department of Chemistry and Center for Applied Space Technology and Microgravity (ZARM) in Germany says that "efficient phase separation in reduced gravitational environments is an obstacle for human space exploration and known since the first flights to space in the 1960s. This phenomenon is a particular challenge for the life support system onboard spacecraft and the International Space Station (ISS) as oxygen for the crew is produced in water electrolyzer systems and requires separation from the electrode and liquid electrolyte." The underlying issue is buoyancy. Imagine a glass of fizzy soda. On Earth, the bubbles of CO2 quickly float to the top, but in the absence of gravity, those bubbles have nowhere to go. They instead stay suspended in the liquid. NASA currently uses centrifuges to force the gasses out, but those machines are large and require significant mass, power, and maintenance. Meanwhile, the team has conducted experiments demonstrating magnets could achieve the same results in some cases. Although diamagnetic forces are well known and understood, their use by engineers in space applications have not been fully explored because gravity makes the technology difficult to demonstrate on Earth. Enter the Center for Applied Space Technology and Microgravity (ZARM) in Germany. There, Brinkert, who has ongoing research funded by the German Aerospace Center (DLR), led the team in successful experimental tests at a special drop tower facility that simulates microgravity conditions. Here, the groups have developed a procedure to detach gas bubbles from electrode surfaces in microgravity environments generated for 9.2s at the Bremen Drop Tower. This study demonstrates for the first time gas bubbles can be 'attracted to' and 'repelled from' a simple neodymium magnet in microgravity by immersing it in different types of aqueous solution. The research could open up new avenues for scientists and engineers developing oxygen systems as well as other space research involving liquid-to-gas phase changes. Dr. Brinkert says that "these effects have tremendous consequences for the further development of phase separation systems, such as for long-term space missions, suggesting that efficient oxygen and, for example, hydrogen production in water (photo-)electrolyzer systems can be achieved even in the near-absence of the buoyant-force." Professor Hanspeter Schaub of University of Colorado Boulder says that "after years of analytical and computational research, being able to use this amazing drop tower in Germany provided concrete proof that this concept will function in the zero-g space environment." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered 1 . Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants 2 , we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B , GATA1 , LRBA and MPL . Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare. Main Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis 3 . Approximately 10,000 rare diseases are known, but fewer than half have a resolved genetic aetiology 1 . Even for diseases with a resolved aetiology, the prospects for diagnosis are severely diminished by fragmentary phenotyping and the restriction of testing to disease-specific panels of genes. It may require more than 20 physician visits over several years to determine a molecular cause 4 . Recent development of WGS technology enables systematic, comprehensive genetic testing in integrated health systems, together with aetiological discovery in the coding and non-coding genome. We performed WGS for 13,037 individuals enrolled at 57 National Health Service (NHS) hospitals in the United Kingdom and 26 hospitals in other countries (Fig. 1a , Extended Data Fig. 1a and Supplementary Table 1 ), in three batches, to clinical standard (Fig. 1b ). The participants were distributed approximately uniformly across the sexes (Supplementary Table 1 ) and approximately according to the distribution reported by the UK census across ethnic groups (Fig. 1c ; ). Each participant was assigned to one of 18 domains with pre-specified enrolment criteria (Supplementary Table 1 ): 7,388 individuals were assigned to one of 15 rare disease domains, 50 individuals to a control domain, 4,835 individuals to a domain called the Rare Diseases Pilot of Genomics England Ltd (GEL) and 764 individuals to a domain comprising UK Biobank participants with extreme red blood cell indices (Extended Data Fig. 1b , Supplementary Information and Supplementary Table 1 ). Sample sizes varied across domains, primarily owing to differences in recruitment rates, limiting the efficiency of the study design. In total, 9,802 of the participants (75%) had a rare disease or an extreme measurement of a quantitative trait, of whom 9,024 were probands and 778 were affected relatives. The patients presented with pathologies of many organ systems, which we phenotyped using Human Phenotype Ontology (HPO) terms for all of the rare disease domains except the domain comprising Leber’s hereditary optic neuropathy and the domain comprising Ehler–Danlos/Ehler–Danlos-like syndromes (Fig. 2a and Extended Data Fig. 1c ). The GEL domain released only a binary affection phenotype for these analyses. In total, 19,605 HPO terms were assigned to patients. Fig. 1: Study overview. a , Schematic of the diagnostic and research processes. Blue, patients are recruited, HPO and pedigree data are collected, DNA is extracted and sequenced and WGS data are transferred for quality control and variant prioritization. Green, variants are assessed and diagnoses are returned. Orange, the complete data are analysed by association and co-segregation to identify aetiological variants, disease-mediating genes and regulatory regions; functional studies and model systems are used to study disease mechanisms. b , Histograms of read coverage across the 13,037 participants, stratified by WGS read length (100 bp, 125 bp and 150 bp). c , Projection of genetic data of the 13,037 participants onto the first two principal components of variation in the 1000 Genomes Project and the distribution of participant ancestry. d , Histograms illustrating the observed distribution of the minor allele frequency (MAF) of variants called in the MSUP ( n = 10,259), stratified by type (SNV or indel). Variants are labelled novel if they were uncatalogued in the 1000 Genomes, UK10K, TOPMed, gnomAD and HGMD Pro databases. MAC, minor allele count. e , The number of novel variants stratified by the ancestry groups in which they were observed (yellow, present; navy, absent). f , The sizes of genetically determined networks of closely related individuals across the 13,037 participants. Inset, distributions of network sizes for each rare disease domain. BPD, bleeding, thrombotic and platelet disorders; CSVD, cerebral small vessel disease; EDS, Ehler–Danlos and Ehler–Danlos-like syndromes; HCM, hypertrophic cardiomyopathy; ICP, intrahepatic cholestasis of pregnancy; IRD, inherited retinal disorders; LHON, Leber’s hereditary optic neuropathy; MPMT, multiple primary malignant tumours; NDD, neurological and developmental disorders; NPD, neuropathic pain disorders; PAH, pulmonary arterial hypertension; PID, primary immune disorders; PMG: primary membranoproliferative glomerulonephritis; SMD, stem cell and myeloid disorders; SRNS, steroid-resistant nephrotic syndrome. Full size image Fig. 2: Variant reporting and genetic associations with rare diseases. a , The frequency of probands by domain (top) and by top-level HPO-phenotype abnormality term (right). The heat map shows the proportion of probands in each domain that were assigned a particular top-level HPO term (shown abbreviated). b , The number of DGGs shared by pairs of domains (left). Pre-screening level for each domain indicated in red (full), blue (partial) or green (none). The proportion of cases for which a clinical report was issued (right). c , The number of reports issued by DGG ordered inversely by count. Dashed lines indicate quartiles of the count distribution. Inset, the number of distinct clinically reported variants stratified by variant type. The colours in each bar indicate the proportion of variants that are known or novel (as defined in the main", "role": "user" }, { "content": "A research program pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government which aims to introduce routine genetic diagnostic testing in the NHS. The present study, led by researchers at the National Institute for Health Research BioResource together with Genomics England, demonstrates that sequencing the whole genomes of large numbers of individuals in a standardized way can improve the diagnosis and treatment of patients with rare diseases. The researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision. The program, the results of which were published today in two articles in the journal Nature, offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. The integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months. \"Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed,\" says Willem Ouwehand, Professor of Experimental Haematology at the University of Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. \"We felt it was vital to shorten this odyssey for patients and parents.\" \"This research shows that quicker and better genetic diagnosis will be possible for more NHS patients.\" In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases. The team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease—a few hundred 'needles in the haystack.\" In one study from the program, published as a standalone article in Nature, researchers examined 886 patients with primary immunodeficiency—a condition that affects the ability of the immune system to fight infections by microbes—and identified four novel associated genes. \"Providing the best treatment and the most appropriate care for patients with inherited immune disorders depends absolutely on a conclusive molecular diagnosis,\" says Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London. \"Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care.\" Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease. The team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the 'switches and dimmers' of the genome—the regulatory elements in DNA that control the activity of the thousands of genes. The team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analyzed for each patient. \"We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis,\" says Dr. Ernest Turro from the University of Cambridge and the NIHR BioResource. \"Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases.\" Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource. \"In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield\" says Dr. Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care and who together with the Chief Medical Officer Professor Chris Whitty has the overall responsibility for the National Institute for Health Research. \"The NIHR-funded researchers on this scientific report were part of those earliest discussions as we sought to ensure we could deliver the science and transform it into clinical practice across the NHS. This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings. \"The pioneering work undertaken by the NHS in partnership with Genomics England and academic researchers across the UK has laid the foundation for applying the same genome test to patients with COVID-19, with the hope of finding clues why some patients experience such a severe form of this new disease.\" Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. The sequencing of whole genomes will expand to one million genomes per year by 2024. Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the 'standard of care,' ensuring equivalent care across the country. The benefits include a hastened diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered 1 . Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants 2 , we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B , GATA1 , LRBA and MPL . Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare. Main Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis 3 . Approximately 10,000 rare diseases are known, but fewer than half have a resolved genetic aetiology 1 . Even for diseases with a resolved aetiology, the prospects for diagnosis are severely diminished by fragmentary phenotyping and the restriction of testing to disease-specific panels of genes. It may require more than 20 physician visits over several years to determine a molecular cause 4 . Recent development of WGS technology enables systematic, comprehensive genetic testing in integrated health systems, together with aetiological discovery in the coding and non-coding genome. We performed WGS for 13,037 individuals enrolled at 57 National Health Service (NHS) hospitals in the United Kingdom and 26 hospitals in other countries (Fig. 1a , Extended Data Fig. 1a and Supplementary Table 1 ), in three batches, to clinical standard (Fig. 1b ). The participants were distributed approximately uniformly across the sexes (Supplementary Table 1 ) and approximately according to the distribution reported by the UK census across ethnic groups (Fig. 1c ; ). Each participant was assigned to one of 18 domains with pre-specified enrolment criteria (Supplementary Table 1 ): 7,388 individuals were assigned to one of 15 rare disease domains, 50 individuals to a control domain, 4,835 individuals to a domain called the Rare Diseases Pilot of Genomics England Ltd (GEL) and 764 individuals to a domain comprising UK Biobank participants with extreme red blood cell indices (Extended Data Fig. 1b , Supplementary Information and Supplementary Table 1 ). Sample sizes varied across domains, primarily owing to differences in recruitment rates, limiting the efficiency of the study design. In total, 9,802 of the participants (75%) had a rare disease or an extreme measurement of a quantitative trait, of whom 9,024 were probands and 778 were affected relatives. The patients presented with pathologies of many organ systems, which we phenotyped using Human Phenotype Ontology (HPO) terms for all of the rare disease domains except the domain comprising Leber’s hereditary optic neuropathy and the domain comprising Ehler–Danlos/Ehler–Danlos-like syndromes (Fig. 2a and Extended Data Fig. 1c ). The GEL domain released only a binary affection phenotype for these analyses. In total, 19,605 HPO terms were assigned to patients. Fig. 1: Study overview. a , Schematic of the diagnostic and research processes. Blue, patients are recruited, HPO and pedigree data are collected, DNA is extracted and sequenced and WGS data are transferred for quality control and variant prioritization. Green, variants are assessed and diagnoses are returned. Orange, the complete data are analysed by association and co-segregation to identify aetiological variants, disease-mediating genes and regulatory regions; functional studies and model systems are used to study disease mechanisms. b , Histograms of read coverage across the 13,037 participants, stratified by WGS read length (100 bp, 125 bp and 150 bp). c , Projection of genetic data of the 13,037 participants onto the first two principal components of variation in the 1000 Genomes Project and the distribution of participant ancestry. d , Histograms illustrating the observed distribution of the minor allele frequency (MAF) of variants called in the MSUP ( n = 10,259), stratified by type (SNV or indel). Variants are labelled novel if they were uncatalogued in the 1000 Genomes, UK10K, TOPMed, gnomAD and HGMD Pro databases. MAC, minor allele count. e , The number of novel variants stratified by the ancestry groups in which they were observed (yellow, present; navy, absent). f , The sizes of genetically determined networks of closely related individuals across the 13,037 participants. Inset, distributions of network sizes for each rare disease domain. BPD, bleeding, thrombotic and platelet disorders; CSVD, cerebral small vessel disease; EDS, Ehler–Danlos and Ehler–Danlos-like syndromes; HCM, hypertrophic cardiomyopathy; ICP, intrahepatic cholestasis of pregnancy; IRD, inherited retinal disorders; LHON, Leber’s hereditary optic neuropathy; MPMT, multiple primary malignant tumours; NDD, neurological and developmental disorders; NPD, neuropathic pain disorders; PAH, pulmonary arterial hypertension; PID, primary immune disorders; PMG: primary membranoproliferative glomerulonephritis; SMD, stem cell and myeloid disorders; SRNS, steroid-resistant nephrotic syndrome. Full size image Fig. 2: Variant reporting and genetic associations with rare diseases. a , The frequency of probands by domain (top) and by top-level HPO-phenotype abnormality term (right). The heat map shows the proportion of probands in each domain that were assigned a particular top-level HPO term (shown abbreviated). b , The number of DGGs shared by pairs of domains (left). Pre-screening level for each domain indicated in red (full), blue (partial) or green (none). The proportion of cases for which a clinical report was issued (right). c , The number of reports issued by DGG ordered inversely by count. Dashed lines indicate quartiles of the count distribution. Inset, the number of distinct clinically reported variants stratified by variant type. The colours in each bar indicate the proportion of variants that are known or novel (as defined in the main<|im_end|> <|im_start|>assistant A research program pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government which aims to introduce routine genetic diagnostic testing in the NHS. The present study, led by researchers at the National Institute for Health Research BioResource together with Genomics England, demonstrates that sequencing the whole genomes of large numbers of individuals in a standardized way can improve the diagnosis and treatment of patients with rare diseases. The researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision. The program, the results of which were published today in two articles in the journal Nature, offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. The integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months. "Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed," says Willem Ouwehand, Professor of Experimental Haematology at the University of Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. "We felt it was vital to shorten this odyssey for patients and parents." "This research shows that quicker and better genetic diagnosis will be possible for more NHS patients." In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases. The team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease—a few hundred 'needles in the haystack." In one study from the program, published as a standalone article in Nature, researchers examined 886 patients with primary immunodeficiency—a condition that affects the ability of the immune system to fight infections by microbes—and identified four novel associated genes. "Providing the best treatment and the most appropriate care for patients with inherited immune disorders depends absolutely on a conclusive molecular diagnosis," says Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London. "Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care." Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease. The team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the 'switches and dimmers' of the genome—the regulatory elements in DNA that control the activity of the thousands of genes. The team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analyzed for each patient. "We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis," says Dr. Ernest Turro from the University of Cambridge and the NIHR BioResource. "Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases." Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource. "In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield" says Dr. Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care and who together with the Chief Medical Officer Professor Chris Whitty has the overall responsibility for the National Institute for Health Research. "The NIHR-funded researchers on this scientific report were part of those earliest discussions as we sought to ensure we could deliver the science and transform it into clinical practice across the NHS. This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings. "The pioneering work undertaken by the NHS in partnership with Genomics England and academic researchers across the UK has laid the foundation for applying the same genome test to patients with COVID-19, with the hope of finding clues why some patients experience such a severe form of this new disease." Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. The sequencing of whole genomes will expand to one million genomes per year by 2024. Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the 'standard of care,' ensuring equivalent care across the country. The benefits include a hastened diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system) 1 . It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation 2 . However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G i protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu–G i structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs. Main The activation of class C GPCRs is directly linked with their capability to form dimers. For mGlus, a constitutive homodimer is essential for relaying the glutamate-induced signalling from the extracellular domain (ECD) of the receptor to its transmembrane domain (TMD) 1 , and occupation of both ECDs with the agonist is required for full activity 3 . However, only one receptor subunit in a dimer is responsible for G-protein activation, which suggests an asymmetric signal transduction mode of mGlus 2 . In addition, previous fluorescence resonance energy transfer analysis of some class C GPCRs has suggested that only small conformational changes occur within the TMD of the receptor upon activation 4 , 5 , which is in contrast to class A and B GPCRs in which the TMD undergoes a pronounced conformational rearrangement to accommodate the G protein 6 , 7 . To disclose the molecular details that define G-protein recognition and the asymmetric activation of class C GPCRs, we solved the fully active structures of mGlu2 and mGlu4 (representative of group II and III mGlus, respectively) in complex with heterotrimeric G i protein using single-particle cryo-electron microscopy (cryo-EM). These structures, together with functional data, provide important structural and mechanistic insights into the G-protein binding and receptor activation of class C GPCRs. Cryo-EM structures of mGlu–G i complexes We prepared the mGlu2–G i and mGlu4–G i complexes by co-expressing and co-purifying a modified mGlu2 (Methods) and the wild-type mGlu4 with the G i1 and G i3 proteins, respectively, in the presence of an agonist (LY354740 for mGlu2 8 and l -serine- O -phosphate for mGlu4 9 ) and positive allosteric modulator (PAM) (JNJ-40411813 for mGlu2 10 and VU0364770 for mGlu4 11 ) (Extended Data Fig. 1a, b, h, i , Supplementary Fig. 1 ). We further stabilized the mGlu2–G i1 complex by adding the nanobody DN13 (International Patent Application WO 2016/001417 A1), which binds to the Venus flytrap domain (VFT) in the mGlu2 ECD and acts as a PAM 12 . Our cryo-EM studies yielded two composite maps of the mGlu2–G i1 and mGlu4–G i3 complexes at resolutions of 3.1 Å (ECDs of mGlu2) and 3.5 Å (G i1 and the TMDs of mGlu2), and 3.1 Å (ECDs of mGlu4) and 4.0 Å (overall mGlu4–G i3 ) (Extended Data Figs. 1 c–g, j–n, 2 , Extended Data Table 1 ). The maps enabled us to build the fully active models of mGlu2 and mGlu4 with unambiguous placement of side chains for most of the residues in the receptors, G proteins and the nanobody DN13, as well as all of the ligands (except for the PAM in the mGlu4–G i3 structure) (Extended Data Fig. 3 ). We compared the two mGlu–G i structures with previously published agonist-bound structures of mGlu5 13 and mGlu2 VFT 14 , 15 , which revealed a similar close conformation of the VFT of the receptor and a common agonist-binding site that is formed by both lobes of the VFT (Extended Data Fig. 4a, b ). Furthermore, the G i -bound mGlu2 and mGlu4 structures exhibit a cysteine-rich domain in proximity to the extracellular loop (ECL) 2 of the receptor (Extended Data Fig. 4c ), although observation of detailed interactions is limited by the poor resolution of the cryo-EM maps in this region. This structural feature has previously been observed in the agonist-bound mGlu5 structure, and has been implied to propagate the agonist-induced conformational change at the VFT to the TMD 13 . These structural similarities suggest that the agonists may trigger receptor activation in different mGlus in a similar manner. Unique G-protein-binding site in mGlus The structures of G i -bound mGlu2 and mGlu4 support the asymmetric activation of class C GPCRs (Fig. 1 ). It is apparent that two G-protein heterotrimers would form a severe clash if both receptor subunits were activated (Extended Data Fig. 4i ). Notably, the large outward movement of helix VI that represents a hallmark of receptor activation in class A and B GPCRs 6 , 7 was not observed in the mGlu2–G i1 and mGlu4–G i3 structures, as compared to the inactive structures of mGlu2 16 and mGlu5 13 (Extended Data Fig. 4d ). The helical bundles of the TMDs of the two receptor subunits in both of the mGlu–G i complexes are structurally similar to one another, with a Cα root mean square deviation of 1.8 Å (mGlu2–G i1 ) and 1.7 Å (mGlu4–G i3 ), respectively. The largest conformational deviation on the intracellular surface between the G i -bound and G i -free subunits occurs in the three intracellular loops (ICL1, ICL2 and ICL3) and the intracellular tips of helices III, IV and V (Extended Data Fig. 4e, f ). These observations suggest that mGlus recognize G proteins in a manner different from that of class A and B GPCRs. Fig. 1: Overall structures of mGlu2–G i1 and mGlu4–G i3 complexes. a , Cryo-EM", "role": "user" }, { "content": "Metabotropic glutamate receptors (mGlus), which belong to class C G-protein-coupled receptor (GPCR) family, play key roles in modulating neuronal excitability and synaptic transmission in the central nervous system. The mGlus (mGlu1-8) identified in humans serve as therapeutic targets for a variety of neurological and psychiatric disorders such as Parkinson's disease, Alzheimer's disease and schizophrenia, but drugs targeting the mGlus are not currently available. In two back-to-back studies published in Nature, a team of researchers led by Wu Beili, Zhao Qiang, Wang Mingwei and Liu Hong at the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences (CAS), collaborating with research groups led by Sun Fei at Institute of Biophysics of CAS and by Liu Jianfeng from Huazhong University of Science and Technology, respectively, determined six cryo-electron microscopy (cryo-EM) structures of several mGlus in distinct functional and dimeric states, which offers opportunities to develop new treatment for neurological and psychiatric diseases. The researchers solved the structures of mGlu2 and mGlu7 homodimers in the inactive state; the structures revealed distinct dimerization modes. Using mutagenesis and cell signaling assays, the researchers found that the transmembrane domain (TMD) dimer interface in the inactive mGlu2 homodimer is subtype-specific and has a critical role in stabilizing the inactive conformation of the receptor. They determined the structures of mGlu2 homodimer in the inactive, intermediate activation (Gi protein-free) and fully activate (Gi protein-bound) states. The structure of mGlu4 in complex with the Gi protein reveals a similar dimeric association mode, suggesting that different mGlus may modulate receptor activation in a similar manner. Additionally, the researchers found that extracellular domains (ECDs) of both subunits are occupied by the agonist, but only one TMD is capable of coupling to G protein. The asymmetric dimer association provides different interaction environments for the two subunits and may cause distinct conformational changes within the two TMDs, which only allow one subunit to recognize the G protein. The G protein then forms a spatial hindrance to block the G protein coupling by the other subunit. The studies offer the first thorough view of receptor conformational changes during the process of mGlu activation and give valuable insights into asymmetric activation of mGlus. They highlight the importance of cooperativity between different subunits as well as between different receptor domains in controlling receptor function, thereby expanding the knowledge about signal transduction of class C GPCRs. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system) 1 . It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation 2 . However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G i protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu–G i structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs. Main The activation of class C GPCRs is directly linked with their capability to form dimers. For mGlus, a constitutive homodimer is essential for relaying the glutamate-induced signalling from the extracellular domain (ECD) of the receptor to its transmembrane domain (TMD) 1 , and occupation of both ECDs with the agonist is required for full activity 3 . However, only one receptor subunit in a dimer is responsible for G-protein activation, which suggests an asymmetric signal transduction mode of mGlus 2 . In addition, previous fluorescence resonance energy transfer analysis of some class C GPCRs has suggested that only small conformational changes occur within the TMD of the receptor upon activation 4 , 5 , which is in contrast to class A and B GPCRs in which the TMD undergoes a pronounced conformational rearrangement to accommodate the G protein 6 , 7 . To disclose the molecular details that define G-protein recognition and the asymmetric activation of class C GPCRs, we solved the fully active structures of mGlu2 and mGlu4 (representative of group II and III mGlus, respectively) in complex with heterotrimeric G i protein using single-particle cryo-electron microscopy (cryo-EM). These structures, together with functional data, provide important structural and mechanistic insights into the G-protein binding and receptor activation of class C GPCRs. Cryo-EM structures of mGlu–G i complexes We prepared the mGlu2–G i and mGlu4–G i complexes by co-expressing and co-purifying a modified mGlu2 (Methods) and the wild-type mGlu4 with the G i1 and G i3 proteins, respectively, in the presence of an agonist (LY354740 for mGlu2 8 and l -serine- O -phosphate for mGlu4 9 ) and positive allosteric modulator (PAM) (JNJ-40411813 for mGlu2 10 and VU0364770 for mGlu4 11 ) (Extended Data Fig. 1a, b, h, i , Supplementary Fig. 1 ). We further stabilized the mGlu2–G i1 complex by adding the nanobody DN13 (International Patent Application WO 2016/001417 A1), which binds to the Venus flytrap domain (VFT) in the mGlu2 ECD and acts as a PAM 12 . Our cryo-EM studies yielded two composite maps of the mGlu2–G i1 and mGlu4–G i3 complexes at resolutions of 3.1 Å (ECDs of mGlu2) and 3.5 Å (G i1 and the TMDs of mGlu2), and 3.1 Å (ECDs of mGlu4) and 4.0 Å (overall mGlu4–G i3 ) (Extended Data Figs. 1 c–g, j–n, 2 , Extended Data Table 1 ). The maps enabled us to build the fully active models of mGlu2 and mGlu4 with unambiguous placement of side chains for most of the residues in the receptors, G proteins and the nanobody DN13, as well as all of the ligands (except for the PAM in the mGlu4–G i3 structure) (Extended Data Fig. 3 ). We compared the two mGlu–G i structures with previously published agonist-bound structures of mGlu5 13 and mGlu2 VFT 14 , 15 , which revealed a similar close conformation of the VFT of the receptor and a common agonist-binding site that is formed by both lobes of the VFT (Extended Data Fig. 4a, b ). Furthermore, the G i -bound mGlu2 and mGlu4 structures exhibit a cysteine-rich domain in proximity to the extracellular loop (ECL) 2 of the receptor (Extended Data Fig. 4c ), although observation of detailed interactions is limited by the poor resolution of the cryo-EM maps in this region. This structural feature has previously been observed in the agonist-bound mGlu5 structure, and has been implied to propagate the agonist-induced conformational change at the VFT to the TMD 13 . These structural similarities suggest that the agonists may trigger receptor activation in different mGlus in a similar manner. Unique G-protein-binding site in mGlus The structures of G i -bound mGlu2 and mGlu4 support the asymmetric activation of class C GPCRs (Fig. 1 ). It is apparent that two G-protein heterotrimers would form a severe clash if both receptor subunits were activated (Extended Data Fig. 4i ). Notably, the large outward movement of helix VI that represents a hallmark of receptor activation in class A and B GPCRs 6 , 7 was not observed in the mGlu2–G i1 and mGlu4–G i3 structures, as compared to the inactive structures of mGlu2 16 and mGlu5 13 (Extended Data Fig. 4d ). The helical bundles of the TMDs of the two receptor subunits in both of the mGlu–G i complexes are structurally similar to one another, with a Cα root mean square deviation of 1.8 Å (mGlu2–G i1 ) and 1.7 Å (mGlu4–G i3 ), respectively. The largest conformational deviation on the intracellular surface between the G i -bound and G i -free subunits occurs in the three intracellular loops (ICL1, ICL2 and ICL3) and the intracellular tips of helices III, IV and V (Extended Data Fig. 4e, f ). These observations suggest that mGlus recognize G proteins in a manner different from that of class A and B GPCRs. Fig. 1: Overall structures of mGlu2–G i1 and mGlu4–G i3 complexes. a , Cryo-EM<|im_end|> <|im_start|>assistant Metabotropic glutamate receptors (mGlus), which belong to class C G-protein-coupled receptor (GPCR) family, play key roles in modulating neuronal excitability and synaptic transmission in the central nervous system. The mGlus (mGlu1-8) identified in humans serve as therapeutic targets for a variety of neurological and psychiatric disorders such as Parkinson's disease, Alzheimer's disease and schizophrenia, but drugs targeting the mGlus are not currently available. In two back-to-back studies published in Nature, a team of researchers led by Wu Beili, Zhao Qiang, Wang Mingwei and Liu Hong at the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences (CAS), collaborating with research groups led by Sun Fei at Institute of Biophysics of CAS and by Liu Jianfeng from Huazhong University of Science and Technology, respectively, determined six cryo-electron microscopy (cryo-EM) structures of several mGlus in distinct functional and dimeric states, which offers opportunities to develop new treatment for neurological and psychiatric diseases. The researchers solved the structures of mGlu2 and mGlu7 homodimers in the inactive state; the structures revealed distinct dimerization modes. Using mutagenesis and cell signaling assays, the researchers found that the transmembrane domain (TMD) dimer interface in the inactive mGlu2 homodimer is subtype-specific and has a critical role in stabilizing the inactive conformation of the receptor. They determined the structures of mGlu2 homodimer in the inactive, intermediate activation (Gi protein-free) and fully activate (Gi protein-bound) states. The structure of mGlu4 in complex with the Gi protein reveals a similar dimeric association mode, suggesting that different mGlus may modulate receptor activation in a similar manner. Additionally, the researchers found that extracellular domains (ECDs) of both subunits are occupied by the agonist, but only one TMD is capable of coupling to G protein. The asymmetric dimer association provides different interaction environments for the two subunits and may cause distinct conformational changes within the two TMDs, which only allow one subunit to recognize the G protein. The G protein then forms a spatial hindrance to block the G protein coupling by the other subunit. The studies offer the first thorough view of receptor conformational changes during the process of mGlu activation and give valuable insights into asymmetric activation of mGlus. They highlight the importance of cooperativity between different subunits as well as between different receptor domains in controlling receptor function, thereby expanding the knowledge about signal transduction of class C GPCRs. <|im_end|>

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2,169

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Steady-state solid-liquid interfaces allow both analytic description as sharp-interface profiles, and numerical simulation via phase-field modeling as stationary diffuse-interface microstructures. Profiles for sharp interfaces reveal their exact shapes and allow identification of the thermodynamic origin of all interfacial capillary fields, including distributions of curvature, thermochemical potential, gradients, fluxes, and surface Laplacians. By contrast, simulated diffuse interface images allow thermodynamic evolution and measurement of interfacial temperatures and fluxes. Quantitative results using both approaches verify these capillary fields and their divergent heat flow, to provide insights into interface energy balances, dynamic pattern formation, and novel methods for microstructure control. The microgravity environment of low-Earth orbit was proven useful in past studies of solidification phenomena. We suggest that NASA’s ISS National Lab can uniquely accommodate aspects of experimental research needed to explore these novel topics. Introduction Over the past decade, one of the present authors published studies applying field-theoretic methods to identify and quantitate interfacial thermodynamic fields 1 , 2 . Traditional solidification analyses of pure materials and alloys employ the energy and species assays when analyzing solid-liquid transformations that rely on \"Stefan balances” 3 . Stefan balances directly relate interfacial growth speed to first-order energy and solute exchanges. Stefan balances, consequently, overlook higher-order energy and solute contributions that subtly derive from the higher-order actions of capillary forces, and represent small, but significant, deterministic interface perturbations that affect solidification kinetics. Along with several other investigations, e.g., 4 , 5 , the present authors developed precision post-processing numerical methods that analyzed and measured interfacial parameters using multiphase-field simulations of selected stationary microstructures. Steady-state simulations allow measurement of interfacial temperature fields along curved diffuse interfaces, described numerically by \"isolines” of their paired phase-field indices 6 , 7 , 8 . Results from those studies, when compared with predictions derived from variational analyses of similarly shaped, but perfectly sharp, solid-liquid ( s / ℓ ) profiles, led to understanding and appreciation of how capillary-mediated interfacial energy sources and sinks arise deterministically, modify interface energy balances in pure systems, and ultimately influence interface motion and pattern-formation dynamics. Hard experimental evidence, however, still eludes us, and is needed to elucidate interface capillary effects, and to support the exploration of follow-on efforts to control them in practical solidification and crystal growth processes. How, for example, would one determine whether or not capillary-mediated interfacial energy exchanges and species transfer—in addition to just random noise 9 , 10 —impart significant influence on interface dynamics, stability, and pattern formation? The present absence of needed experimental evidence is due to as yet unmet challenges in the experimental measurements needed to probe minuscule milli-Kelvin temperature variations occurring over micrometer interfacial length scales, and to accomplish these difficult measurements on moving interfaces at their melting temperature. The purpose of this paper is to provide a wider awareness of higher-order interfacial capillary effects to researchers interested in exploring further uses of the microgravity environment for basic solidification research aboard NASA’s ISS-National Laboratory. Theory and new examples are provided herein to demonstrate the presence of deterministic—and thus controllable—capillary fields that act on selected two-phase microstructures in pure crystal-melt systems. The now classical analyses of solid-liquid interfacial stability, by Mullins and Sekerka, and, independently, that by Voronkov, describe linear dynamics of random perturbations acting on planar interfaces and spherical precipitates 11 , 12 , 13 . The basis functions with which these investigators chose to represent \"random” interfacial disturbances mathematically along isotropic planar s / ℓ interfaces were 2-D sinusoids, with waveforms described as \$y=\\delta \\sin {k}_{x}x\$ . Here x and y are a perturbation’s physical coordinates; δ is the wave’s y -amplitude; and k x = 2 π / λ is an arbitrary wavenumber [m −1 ], the value of which is the number of cycles (waves) per unit distance in the x -direction. The wavenumber admits all possible wavelengths, λ , from near zero, up to the size of the planar solidification front. Their choice of a \"spectrum” of sinusoidal perturbations underscores their stochastic description of interfacial disturbances—now a well-understood approach, and widely accepted by the solidification and crystal growth communities. Most notably perhaps, linear stability theory in its long-wave limit, captures and integrates all the results of constitutional supercooling theory, which was the prior accepted stability paradigm for s / ℓ interfaces of the 1950s 14 . More than a century ago, however, Henry Poincaré cautioned about assigning randomness to \"explain” ostensibly chaotic events observed in physics and elsewhere, stating that, A very small cause that escapes our notice determines a considerable effect that we cannot fail to see, and then we say that the effect is due to chance. (Science et Méthode,1908). Interfacial instability and microstructure pattern formation, in our opinion, remain no exceptions to Poincaré’s prescient warning about randomness. Fifty years ago, however, it was already demonstrated by direct observations 15 that planar interfaces can spontaneously and reproducibly initiate deterministic , not random, instabilities and patterns. Specifically, interfacial instabilities in dilute alloys and nominally pure melts evolve into cells and then dendrites—ubiquitous s / ℓ microstructures found in metal ingots and castings, which were described two decades earlier by Bruce Chalmers and his co-workers 16 , 17 . The sequence of instabilities observed on otherwise featureless s / ℓ interfaces always occurred where grain boundaries, sub-boundaries, or even single dislocations, intersected the interface. Deterministic instabilities amplified around grain boundary intersections into 2-D single and double ridges, which then split into periodic chains of 3-D hillocks. Isolated single and double rings also reproducibly formed where individual dislocations intersected the s / ℓ interface. In regions that lacked significant substructure, a more chaotic surface pattern gradually evolved, which encroached from remote edge-meniscuses that always surround s / ℓ interfaces where they contact their confining crucible walls. More recently, Shang and co-workers used phase-field methods to conclude, that the underlying mechanism for dendritic side branching was deterministic rather than stochastic, and that anisotropy and curvature, not noise, were the most important factors determining detailed microstructure 18 . It was not known, until recently, whether deterministic", "role": "user" }, { "content": "Florida Tech professor emeritus Martin Glicksman's latest metals/materials science research has implications for the metal casting industry, but it also has a profound personal connection inspired by two late colleagues. Glicksman's research, \"Surface Laplacian of interfacial thermochemical potential: itsrole in solid-liquid pattern formation,\" was published in the November edition of Springer Nature's partner journal Microgravity. The findings may lead to a better understanding of the solidification of metal castings, allowing for engineers to potentially make longer-lasting engines and stronger aircraft and advance additive manufacturing. \"The casting, welding, and primary metals production are all multi-billion-dollar businesses of great societal importance, when you think about steel, aluminum, copper—all important engineering materials,\" Glicksman said. \"You can appreciate we're talking about materials, for which even small improvements are worth a lot.\" Much as crystals form when water freezes, similar things occur when a molten metal alloy is solidified to create cast products. Glicksman's research reveals that during solidification of the metal alloy, surface tension between crystal and melt, as well as the curvature variations of crystals during growth, drives heat flow, even on stationary interfaces. This basic discovery is fundamentally different from the commonly used Stefan balances in casting theory, where the heat energy emitted from a growing crystal is proportional to its growth speed. Glicksman noted that crystallite's curvature reflects its chemical potential: a convex curvature slightly lowers the melting point, while a concave curvature slightly raises the melting point. That is well known from thermodynamics. What is new, and now proven, is that gradients of that curvature can induce additional heat flows during solidification that are not considered in conventional casting theories. Moreover, these heat flows are \"deterministic\" not stochastic, like random noise, and could, in principle, be controlled to advantage during casting processes to modify alloy microstructures and improve properties. \"When you have complicated crystalline microstructures freezing, curvature-induced heat flows occur that could be controlled,\" Glicksman said. \"Those heat flows in the case of a real alloy casting could, if controlled by chemical additions or physical effects, such as pressure or strong magnetic fields, improve the microstructure, which ultimately controls the chemical and mechanical properties of cast alloys, welded structures and even 3D-printed materials.\" Beyond its scientific significance, this research is of great personal importance to Glicksman largely due to late colleagues who helped support it. One of those colleagues is Paul Steen, a fluid mechanics professor at Cornell University who passed away last year. Steen had helped Glicksman with microgravity materials research years ago, utilizing space shuttle fluid mechanics and materials research. Springer Nature dedicated the November issue of Microgravity to Steen and contacted Glicksman about writing a scientific paper in his memory concerning this research. \"It spurred me on to put something together that was interesting, and that Paul would have especially appreciated. And of course, many readers looking at this research paper are also interested in areas that Paul contributed to, which is interfacial thermodynamics,\" Glicksman said. Another colleague who inspired Glicksman's paper was Semen Koksal, a Florida Tech mathematics professor, department head and academic affairs vice president who passed away in March 2020. Glicksman described her as a kind, intelligent person who was a delight to be around, noting that she was helpful providing her mathematical expertise to his research. \"She and I were good buddies, and she was deeply interested in my work. Semen helped me when I was stuck formulating the differential equations to explain the phenomenon of curvature-induced heat flow,\" Glicksman said. \"We spent a lot of time discussing my equations and how to formulate them, their restrictions, and so on. She was a person I consulted with and was so helpful in formulating the mathematical theory and helping me to get it right.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Steady-state solid-liquid interfaces allow both analytic description as sharp-interface profiles, and numerical simulation via phase-field modeling as stationary diffuse-interface microstructures. Profiles for sharp interfaces reveal their exact shapes and allow identification of the thermodynamic origin of all interfacial capillary fields, including distributions of curvature, thermochemical potential, gradients, fluxes, and surface Laplacians. By contrast, simulated diffuse interface images allow thermodynamic evolution and measurement of interfacial temperatures and fluxes. Quantitative results using both approaches verify these capillary fields and their divergent heat flow, to provide insights into interface energy balances, dynamic pattern formation, and novel methods for microstructure control. The microgravity environment of low-Earth orbit was proven useful in past studies of solidification phenomena. We suggest that NASA’s ISS National Lab can uniquely accommodate aspects of experimental research needed to explore these novel topics. Introduction Over the past decade, one of the present authors published studies applying field-theoretic methods to identify and quantitate interfacial thermodynamic fields 1 , 2 . Traditional solidification analyses of pure materials and alloys employ the energy and species assays when analyzing solid-liquid transformations that rely on "Stefan balances” 3 . Stefan balances directly relate interfacial growth speed to first-order energy and solute exchanges. Stefan balances, consequently, overlook higher-order energy and solute contributions that subtly derive from the higher-order actions of capillary forces, and represent small, but significant, deterministic interface perturbations that affect solidification kinetics. Along with several other investigations, e.g., 4 , 5 , the present authors developed precision post-processing numerical methods that analyzed and measured interfacial parameters using multiphase-field simulations of selected stationary microstructures. Steady-state simulations allow measurement of interfacial temperature fields along curved diffuse interfaces, described numerically by "isolines” of their paired phase-field indices 6 , 7 , 8 . Results from those studies, when compared with predictions derived from variational analyses of similarly shaped, but perfectly sharp, solid-liquid ( s / ℓ ) profiles, led to understanding and appreciation of how capillary-mediated interfacial energy sources and sinks arise deterministically, modify interface energy balances in pure systems, and ultimately influence interface motion and pattern-formation dynamics. Hard experimental evidence, however, still eludes us, and is needed to elucidate interface capillary effects, and to support the exploration of follow-on efforts to control them in practical solidification and crystal growth processes. How, for example, would one determine whether or not capillary-mediated interfacial energy exchanges and species transfer—in addition to just random noise 9 , 10 —impart significant influence on interface dynamics, stability, and pattern formation? The present absence of needed experimental evidence is due to as yet unmet challenges in the experimental measurements needed to probe minuscule milli-Kelvin temperature variations occurring over micrometer interfacial length scales, and to accomplish these difficult measurements on moving interfaces at their melting temperature. The purpose of this paper is to provide a wider awareness of higher-order interfacial capillary effects to researchers interested in exploring further uses of the microgravity environment for basic solidification research aboard NASA’s ISS-National Laboratory. Theory and new examples are provided herein to demonstrate the presence of deterministic—and thus controllable—capillary fields that act on selected two-phase microstructures in pure crystal-melt systems. The now classical analyses of solid-liquid interfacial stability, by Mullins and Sekerka, and, independently, that by Voronkov, describe linear dynamics of random perturbations acting on planar interfaces and spherical precipitates 11 , 12 , 13 . The basis functions with which these investigators chose to represent "random” interfacial disturbances mathematically along isotropic planar s / ℓ interfaces were 2-D sinusoids, with waveforms described as $y=\delta \sin {k}_{x}x$ . Here x and y are a perturbation’s physical coordinates; δ is the wave’s y -amplitude; and k x = 2 π / λ is an arbitrary wavenumber [m −1 ], the value of which is the number of cycles (waves) per unit distance in the x -direction. The wavenumber admits all possible wavelengths, λ , from near zero, up to the size of the planar solidification front. Their choice of a "spectrum” of sinusoidal perturbations underscores their stochastic description of interfacial disturbances—now a well-understood approach, and widely accepted by the solidification and crystal growth communities. Most notably perhaps, linear stability theory in its long-wave limit, captures and integrates all the results of constitutional supercooling theory, which was the prior accepted stability paradigm for s / ℓ interfaces of the 1950s 14 . More than a century ago, however, Henry Poincaré cautioned about assigning randomness to "explain” ostensibly chaotic events observed in physics and elsewhere, stating that, A very small cause that escapes our notice determines a considerable effect that we cannot fail to see, and then we say that the effect is due to chance. (Science et Méthode,1908). Interfacial instability and microstructure pattern formation, in our opinion, remain no exceptions to Poincaré’s prescient warning about randomness. Fifty years ago, however, it was already demonstrated by direct observations 15 that planar interfaces can spontaneously and reproducibly initiate deterministic , not random, instabilities and patterns. Specifically, interfacial instabilities in dilute alloys and nominally pure melts evolve into cells and then dendrites—ubiquitous s / ℓ microstructures found in metal ingots and castings, which were described two decades earlier by Bruce Chalmers and his co-workers 16 , 17 . The sequence of instabilities observed on otherwise featureless s / ℓ interfaces always occurred where grain boundaries, sub-boundaries, or even single dislocations, intersected the interface. Deterministic instabilities amplified around grain boundary intersections into 2-D single and double ridges, which then split into periodic chains of 3-D hillocks. Isolated single and double rings also reproducibly formed where individual dislocations intersected the s / ℓ interface. In regions that lacked significant substructure, a more chaotic surface pattern gradually evolved, which encroached from remote edge-meniscuses that always surround s / ℓ interfaces where they contact their confining crucible walls. More recently, Shang and co-workers used phase-field methods to conclude, that the underlying mechanism for dendritic side branching was deterministic rather than stochastic, and that anisotropy and curvature, not noise, were the most important factors determining detailed microstructure 18 . It was not known, until recently, whether deterministic<|im_end|> <|im_start|>assistant Florida Tech professor emeritus Martin Glicksman's latest metals/materials science research has implications for the metal casting industry, but it also has a profound personal connection inspired by two late colleagues. Glicksman's research, "Surface Laplacian of interfacial thermochemical potential: itsrole in solid-liquid pattern formation," was published in the November edition of Springer Nature's partner journal Microgravity. The findings may lead to a better understanding of the solidification of metal castings, allowing for engineers to potentially make longer-lasting engines and stronger aircraft and advance additive manufacturing. "The casting, welding, and primary metals production are all multi-billion-dollar businesses of great societal importance, when you think about steel, aluminum, copper—all important engineering materials," Glicksman said. "You can appreciate we're talking about materials, for which even small improvements are worth a lot." Much as crystals form when water freezes, similar things occur when a molten metal alloy is solidified to create cast products. Glicksman's research reveals that during solidification of the metal alloy, surface tension between crystal and melt, as well as the curvature variations of crystals during growth, drives heat flow, even on stationary interfaces. This basic discovery is fundamentally different from the commonly used Stefan balances in casting theory, where the heat energy emitted from a growing crystal is proportional to its growth speed. Glicksman noted that crystallite's curvature reflects its chemical potential: a convex curvature slightly lowers the melting point, while a concave curvature slightly raises the melting point. That is well known from thermodynamics. What is new, and now proven, is that gradients of that curvature can induce additional heat flows during solidification that are not considered in conventional casting theories. Moreover, these heat flows are "deterministic" not stochastic, like random noise, and could, in principle, be controlled to advantage during casting processes to modify alloy microstructures and improve properties. "When you have complicated crystalline microstructures freezing, curvature-induced heat flows occur that could be controlled," Glicksman said. "Those heat flows in the case of a real alloy casting could, if controlled by chemical additions or physical effects, such as pressure or strong magnetic fields, improve the microstructure, which ultimately controls the chemical and mechanical properties of cast alloys, welded structures and even 3D-printed materials." Beyond its scientific significance, this research is of great personal importance to Glicksman largely due to late colleagues who helped support it. One of those colleagues is Paul Steen, a fluid mechanics professor at Cornell University who passed away last year. Steen had helped Glicksman with microgravity materials research years ago, utilizing space shuttle fluid mechanics and materials research. Springer Nature dedicated the November issue of Microgravity to Steen and contacted Glicksman about writing a scientific paper in his memory concerning this research. "It spurred me on to put something together that was interesting, and that Paul would have especially appreciated. And of course, many readers looking at this research paper are also interested in areas that Paul contributed to, which is interfacial thermodynamics," Glicksman said. Another colleague who inspired Glicksman's paper was Semen Koksal, a Florida Tech mathematics professor, department head and academic affairs vice president who passed away in March 2020. Glicksman described her as a kind, intelligent person who was a delight to be around, noting that she was helpful providing her mathematical expertise to his research. "She and I were good buddies, and she was deeply interested in my work. Semen helped me when I was stuck formulating the differential equations to explain the phenomenon of curvature-induced heat flow," Glicksman said. "We spent a lot of time discussing my equations and how to formulate them, their restrictions, and so on. She was a person I consulted with and was so helpful in formulating the mathematical theory and helping me to get it right." <|im_end|>

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60022, 11, 323, 6156, 37182, 5788, 527, 682, 7447, 70173, 54135, 9873, 315, 2294, 59529, 12939, 11, 994, 499, 1781, 922, 9699, 11, 25674, 11, 24166, 87247, 3062, 15009, 7384, 1359, 480, 1228, 82, 1543, 1071, 13, 330, 2675, 649, 15763, 584, 2351, 7556, 922, 7384, 11, 369, 902, 1524, 2678, 18637, 527, 5922, 264, 2763, 1210, 24191, 439, 48473, 1376, 994, 3090, 94477, 11, 4528, 2574, 12446, 994, 264, 22337, 2002, 9501, 46964, 374, 6573, 1908, 311, 1893, 6445, 3956, 13, 480, 1228, 82, 1543, 596, 3495, 21667, 430, 2391, 6573, 2461, 315, 279, 9501, 46964, 11, 7479, 24408, 1990, 26110, 323, 30099, 11, 439, 1664, 439, 279, 83233, 27339, 315, 48473, 2391, 6650, 11, 20722, 8798, 6530, 11, 1524, 389, 53735, 25066, 13, 1115, 6913, 18841, 374, 43593, 2204, 505, 279, 17037, 1511, 50002, 39954, 304, 25146, 10334, 11, 1405, 279, 8798, 4907, 48042, 505, 264, 7982, 26110, 374, 55272, 311, 1202, 6650, 4732, 13, 480, 1228, 82, 1543, 10555, 430, 64568, 635, 596, 83233, 27053, 1202, 11742, 4754, 25, 264, 67030, 83233, 10284, 73115, 279, 50684, 1486, 11, 1418, 264, 3613, 525, 83233, 10284, 25930, 279, 50684, 1486, 13, 3011, 374, 1664, 3967, 505, 30945, 80011, 13, 3639, 374, 502, 11, 323, 1457, 17033, 11, 374, 430, 53249, 315, 430, 83233, 649, 49853, 5217, 8798, 28555, 2391, 6573, 2461, 430, 527, 539, 6646, 304, 21349, 25146, 26018, 13, 23674, 11, 1521, 8798, 28555, 527, 330, 67, 16890, 4633, 1, 539, 96340, 11, 1093, 4288, 12248, 11, 323, 1436, 11, 304, 17966, 11, 387, 14400, 311, 9610, 2391, 25146, 11618, 311, 5719, 46964, 8162, 47194, 323, 7417, 6012, 13, 330, 4599, 499, 617, 17395, 64568, 483, 8162, 47194, 43318, 11, 83233, 38973, 8798, 28555, 12446, 430, 1436, 387, 14400, 1359, 480, 1228, 82, 1543, 1071, 13, 330, 23025, 8798, 28555, 304, 279, 1162, 315, 264, 1972, 46964, 25146, 1436, 11, 422, 14400, 555, 11742, 38314, 477, 7106, 6372, 11, 1778, 439, 7410, 477, 3831, 24924, 5151, 11, 7417, 279, 8162, 7993, 11, 902, 13967, 11835, 279, 11742, 323, 22936, 6012, 315, 6445, 95851, 11, 82161, 14726, 323, 1524, 220, 18, 35, 43245, 291, 7384, 1210, 31886, 1202, 12624, 26431, 11, 420, 3495, 374, 315, 2294, 4443, 12939, 311, 480, 1228, 82, 1543, 14090, 4245, 311, 3389, 18105, 889, 9087, 1862, 433, 13, 3861, 315, 1884, 18105, 374, 7043, 3441, 268, 11, 264, 15962, 30126, 14561, 520, 56819, 3907, 889, 5946, 3201, 1566, 1060, 13, 3441, 268, 1047, 9087, 480, 1228, 82, 1543, 449, 8162, 71891, 7384, 3495, 1667, 4227, 11, 35988, 3634, 45641, 15962, 30126, 323, 7384, 3495, 13, 67915, 22037, 12514, 279, 6841, 4360, 315, 18654, 71891, 311, 3441, 268, 323, 25559, 480, 1228, 82, 1543, 922, 4477, 264, 12624, 5684, 304, 813, 5044, 18815, 420, 3495, 13, 330, 2181, 85747, 757, 389, 311, 2231, 2555, 3871, 430, 574, 7185, 11, 323, 430, 7043, 1053, 617, 5423, 26893, 13, 1628, 315, 3388, 11, 1690, 13016, 3411, 520, 420, 3495, 5684, 527, 1101, 8173, 304, 5789, 430, 7043, 20162, 311, 11, 902, 374, 958, 22974, 532, 30945, 80011, 1359, 480, 1228, 82, 1543, 1071, 13, 13596, 37444, 889, 14948, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Epidermal growth factor receptor ( EGFR ) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC) 1 , 2 , 3 . Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations 4 , 5 , 6 . However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown 1 , 3 , 7 , 8 , 9 , 10 . Here we characterize the mutational landscape in 16,715 patients with EGFR -mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR -mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations. Main Patients with classical EGFR mutations (L858R or exon 19 deletions (Ex19del)) show marked improvements in clinical outcomes when treated with first-, second- or third-generation tyrosine kinase inhibitors (TKIs) 4 , 5 , 6 , 11 . Other EGFR mutations in the kinase domain (exons 18−21) have also been established as oncogenic drivers of NSCLC 8 . Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors 1 , 3 , 7 , 8 , 9 , 10 , including osimertinib 12 . Atypical EGFR mutations with US Food and Drug Administration (FDA)-approved treatments are EGFR S768I, L861Q and G719X, for which afatinib was deemed effective on the basis of retrospective studies 13 , 14 , 15 , and the EGFR/MET bispecific antibody amivantamab for exon 20 insertions (Ex20ins) 16 . There are no clear established guidelines for EGFR TKI treatment for patients with atypical EGFR mutations without an FDA-approved TKI, often resulting in patients receiving chemotherapy. Clinical trial design and treatment of patients with atypical EGFR mutations often rely on mutated-exon location to predict treatment, although heterogeneity in drug sensitivity across a single exon has been observed 1 , 8 , 17 . Therefore, there is an unmet clinical need to establish a system for classifying EGFR mutations that is predictive of drug sensitivity and for more robust clinical trial design. Clinical outcomes for atypical mutations To characterize the molecular landscape of EGFR -mutant NSCLC, we used 5 patient databases with genomic profiling ( Methods ), representing 16,715 patients with EGFR -mutant NSCLC. There were 11,619 patients in whom primary and/or co-occurring mutations were recorded on a per-patient basis (Extended Data Fig. 1a ). Among those patients, 67.1% had classical EGFR mutations (L858R and/or Ex19del with or without T790M); 30.8% had atypical EGFR mutations, including Ex20ins (9.1%), atypical mutations (12.6%), or a complex mutation including an atypical mutation (9.1%); and 2.2% had a classical mutation with T790M and an atypical mutation (Fig. 1a , Extended Data Fig. 1b ). Atypical EGFR mutations ( n = 7,199) occurred primarily in exons 18 (23.7%) and 20 (20.9% insertions and 19.2% point mutations; Fig. 1b ). Prevalent hotspots for atypical mutations were the P-loop (L718–V726, 13.6%) and the C-terminal loop of the αC-helix (A767–G779, 29.4%, Fig. 1c ). Fig. 1: Atypical EGFR mutations are associated with worse patient outcomes. a , Percentage of patients with NSCLC containing classical and atypical EGFR mutations ( n = 11,619 patients). Classical EGFR mutations are L858R, T790M and various Ex19dels ( Methods ). b , Percentage of atypical EGFR mutations observed in patients with NSCLC ( n = 7,199 mutations). Atypical EGFR mutations are defined as non-classical, non-synonymous mutations. c , Lollipop plot of frequency of atypical EGFR mutations in patients with NSCLC ( n = 7,199 mutations). EGFR mutations associated with acquired drug resistance are highlighted in red. d , Kaplan–Meier plot of time to treatment failure (TTF) (time from TKI commencement until radiologic progression, discontinuation, or death) of patients with NSCLC tumours containing classical ( n = 245 patients) or atypical ( n = 109 patients) EGFR mutations after EGFR TKI treatment. e , Forest plot of HR calculated from Kaplan–Meier plots of patients with various subsets of atypical mutations or classical EGFR mutations. In d , e , HR and P value were calculated using two-sided Mantel–Cox log-rank tests. Data are HR ± 95% confidence interval. All atypical, n = 109; all atypical without Ex20ins, n = 97; exon 18, n = 29; exon 19, n = 22; exon 20, n = 41; exon 21, n = 18. NS, not significant. Source data . Full size image To assess the effect of atypical EGFR mutations on patient outcomes, we determined the time to treatment failure 18 (TTF) of patients with NSCLC containing classical or atypical EGFR mutations. When treated with an EGFR TKI, patients with atypical EGFR mutations had a shorter TTF compared with patients with classical EGFR mutations (Fig. 1d , hazard ratio (HR) = 1.8, P < 0.0001), even when patients with Ex20ins were excluded from the analysis (Fig. 1e , HR = 1.6, P < 0.0001) or when patients were stratified by mutation exon location (Fig. 1e , Extended Data Fig. 1c ). When patients were stratified by TKI treatment, those with classical EGFR mutations had a longer TTF than those with atypical EGFR mutations when treated with first-generation (HR = 1.9, P = 0.0005) or third-generation TKIs (HR = 3.0, P < 0.0001) (Extended Data Fig. 1d, e ). A similar trend was observed for second-generation TKIs; however, the difference was not statistically significant (HR = 1.7, P = 0.10) (Extended Data Fig. 1f ). Validating these findings in the cBioPortal database, patients with atypical EGFR mutations had a shorter progression free interval 19 and overall survival,", "role": "user" }, { "content": "Researchers from The University of Texas MD Anderson Cancer Center have discovered that grouping epidermal growth factor receptor (EGFR) mutations by structure and function provides an accurate framework to match patients with non-small cell lung cancer (NSCLC) to the right drugs. The findings, published today in Nature, identify four subgroups of mutations and introduce a new strategy for testing tyrosine kinase inhibitors (TKIs), as well as instant clinical opportunities for approved targeted therapies. \"More than 70 different EGFR mutations have been identified in patients, but drugs have only been approved for a handful of them. One of the immediate implications of our research is the discovery that therapies we already have may work for many of these mutations. For some mutations, older drugs may actually work better, and for other mutations, newer drugs work better,\" said John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology and senior author of the study. \"Right now, in the absence of guidance, clinicians often use the newest treatment for all EGFR mutations. This model can help us pick better therapies for patients immediately and hopefully develop better drugs for specific subgroups of mutations.\" First-, second- and third-generation TKIs use different mechanisms to target the EGFR protein. Heymach and his team found that drugs work better for certain subgroups based on how the mutations within a given group functionally impact the drug-binding pocket on the protein. The four EGFR-mutant NSCLC subgroups identified by the team are: Classical-like mutations, with little to no impact on drug bindingT790M-like mutations, which contain at least one mutation in the hydrophobic cleft and often are acquired after resistance to a first-generation targeted therapyExon 20 loop insertion mutations, characterized by insertions of additional amino acids in the loop after the C-terminal end of the αC-helix in exon 20P-loop αC-helix compression (PACC) mutations on the interior surface of the ATP binding pocket or C-terminal end of the αC-helix The current approach to testing new drugs in EGFR-mutant NSCLC is based on exon number, which indicates where the mutation occurs within a linear portion of the DNA. Grouping mutations by exon has produced mostly heterogeneous results in clinical studies and laboratory models, which the authors note seems to indicate a poor correlation between exon number and drug sensitivity or resistance. \"Within a given exon, mutations vary widely. We organized mutations based on how they impact the EGFR structure and drug binding instead, which allows for testing a drug across a whole group of mutations that are structurally similar at the same time,\" Heymach said. \"We believe this could become the new standard approach for classifying and describing mutations and then pairing them with the right drug.\" Big data reveals diversity in atypical mutations Mutations in the EGFR protein are present in about 15% of NSCLCs in North America and about 30 to 40% in Asia. Overall, more than 70 different types of EGFR mutations exist. \"Classical\" mutations tend to respond well to FDA-approved targeted therapies, but effective therapies and guidelines for the remaining \"atypical\" mutations have been lacking. For this study, the researchers analyzed data from 16,175 patients with EGFR-mutant NSCLC from five different patient databases. Primary and co-occurring mutations were recorded for 11,619 patients. Of those, 67.1% had classical EGFR mutations, 30.8% had atypical EGFR mutations and 2.2% had both. One of the key databases to provide detailed molecular and outcome information for the study was the Genomic Marker-Guided Therapy Initiative (GEMINI), a big data project of the Lung Cancer Moon Shot, part of MD Anderson's Moon Shots Program, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients' lives. For both classical and atypical EGFR mutations, the team analyzed the time to treatment failure (TTF), an indication of how quickly a cancer becomes resistant to therapy. The researchers found a shorter TTF and lower overall survival for patients with atypical mutations regardless of treatment type. Patients with classical mutations treated with first- and third-generation TKIs had a longer TTF. The researchers then created a panel of 76 cell lines with EGFR mutations and screened those cell lines against 18 EGFR inhibitors, which revealed the four distinct subgroups. Comparing the correlation to drug sensitivity by subgroup, versus exons, showed that the structure-based subgroups were more predictive than exon-based groups. The subgroup approach was further validated by machine learning to analyze data by classification and regression trees. Classical-like mutations were sensitive to all classes of TKIs, particularly third-generation TKIs. Exon 20 loop insertion mutations remained the most heterogeneous subgroup, with certain mutations responding best to second-generation TKIs. T790M-like mutations were sensitive to ALK and PKC inhibitors, with some mutations retaining sensitivity to third-generation TKIs. PACC mutations were most sensitive to second-generation TKIs. \"Proteins aren't linear, so grouping mutations by exon didn't seem an intuitive approach to me when I started thinking about how to match the right drug to the right mutation seen in patients,\" said Jacqulyne Robichaux, Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology Research and lead author of the study. \"Proteins are three dimensional, and this led us to investigate if there were areas of the proteins that correlate with drug sensitivity when mutated, which is what we found. These subgroups share properties in their structure that directly relate to their function and retrospectively predicted patient outcomes better than the traditional approach.\" Further emphasis on the role of next-generation sequencing and future studies The study also highlights the importance of biomarker testing for all patients with a new diagnosis or recurrence of NSCLC. Current next-generation sequencing methods have the ability to detect the full spectrum of known oncogenic driver EGFR mutations, virtually all of which fall into one of the four structure-based subgroups. The authors note that this is especially important for rare mutations, which are more difficult to study through a traditional clinical trial approach based on individual mutations. Future prospective studies will help refine and inform the subgroup framework. \"This is an important advance for patients because, right now, there is no FDA-approved targeted therapy for the majority of EGFR mutations, leaving clinicians in the dark as to what drug to use for which mutation,\" Heymach said. \"Now, based on the structural group in which the mutation falls, we can better match the best drug for a given mutation. Going forward, this may also help focus drug development efforts, by testing drugs against an entire group of mutations that are structurally similar, rather than against individual mutations.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Epidermal growth factor receptor ( EGFR ) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC) 1 , 2 , 3 . Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations 4 , 5 , 6 . However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown 1 , 3 , 7 , 8 , 9 , 10 . Here we characterize the mutational landscape in 16,715 patients with EGFR -mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR -mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations. Main Patients with classical EGFR mutations (L858R or exon 19 deletions (Ex19del)) show marked improvements in clinical outcomes when treated with first-, second- or third-generation tyrosine kinase inhibitors (TKIs) 4 , 5 , 6 , 11 . Other EGFR mutations in the kinase domain (exons 18−21) have also been established as oncogenic drivers of NSCLC 8 . Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors 1 , 3 , 7 , 8 , 9 , 10 , including osimertinib 12 . Atypical EGFR mutations with US Food and Drug Administration (FDA)-approved treatments are EGFR S768I, L861Q and G719X, for which afatinib was deemed effective on the basis of retrospective studies 13 , 14 , 15 , and the EGFR/MET bispecific antibody amivantamab for exon 20 insertions (Ex20ins) 16 . There are no clear established guidelines for EGFR TKI treatment for patients with atypical EGFR mutations without an FDA-approved TKI, often resulting in patients receiving chemotherapy. Clinical trial design and treatment of patients with atypical EGFR mutations often rely on mutated-exon location to predict treatment, although heterogeneity in drug sensitivity across a single exon has been observed 1 , 8 , 17 . Therefore, there is an unmet clinical need to establish a system for classifying EGFR mutations that is predictive of drug sensitivity and for more robust clinical trial design. Clinical outcomes for atypical mutations To characterize the molecular landscape of EGFR -mutant NSCLC, we used 5 patient databases with genomic profiling ( Methods ), representing 16,715 patients with EGFR -mutant NSCLC. There were 11,619 patients in whom primary and/or co-occurring mutations were recorded on a per-patient basis (Extended Data Fig. 1a ). Among those patients, 67.1% had classical EGFR mutations (L858R and/or Ex19del with or without T790M); 30.8% had atypical EGFR mutations, including Ex20ins (9.1%), atypical mutations (12.6%), or a complex mutation including an atypical mutation (9.1%); and 2.2% had a classical mutation with T790M and an atypical mutation (Fig. 1a , Extended Data Fig. 1b ). Atypical EGFR mutations ( n = 7,199) occurred primarily in exons 18 (23.7%) and 20 (20.9% insertions and 19.2% point mutations; Fig. 1b ). Prevalent hotspots for atypical mutations were the P-loop (L718–V726, 13.6%) and the C-terminal loop of the αC-helix (A767–G779, 29.4%, Fig. 1c ). Fig. 1: Atypical EGFR mutations are associated with worse patient outcomes. a , Percentage of patients with NSCLC containing classical and atypical EGFR mutations ( n = 11,619 patients). Classical EGFR mutations are L858R, T790M and various Ex19dels ( Methods ). b , Percentage of atypical EGFR mutations observed in patients with NSCLC ( n = 7,199 mutations). Atypical EGFR mutations are defined as non-classical, non-synonymous mutations. c , Lollipop plot of frequency of atypical EGFR mutations in patients with NSCLC ( n = 7,199 mutations). EGFR mutations associated with acquired drug resistance are highlighted in red. d , Kaplan–Meier plot of time to treatment failure (TTF) (time from TKI commencement until radiologic progression, discontinuation, or death) of patients with NSCLC tumours containing classical ( n = 245 patients) or atypical ( n = 109 patients) EGFR mutations after EGFR TKI treatment. e , Forest plot of HR calculated from Kaplan–Meier plots of patients with various subsets of atypical mutations or classical EGFR mutations. In d , e , HR and P value were calculated using two-sided Mantel–Cox log-rank tests. Data are HR ± 95% confidence interval. All atypical, n = 109; all atypical without Ex20ins, n = 97; exon 18, n = 29; exon 19, n = 22; exon 20, n = 41; exon 21, n = 18. NS, not significant. Source data . Full size image To assess the effect of atypical EGFR mutations on patient outcomes, we determined the time to treatment failure 18 (TTF) of patients with NSCLC containing classical or atypical EGFR mutations. When treated with an EGFR TKI, patients with atypical EGFR mutations had a shorter TTF compared with patients with classical EGFR mutations (Fig. 1d , hazard ratio (HR) = 1.8, P < 0.0001), even when patients with Ex20ins were excluded from the analysis (Fig. 1e , HR = 1.6, P < 0.0001) or when patients were stratified by mutation exon location (Fig. 1e , Extended Data Fig. 1c ). When patients were stratified by TKI treatment, those with classical EGFR mutations had a longer TTF than those with atypical EGFR mutations when treated with first-generation (HR = 1.9, P = 0.0005) or third-generation TKIs (HR = 3.0, P < 0.0001) (Extended Data Fig. 1d, e ). A similar trend was observed for second-generation TKIs; however, the difference was not statistically significant (HR = 1.7, P = 0.10) (Extended Data Fig. 1f ). Validating these findings in the cBioPortal database, patients with atypical EGFR mutations had a shorter progression free interval 19 and overall survival,<|im_end|> <|im_start|>assistant Researchers from The University of Texas MD Anderson Cancer Center have discovered that grouping epidermal growth factor receptor (EGFR) mutations by structure and function provides an accurate framework to match patients with non-small cell lung cancer (NSCLC) to the right drugs. The findings, published today in Nature, identify four subgroups of mutations and introduce a new strategy for testing tyrosine kinase inhibitors (TKIs), as well as instant clinical opportunities for approved targeted therapies. "More than 70 different EGFR mutations have been identified in patients, but drugs have only been approved for a handful of them. One of the immediate implications of our research is the discovery that therapies we already have may work for many of these mutations. For some mutations, older drugs may actually work better, and for other mutations, newer drugs work better," said John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology and senior author of the study. "Right now, in the absence of guidance, clinicians often use the newest treatment for all EGFR mutations. This model can help us pick better therapies for patients immediately and hopefully develop better drugs for specific subgroups of mutations." First-, second- and third-generation TKIs use different mechanisms to target the EGFR protein. Heymach and his team found that drugs work better for certain subgroups based on how the mutations within a given group functionally impact the drug-binding pocket on the protein. The four EGFR-mutant NSCLC subgroups identified by the team are: Classical-like mutations, with little to no impact on drug bindingT790M-like mutations, which contain at least one mutation in the hydrophobic cleft and often are acquired after resistance to a first-generation targeted therapyExon 20 loop insertion mutations, characterized by insertions of additional amino acids in the loop after the C-terminal end of the αC-helix in exon 20P-loop αC-helix compression (PACC) mutations on the interior surface of the ATP binding pocket or C-terminal end of the αC-helix The current approach to testing new drugs in EGFR-mutant NSCLC is based on exon number, which indicates where the mutation occurs within a linear portion of the DNA. Grouping mutations by exon has produced mostly heterogeneous results in clinical studies and laboratory models, which the authors note seems to indicate a poor correlation between exon number and drug sensitivity or resistance. "Within a given exon, mutations vary widely. We organized mutations based on how they impact the EGFR structure and drug binding instead, which allows for testing a drug across a whole group of mutations that are structurally similar at the same time," Heymach said. "We believe this could become the new standard approach for classifying and describing mutations and then pairing them with the right drug." Big data reveals diversity in atypical mutations Mutations in the EGFR protein are present in about 15% of NSCLCs in North America and about 30 to 40% in Asia. Overall, more than 70 different types of EGFR mutations exist. "Classical" mutations tend to respond well to FDA-approved targeted therapies, but effective therapies and guidelines for the remaining "atypical" mutations have been lacking. For this study, the researchers analyzed data from 16,175 patients with EGFR-mutant NSCLC from five different patient databases. Primary and co-occurring mutations were recorded for 11,619 patients. Of those, 67.1% had classical EGFR mutations, 30.8% had atypical EGFR mutations and 2.2% had both. One of the key databases to provide detailed molecular and outcome information for the study was the Genomic Marker-Guided Therapy Initiative (GEMINI), a big data project of the Lung Cancer Moon Shot, part of MD Anderson's Moon Shots Program, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients' lives. For both classical and atypical EGFR mutations, the team analyzed the time to treatment failure (TTF), an indication of how quickly a cancer becomes resistant to therapy. The researchers found a shorter TTF and lower overall survival for patients with atypical mutations regardless of treatment type. Patients with classical mutations treated with first- and third-generation TKIs had a longer TTF. The researchers then created a panel of 76 cell lines with EGFR mutations and screened those cell lines against 18 EGFR inhibitors, which revealed the four distinct subgroups. Comparing the correlation to drug sensitivity by subgroup, versus exons, showed that the structure-based subgroups were more predictive than exon-based groups. The subgroup approach was further validated by machine learning to analyze data by classification and regression trees. Classical-like mutations were sensitive to all classes of TKIs, particularly third-generation TKIs. Exon 20 loop insertion mutations remained the most heterogeneous subgroup, with certain mutations responding best to second-generation TKIs. T790M-like mutations were sensitive to ALK and PKC inhibitors, with some mutations retaining sensitivity to third-generation TKIs. PACC mutations were most sensitive to second-generation TKIs. "Proteins aren't linear, so grouping mutations by exon didn't seem an intuitive approach to me when I started thinking about how to match the right drug to the right mutation seen in patients," said Jacqulyne Robichaux, Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology Research and lead author of the study. "Proteins are three dimensional, and this led us to investigate if there were areas of the proteins that correlate with drug sensitivity when mutated, which is what we found. These subgroups share properties in their structure that directly relate to their function and retrospectively predicted patient outcomes better than the traditional approach." Further emphasis on the role of next-generation sequencing and future studies The study also highlights the importance of biomarker testing for all patients with a new diagnosis or recurrence of NSCLC. Current next-generation sequencing methods have the ability to detect the full spectrum of known oncogenic driver EGFR mutations, virtually all of which fall into one of the four structure-based subgroups. The authors note that this is especially important for rare mutations, which are more difficult to study through a traditional clinical trial approach based on individual mutations. Future prospective studies will help refine and inform the subgroup framework. "This is an important advance for patients because, right now, there is no FDA-approved targeted therapy for the majority of EGFR mutations, leaving clinicians in the dark as to what drug to use for which mutation," Heymach said. "Now, based on the structural group in which the mutation falls, we can better match the best drug for a given mutation. Going forward, this may also help focus drug development efforts, by testing drugs against an entire group of mutations that are structurally similar, rather than against individual mutations." <|im_end|>

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2,984

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Light-dependent or light-stimulated catalysis provides a multitude of perspectives for implementation in technological or biomedical applications. Despite substantial progress made in the field of photobiocatalysis, the number of usable light-responsive enzymes is still very limited. Flavoproteins have exceptional potential for photocatalytic applications because the name-giving cofactor intrinsically features light-dependent reactivity, undergoing photoreduction with a variety of organic electron donors. However, in the vast majority of these enzymes, photoreactivity of the enzyme-bound flavin is limited or even suppressed. Here, we present a flavoprotein monooxygenase in which catalytic activity is controllable by blue light illumination. The reaction depends on the presence of nicotinamide nucleotide-type electron donors, which do not support the reaction in the absence of light. Employing various experimental approaches, we demonstrate that catalysis depends on a protein-mediated photoreduction of the flavin cofactor, which proceeds via a radical mechanism and a transient semiquinone intermediate. Introduction Photoswitchable catalysts hold great promise for a variety of applications. It is therefore not surprising that substantial efforts are made for the development of artificial photochemical catalysts, photoenzymes 1 , and synthetic optogenetic tools 2 . Based on the photochemical properties of flavin, flavoproteins bear particularly great potential for optoenzymatic applications. For example, naturally occurring flavin cofactors such as FMN and FAD are known to undergo photoinduced reduction 3 . In the process, various electron donors, such as amino acids, aromatic compounds, EDTA, but also intramolecular substituents are oxidized 4 . However, so far, only a handful of flavin photoproteins have been identified. Amongst them, the ubiquitous and well-characterized group of DNA photolyases is difficult to exploit for biotechnological applications due to their sophisticated adaptations to the DNA substrate. Another heterogeneous class of flavin photoproteins comprising LOV domains, BLUF proteins, and cryptochromes employ the photoactivated flavin redox cycle for signaling purposes without the involvement of an external organic substrate. While major breakthroughs were made in the photochemical use of flavin ene-reductases 5 , 6 , 7 and the recently discovered photodecarboxylase 8 , 9 , the applicability of most flavoproteins is impeded due to efficient shielding of protein-bound cofactors against light-induced excitation 10 . Most likely, the prevention of photoinduced generation of reactive oxygen species in the cellular environment, usually achieved by efficient quenching of singlet or triplet excited states 11 , has been a strong selective pressure in the evolution of these enzymes. It is therefore generally accepted that photoreduction, when observed in flavoenzymes, can be attributed to photoreactivity of free flavin, which is present in small quantities in most flavoprotein preparations due to degradation and/or binding equilibria 10 . Undirected, diffusive charge transfer subsequently leads to the observed reduction of the protein-internal flavin cofactor. This mechanism has been extensively tested for biotechnological application with various classes of non-photochemically accessible flavoenzymes 12 . In this study, we show that the catalytic activity of the flavoprotein monooxygenase (FPMO) PqsL can be triggered by blue-light illumination. The enzyme is involved in the biosynthesis of 2-alkyl-4-hydroxyquinoline N -oxides (AQNO) in the opportunistic pathogen Pseudomonas aeruginosa . It is homologous to group A FPMOs 13 and has a relatively high similarity to p -hydroxybenzoate hydroxylase (pHBH), the most thoroughly studied FPMO 14 . Group A monooxygenases usually hydroxylate mono- or polysubstituted aromatic rings and utilize NAD(P)H as hydride donor. In contrast, PqsL catalyzes the hydroxylation of an aromatic-amine group, a rather uncommon reaction, and remarkably shows no intrinsic catalytic activity with NAD(P)H as cosubstrate 15 . Here, we provide experimental evidence that the protein-internal FAD of PqsL is reduced by NAD(P)H in a light-dependent, enzyme-associated reaction which is severalfold faster than the photoreduction of free flavin. Structural and functional studies indicate that canonical transient binding of NAD(P)H is compatible with photoexcitation. Using an engineered variant of PqsL, we further demonstrate that stabilization of the protein-cofactor complex does not diminish photoreactivity, indicating that primarily the conformation of the flavin ring and its microenvironment are relevant for photoreduction. We moreover elucidate the charge transfer between NAD(P)H and FAD, in which the protein-bound flavin reacts similarly to free flavin, involving a two-step reaction with single-electron transfer, leading to a transient neutral semiquinone intermediate. Results Blue light induces catalytic activity of PqsL PqsL is a monooxygenase involved in AQNO biosynthesis in P. aeruginosa . Its catalytic activity was found to depend on the presence of reduced flavin, e.g., provided by a flavin reductase 15 . In that regard, the enzyme functions similarly to the two-component monooxygenases, in which the FAD cofactor migrates between a monooxygenase and a cognate reductase. In the process of analyzing PqsL cofactor exchange and charge transfer we discovered an interesting anomaly: the enzyme slowly oxidized NAD(P)H when the reaction was monitored in a spectrophotometer cuvette, whereas no consumption of the cosubstrate was observable when the reaction was analyzed by, e.g., HPLC. We concluded that the PqsL reductive half reaction must be positively influenced by light. To test our hypothesis, we analyzed if PqsL-catalyzed product formation could be observed with NAD(P)H as electron donor depending on whether the samples were illuminated or not. Due to instability of the PqsL reaction product 2-hydroxylaminobenzoylacetate (2-HABA), we used a coupled assay for detection in which the substrate, 2-aminobenzoylacetate (2-ABA), and 2-HABA are enzymatically converted to the stable alkyl quinolone derivatives 2-heptyl-4(1 H )-quinolone (HHQ) and 2-heptyl-4-hydroxyquinoline- N -oxide (HQNO), respectively (Fig. 1a ). Both compounds can then be quantified by HPLC. As displayed in Fig. 1b , HQNO formation increased as linear function of blue-light intensity whereas no product was detected in the dark, indicating that NAD(P)H is not accepted as electron donor in the absence of light. We also grew cultures of P. aeruginosa PAO1 with blue-light illumination under aerobic conditions. However, no difference in AQNO/non-AQNO metabolite ratio was observed. Instead a complex phenotype with reduced general levels of AQ pathway metabolites and other secondary metabolites such as phenazines was observed in response to illumination, which is consistent with previous reports 16 . Fig. 1: Blue-light-induced activity of PqsL. a Reaction of PqsL within the alkyl quinolone biosynthetic pathway. The downstream/parallel", "role": "user" }, { "content": "Enzymes are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this ability that makes them useful as catalysts in biotechnology, for example, to create chemical products such as pharmaceutics. A topic that is currently being widely discussed is photoinduced catalysis, in which researchers harness the ability to start biochemical reactions using light. This process requires enzymes that can be activated by means of light. It is not, however, a simple matter to incorporate the few naturally occurring light-activatable enzymes into biotechnological processes, as they are highly specialised and difficult to manipulate. Researchers at the Universities of Münster (Germany) and Pavia (Italy) have now identified an enzyme that becomes catalytically active when exposed to blue light and which immediately triggers a reaction hitherto unknown in enzymology. The reaction in question is a special monooxygenase reaction, in which an oxygen atom is transferred to the substrate. The reaction is supported by a helper molecule that delivers two electrons stepwise. Previously, it had been assumed that such a light-dependent reaction cannot occur in enzymes. \"The enzyme we have identified belongs to a very large family of enzymes, and it is realistic to assume that other enzymes that can be activated by light can be produced by means of genetic manipulation and used in a very wide range of applications,\" says Dr. Steffen L. Drees, who headed the study and works at the Institute of Molecular Microbiology and Biotechnology at Münster University. One possible application, for example, is the production of pharmaceuticals activated by means of light. The study has been published in the journal Nature Communications. In their study, the researchers investigated the enzyme PqsL, which is found in the opportunistic pathogen Pseudomonas aeruginosa and, originally was not light-dependent. The researchers stimulated the enzyme with blue light and analysed the reaction using a combination of time-resolved spectroscopic and crystallographic techniques. The enzyme belongs to the family of flavoproteins, and typically for this family of proteins, uses a derivative of vitamin B2 as a so-called cofactor for catalysing the incorporation of oxygen into organic molecules. The cosubstrate NADH (reduced nicotinamide adenine dinucleotide) is needed as a \"helper molecule\" for the enzymatic reaction, providing the necessary electrons. The reaction mechanism the researchers observed in their study was previously unknown. Activated by the exposure to light in the flavin-NADH complex, NADH transfers a single electron to the protein-bound flavin. In this way, a flavin radical is created—this is a highly reactive molecule characterised by an unpaired electron. Using time-resolved spectroscopy, the researchers were able to observe how the molecule formed and changed its state. The flavin radical has a very negative redox potential, which means that it has a large capacity for transferring electrons to reaction partners. \"Because of this property, we assume that the flavin radical can also enable additional reactions to take place, which would expand the catalytic potential of this enzyme—as well as of other enzymes too, perhaps,\" says group leader Prof. Susanne Fetzner. The enzyme identified is the only one so far that is not naturally photoactive, and carries out a light-independent reaction in the bacterial cell. \"The three-dimensional structure of the enzyme shows that the outward-facing flavin co-factor might be the key to photoactivation,\" says Simon Ernst, first author of the study. Photoactive enzymes enable a large number of applications—for example, multi-step catalysis in a one-vessel reaction or spatially resolved catalysis, for example, to functionalise surfaces in certain patterns. They can also be useful for so-called prodrug activation in the body or on the skin—this is a process in which a pharmacological substance becomes active only after metabolization in the organism. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Light-dependent or light-stimulated catalysis provides a multitude of perspectives for implementation in technological or biomedical applications. Despite substantial progress made in the field of photobiocatalysis, the number of usable light-responsive enzymes is still very limited. Flavoproteins have exceptional potential for photocatalytic applications because the name-giving cofactor intrinsically features light-dependent reactivity, undergoing photoreduction with a variety of organic electron donors. However, in the vast majority of these enzymes, photoreactivity of the enzyme-bound flavin is limited or even suppressed. Here, we present a flavoprotein monooxygenase in which catalytic activity is controllable by blue light illumination. The reaction depends on the presence of nicotinamide nucleotide-type electron donors, which do not support the reaction in the absence of light. Employing various experimental approaches, we demonstrate that catalysis depends on a protein-mediated photoreduction of the flavin cofactor, which proceeds via a radical mechanism and a transient semiquinone intermediate. Introduction Photoswitchable catalysts hold great promise for a variety of applications. It is therefore not surprising that substantial efforts are made for the development of artificial photochemical catalysts, photoenzymes 1 , and synthetic optogenetic tools 2 . Based on the photochemical properties of flavin, flavoproteins bear particularly great potential for optoenzymatic applications. For example, naturally occurring flavin cofactors such as FMN and FAD are known to undergo photoinduced reduction 3 . In the process, various electron donors, such as amino acids, aromatic compounds, EDTA, but also intramolecular substituents are oxidized 4 . However, so far, only a handful of flavin photoproteins have been identified. Amongst them, the ubiquitous and well-characterized group of DNA photolyases is difficult to exploit for biotechnological applications due to their sophisticated adaptations to the DNA substrate. Another heterogeneous class of flavin photoproteins comprising LOV domains, BLUF proteins, and cryptochromes employ the photoactivated flavin redox cycle for signaling purposes without the involvement of an external organic substrate. While major breakthroughs were made in the photochemical use of flavin ene-reductases 5 , 6 , 7 and the recently discovered photodecarboxylase 8 , 9 , the applicability of most flavoproteins is impeded due to efficient shielding of protein-bound cofactors against light-induced excitation 10 . Most likely, the prevention of photoinduced generation of reactive oxygen species in the cellular environment, usually achieved by efficient quenching of singlet or triplet excited states 11 , has been a strong selective pressure in the evolution of these enzymes. It is therefore generally accepted that photoreduction, when observed in flavoenzymes, can be attributed to photoreactivity of free flavin, which is present in small quantities in most flavoprotein preparations due to degradation and/or binding equilibria 10 . Undirected, diffusive charge transfer subsequently leads to the observed reduction of the protein-internal flavin cofactor. This mechanism has been extensively tested for biotechnological application with various classes of non-photochemically accessible flavoenzymes 12 . In this study, we show that the catalytic activity of the flavoprotein monooxygenase (FPMO) PqsL can be triggered by blue-light illumination. The enzyme is involved in the biosynthesis of 2-alkyl-4-hydroxyquinoline N -oxides (AQNO) in the opportunistic pathogen Pseudomonas aeruginosa . It is homologous to group A FPMOs 13 and has a relatively high similarity to p -hydroxybenzoate hydroxylase (pHBH), the most thoroughly studied FPMO 14 . Group A monooxygenases usually hydroxylate mono- or polysubstituted aromatic rings and utilize NAD(P)H as hydride donor. In contrast, PqsL catalyzes the hydroxylation of an aromatic-amine group, a rather uncommon reaction, and remarkably shows no intrinsic catalytic activity with NAD(P)H as cosubstrate 15 . Here, we provide experimental evidence that the protein-internal FAD of PqsL is reduced by NAD(P)H in a light-dependent, enzyme-associated reaction which is severalfold faster than the photoreduction of free flavin. Structural and functional studies indicate that canonical transient binding of NAD(P)H is compatible with photoexcitation. Using an engineered variant of PqsL, we further demonstrate that stabilization of the protein-cofactor complex does not diminish photoreactivity, indicating that primarily the conformation of the flavin ring and its microenvironment are relevant for photoreduction. We moreover elucidate the charge transfer between NAD(P)H and FAD, in which the protein-bound flavin reacts similarly to free flavin, involving a two-step reaction with single-electron transfer, leading to a transient neutral semiquinone intermediate. Results Blue light induces catalytic activity of PqsL PqsL is a monooxygenase involved in AQNO biosynthesis in P. aeruginosa . Its catalytic activity was found to depend on the presence of reduced flavin, e.g., provided by a flavin reductase 15 . In that regard, the enzyme functions similarly to the two-component monooxygenases, in which the FAD cofactor migrates between a monooxygenase and a cognate reductase. In the process of analyzing PqsL cofactor exchange and charge transfer we discovered an interesting anomaly: the enzyme slowly oxidized NAD(P)H when the reaction was monitored in a spectrophotometer cuvette, whereas no consumption of the cosubstrate was observable when the reaction was analyzed by, e.g., HPLC. We concluded that the PqsL reductive half reaction must be positively influenced by light. To test our hypothesis, we analyzed if PqsL-catalyzed product formation could be observed with NAD(P)H as electron donor depending on whether the samples were illuminated or not. Due to instability of the PqsL reaction product 2-hydroxylaminobenzoylacetate (2-HABA), we used a coupled assay for detection in which the substrate, 2-aminobenzoylacetate (2-ABA), and 2-HABA are enzymatically converted to the stable alkyl quinolone derivatives 2-heptyl-4(1 H )-quinolone (HHQ) and 2-heptyl-4-hydroxyquinoline- N -oxide (HQNO), respectively (Fig. 1a ). Both compounds can then be quantified by HPLC. As displayed in Fig. 1b , HQNO formation increased as linear function of blue-light intensity whereas no product was detected in the dark, indicating that NAD(P)H is not accepted as electron donor in the absence of light. We also grew cultures of P. aeruginosa PAO1 with blue-light illumination under aerobic conditions. However, no difference in AQNO/non-AQNO metabolite ratio was observed. Instead a complex phenotype with reduced general levels of AQ pathway metabolites and other secondary metabolites such as phenazines was observed in response to illumination, which is consistent with previous reports 16 . Fig. 1: Blue-light-induced activity of PqsL. a Reaction of PqsL within the alkyl quinolone biosynthetic pathway. The downstream/parallel<|im_end|> <|im_start|>assistant Enzymes are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this ability that makes them useful as catalysts in biotechnology, for example, to create chemical products such as pharmaceutics. A topic that is currently being widely discussed is photoinduced catalysis, in which researchers harness the ability to start biochemical reactions using light. This process requires enzymes that can be activated by means of light. It is not, however, a simple matter to incorporate the few naturally occurring light-activatable enzymes into biotechnological processes, as they are highly specialised and difficult to manipulate. Researchers at the Universities of Münster (Germany) and Pavia (Italy) have now identified an enzyme that becomes catalytically active when exposed to blue light and which immediately triggers a reaction hitherto unknown in enzymology. The reaction in question is a special monooxygenase reaction, in which an oxygen atom is transferred to the substrate. The reaction is supported by a helper molecule that delivers two electrons stepwise. Previously, it had been assumed that such a light-dependent reaction cannot occur in enzymes. "The enzyme we have identified belongs to a very large family of enzymes, and it is realistic to assume that other enzymes that can be activated by light can be produced by means of genetic manipulation and used in a very wide range of applications," says Dr. Steffen L. Drees, who headed the study and works at the Institute of Molecular Microbiology and Biotechnology at Münster University. One possible application, for example, is the production of pharmaceuticals activated by means of light. The study has been published in the journal Nature Communications. In their study, the researchers investigated the enzyme PqsL, which is found in the opportunistic pathogen Pseudomonas aeruginosa and, originally was not light-dependent. The researchers stimulated the enzyme with blue light and analysed the reaction using a combination of time-resolved spectroscopic and crystallographic techniques. The enzyme belongs to the family of flavoproteins, and typically for this family of proteins, uses a derivative of vitamin B2 as a so-called cofactor for catalysing the incorporation of oxygen into organic molecules. The cosubstrate NADH (reduced nicotinamide adenine dinucleotide) is needed as a "helper molecule" for the enzymatic reaction, providing the necessary electrons. The reaction mechanism the researchers observed in their study was previously unknown. Activated by the exposure to light in the flavin-NADH complex, NADH transfers a single electron to the protein-bound flavin. In this way, a flavin radical is created—this is a highly reactive molecule characterised by an unpaired electron. Using time-resolved spectroscopy, the researchers were able to observe how the molecule formed and changed its state. The flavin radical has a very negative redox potential, which means that it has a large capacity for transferring electrons to reaction partners. "Because of this property, we assume that the flavin radical can also enable additional reactions to take place, which would expand the catalytic potential of this enzyme—as well as of other enzymes too, perhaps," says group leader Prof. Susanne Fetzner. The enzyme identified is the only one so far that is not naturally photoactive, and carries out a light-independent reaction in the bacterial cell. "The three-dimensional structure of the enzyme shows that the outward-facing flavin co-factor might be the key to photoactivation," says Simon Ernst, first author of the study. Photoactive enzymes enable a large number of applications—for example, multi-step catalysis in a one-vessel reaction or spatially resolved catalysis, for example, to functionalise surfaces in certain patterns. They can also be useful for so-called prodrug activation in the body or on the skin—this is a process in which a pharmacological substance becomes active only after metabolization in the organism. <|im_end|>

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315, 2536, 67467, 2464, 2740, 15987, 18779, 16355, 21436, 288, 220, 717, 662, 763, 420, 4007, 11, 584, 1501, 430, 279, 34454, 70504, 5820, 315, 279, 18779, 454, 91748, 1647, 2689, 19472, 521, 320, 37, 8971, 46, 8, 393, 27455, 43, 649, 387, 22900, 555, 6437, 18179, 77052, 13, 578, 49242, 374, 6532, 304, 279, 49554, 74767, 315, 220, 17, 12, 1727, 4010, 12, 19, 2902, 68107, 4223, 36444, 22671, 452, 482, 5241, 3422, 320, 93173, 9173, 8, 304, 279, 86954, 4633, 1853, 11968, 393, 40512, 35685, 300, 34548, 3715, 12252, 662, 1102, 374, 5105, 1640, 788, 311, 1912, 362, 435, 8971, 29967, 220, 1032, 323, 706, 264, 12309, 1579, 38723, 311, 281, 482, 67229, 4223, 8123, 13028, 349, 17055, 87, 4010, 521, 320, 79, 31825, 39, 705, 279, 1455, 27461, 20041, 435, 8971, 46, 220, 975, 662, 5856, 362, 1647, 2689, 19472, 2315, 6118, 17055, 87, 4010, 349, 40774, 12, 477, 99919, 392, 3781, 2844, 82688, 25562, 323, 29166, 452, 1846, 5417, 8, 39, 439, 6409, 67, 1425, 35558, 13, 763, 13168, 11, 393, 27455, 43, 34454, 18854, 288, 279, 17055, 4223, 2354, 315, 459, 82688, 12, 20588, 1912, 11, 264, 4856, 41296, 13010, 11, 323, 49723, 5039, 912, 47701, 34454, 70504, 5820, 449, 452, 1846, 5417, 8, 39, 439, 8119, 392, 71015, 220, 868, 662, 5810, 11, 584, 3493, 22772, 6029, 430, 279, 13128, 12, 10701, 435, 1846, 315, 393, 27455, 43, 374, 11293, 555, 452, 1846, 5417, 8, 39, 304, 264, 3177, 43918, 11, 49242, 75968, 13010, 902, 374, 3285, 3181, 820, 10819, 1109, 279, 4604, 461, 23985, 315, 1949, 18779, 258, 13, 73800, 323, 16003, 7978, 13519, 430, 43553, 41658, 11212, 315, 452, 1846, 5417, 8, 39, 374, 18641, 449, 6685, 40541, 7709, 13, 12362, 459, 46036, 11678, 315, 393, 27455, 43, 11, 584, 4726, 20461, 430, 83938, 315, 279, 13128, 23283, 38691, 6485, 1587, 539, 57160, 4604, 461, 7323, 11, 19392, 430, 15871, 279, 390, 1659, 315, 279, 18779, 258, 10264, 323, 1202, 8162, 24175, 527, 9959, 369, 4604, 461, 23985, 13, 1226, 44643, 97298, 349, 279, 6900, 8481, 1990, 452, 1846, 5417, 8, 39, 323, 435, 1846, 11, 304, 902, 279, 13128, 50962, 18779, 258, 69945, 30293, 311, 1949, 18779, 258, 11, 16239, 264, 1403, 30308, 13010, 449, 3254, 37081, 2298, 8481, 11, 6522, 311, 264, 41658, 21277, 5347, 5118, 258, 606, 29539, 13, 18591, 8868, 3177, 90974, 34454, 70504, 5820, 315, 393, 27455, 43, 393, 27455, 43, 374, 264, 1647, 2689, 19472, 521, 6532, 304, 83555, 9173, 49554, 74767, 304, 393, 13, 34548, 3715, 12252, 662, 11699, 34454, 70504, 5820, 574, 1766, 311, 6904, 389, 279, 9546, 315, 11293, 18779, 258, 11, 384, 1326, 2637, 3984, 555, 264, 18779, 258, 312, 1076, 521, 220, 868, 662, 763, 430, 5363, 11, 279, 49242, 5865, 30293, 311, 279, 1403, 42487, 1647, 2689, 19472, 2315, 11, 304, 902, 279, 435, 1846, 69903, 5739, 9971, 988, 1990, 264, 1647, 2689, 19472, 521, 323, 264, 19329, 349, 312, 1076, 521, 13, 763, 279, 1920, 315, 42118, 393, 27455, 43, 69903, 5739, 9473, 323, 6900, 8481, 584, 11352, 459, 7185, 64048, 25, 279, 49242, 14297, 36172, 1534, 452, 1846, 5417, 8, 39, 994, 279, 13010, 574, 41223, 304, 264, 9618, 22761, 354, 21037, 7015, 58330, 11, 20444, 912, 15652, 315, 279, 8119, 392, 71015, 574, 40635, 994, 279, 13010, 574, 30239, 555, 11, 384, 1326, 2637, 473, 2989, 34, 13, 1226, 20536, 430, 279, 393, 27455, 43, 312, 68243, 4376, 13010, 2011, 387, 40646, 28160, 555, 3177, 13, 2057, 1296, 1057, 31178, 11, 584, 30239, 422, 393, 27455, 43, 1824, 4306, 88, 16284, 2027, 18488, 1436, 387, 13468, 449, 452, 1846, 5417, 8, 39, 439, 17130, 35558, 11911, 389, 3508, 279, 10688, 1051, 75648, 477, 539, 13, 24586, 311, 56399, 315, 279, 393, 27455, 43, 13010, 2027, 220, 17, 2902, 68107, 87, 4010, 8778, 677, 17007, 2303, 75, 68323, 349, 320, 17, 11529, 57650, 705, 584, 1511, 264, 34356, 65033, 369, 18468, 304, 902, 279, 54057, 11, 220, 17, 12, 8778, 677, 17007, 2303, 75, 68323, 349, 320, 17, 12, 57650, 705, 323, 220, 17, 11529, 57650, 527, 32011, 7167, 16489, 311, 279, 15528, 58998, 4010, 934, 258, 337, 606, 43645, 220, 17, 38435, 1625, 75, 12, 19, 7, 16, 473, 883, 12, 36444, 337, 606, 320, 24056, 48, 8, 323, 220, 17, 38435, 1625, 75, 12, 19, 2902, 68107, 4223, 36444, 22671, 12, 452, 482, 55189, 320, 90719, 9173, 705, 15947, 320, 30035, 13, 220, 16, 64, 7609, 11995, 32246, 649, 1243, 387, 10484, 1908, 555, 473, 2989, 34, 13, 1666, 12882, 304, 23966, 13, 220, 16, 65, 1174, 46355, 9173, 18488, 7319, 439, 13790, 734, 315, 6437, 18179, 21261, 20444, 912, 2027, 574, 16914, 304, 279, 6453, 11, 19392, 430, 452, 1846, 5417, 8, 39, 374, 539, 11928, 439, 17130, 35558, 304, 279, 19821, 315, 3177, 13, 1226, 1101, 14264, 27833, 315, 393, 13, 34548, 3715, 12252, 13174, 46, 16, 449, 6437, 18179, 77052, 1234, 91490, 4787, 13, 4452, 11, 912, 6811, 304, 83555, 9173, 92230, 6830, 48, 9173, 28168, 635, 11595, 574, 13468, 13, 12361, 264, 6485, 82423, 449, 11293, 4689, 5990, 315, 83555, 38970, 28168, 3695, 323, 1023, 14580, 28168, 3695, 1778, 439, 14345, 29841, 574, 13468, 304, 2077, 311, 77052, 11, 902, 374, 13263, 449, 3766, 6821, 220, 845, 662, 23966, 13, 220, 16, 25, 8868, 18179, 38973, 5820, 315, 393, 27455, 43, 13, 264, 67941, 315, 393, 27455, 43, 2949, 279, 58998, 4010, 934, 258, 337, 606, 49554, 1910, 18015, 38970, 13, 578, 52452, 14, 47203, 128257, 198, 128256, 78191, 198, 1737, 21436, 288, 527, 279, 8792, 12050, 369, 93532, 41861, 11618, 304, 1475, 5496, 2849, 11, 28462, 25481, 311, 1935, 2035, 30820, 13, 1102, 374, 420, 5845, 430, 3727, 1124, 5505, 439, 51483, 82, 304, 6160, 52536, 11, 369, 3187, 11, 311, 1893, 11742, 3956, 1778, 439, 15430, 25297, 1233, 13, 362, 8712, 430, 374, 5131, 1694, 13882, 14407, 374, 6685, 485, 24921, 34454, 4548, 11, 304, 902, 12074, 33508, 279, 5845, 311, 1212, 93532, 25481, 1701, 3177, 13, 1115, 1920, 7612, 56067, 430, 649, 387, 22756, 555, 3445, 315, 3177, 13, 1102, 374, 539, 11, 4869, 11, 264, 4382, 5030, 311, 33435, 279, 2478, 18182, 31965, 3177, 12, 9035, 15436, 56067, 1139, 6160, 45860, 5848, 11618, 11, 439, 814, 527, 7701, 89004, 323, 5107, 311, 37735, 13, 59250, 520, 279, 75898, 315, 386, 16461, 3751, 320, 51270, 8, 323, 393, 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13010, 17383, 279, 12074, 13468, 304, 872, 4007, 574, 8767, 9987, 13, 15050, 660, 555, 279, 14675, 311, 3177, 304, 279, 18779, 258, 11500, 1846, 39, 6485, 11, 452, 1846, 39, 31711, 264, 3254, 17130, 311, 279, 13128, 50962, 18779, 258, 13, 763, 420, 1648, 11, 264, 18779, 258, 18336, 374, 3549, 2345, 576, 374, 264, 7701, 56563, 43030, 3752, 4147, 555, 459, 653, 77267, 17130, 13, 12362, 892, 11849, 8905, 66425, 51856, 11, 279, 12074, 1051, 3025, 311, 23846, 1268, 279, 43030, 14454, 323, 5614, 1202, 1614, 13, 578, 18779, 258, 18336, 706, 264, 1633, 8389, 2579, 5241, 4754, 11, 902, 3445, 430, 433, 706, 264, 3544, 8824, 369, 51051, 57678, 311, 13010, 8717, 13, 330, 18433, 315, 420, 3424, 11, 584, 9855, 430, 279, 18779, 258, 18336, 649, 1101, 7431, 5217, 25481, 311, 1935, 2035, 11, 902, 1053, 9407, 279, 34454, 70504, 4754, 315, 420, 49242, 60654, 1664, 439, 315, 1023, 56067, 2288, 11, 8530, 1359, 2795, 1912, 7808, 8626, 13, 16687, 20991, 435, 43289, 1215, 13, 578, 49242, 11054, 374, 279, 1193, 832, 779, 3117, 430, 374, 539, 18182, 6685, 3104, 11, 323, 24266, 704, 264, 3177, 98885, 13010, 304, 279, 45964, 2849, 13, 330, 791, 2380, 33520, 6070, 315, 279, 49242, 5039, 430, 279, 52046, 64406, 18779, 258, 1080, 75197, 2643, 387, 279, 1401, 311, 6685, 23863, 1359, 2795, 22021, 74210, 11, 1176, 3229, 315, 279, 4007, 13, 11064, 3104, 56067, 7431, 264, 3544, 1396, 315, 8522, 72318, 3187, 11, 7447, 30308, 34454, 4548, 304, 264, 832, 8437, 36648, 13010, 477, 29079, 398, 20250, 34454, 4548, 11, 369, 3187, 11, 311, 16003, 1082, 27529, 304, 3738, 12912, 13, 2435, 649, 1101, 387, 5505, 369, 779, 19434, 463, 73821, 15449, 304, 279, 2547, 477, 389, 279, 6930, 2345, 576, 374, 264, 1920, 304, 902, 264, 36449, 5848, 20278, 9221, 4642, 1193, 1306, 28168, 2065, 304, 279, 47120, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Infections caused by Acinetobacter baumannii are increasingly antibiotic resistant, generating a significant public health problem. Like many bacteria, A. baumannii adopts a biofilm lifestyle that enhances its antibiotic resistance and environmental resilience. Biofilms represent the predominant mode of microbial life, but research into antibiotic resistance has mainly focused on planktonic cells. We investigated the dynamics of A. baumannii biofilms in the presence of antibiotics. A 3-day exposure of A. baumannii biofilms to sub-inhibitory concentrations of antibiotics had a profound effect, increasing biofilm formation and antibiotic resistance in the majority of biofilm dispersal isolates. Cells dispersing from biofilms were genome sequenced to identify mutations accumulating in their genomes, and network analysis linked these mutations to their phenotypes. Transcriptomics of biofilms confirmed the network analysis results, revealing novel gene functions of relevance to both resistance and biofilm formation. This approach is a rapid and objective tool for investigating resistance dynamics of biofilms. Introduction Acinetobacter baumannii is a Gram-negative pathogen found in hospitals worldwide. 1 It is responsible for opportunistic infections of the bloodstream, urinary tract, and other soft tissues, and can account for up to 20% of infections in Intensive Care Units, causing serious morbidity and mortality. 1 , 2 Acinetobacter baumannii belongs to a group of six pathogens responsible for many multidrug-resistant (MDR) nosocomial infections (the ESKAPE pathogens: Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter spp.). 3 In 2017, A. baumannii was listed at the top of the highest priority “Critical” group of antibiotic-resistant pathogens identified by the World Health Organization as in need of further research. 4 The success of this pathogen is due to a combination of cellular resistance mechanisms and the additional protection provided by its biofilm lifestyle. 5 Acinetobacter baumannii has an arsenal of tools to defend against antimicrobials, including classical mechanisms of antibiotic resistance, such as enzymatic inactivation of antibiotics, target and membrane modifications, and active export of drugs via membrane-localized drug efflux transporters. 6 , 7 , 8 These mechanisms have been extensively studied in planktonically grown A. baumannii . Transcriptomic and mutational studies under antibiotic challenge using A. baumannii planktonic cultures identified mutations and differentially expressed genes directly linked with these known mechanisms of resistance to particular antibiotics. 9 , 10 Resistance and pathogenicity of A. baumannii is enhanced by its ability to form biofilms. 5 Acinetobacter baumannii biofilms can form on various surfaces, including medical devices, where they are persistent sources of contamination and infection. 11 The National Institutes of Health (NIH) estimates that biofilms account for over 80% of microbial infections in the body. 12 Biofilms are a major obstacle to treatment because their cells can display up to a 1000-fold increase in antibiotic resistance compared to planktonic cells. 13 , 14 Biofilms provide additional resistance 5 (also referred to as “biofilm tolerance” 15 , 16 , 17 ) via biofilm-specific mechanisms such as the shielding effect of the biofilm matrix that leads to restricted penetration of antimicrobials, 18 the slower growth rate in deep layers of biofilms, 19 and the presence of persister cells. 20 Biofilms are recognized as the predominant form of bacterial life, with the majority of bacteria living as biofilm communities in diverse environments, including within host organisms. 15 , 21 Nevertheless, compared to the wealth of data collected using planktonic cultures during the history of microbiological research, the biofilm mode of life remains largely underexplored, leading to a growing interest in the ecology of microbial biofilms, and the factors involved in biofilm development and survival. In particular, understanding the processes that occur in biofilms when exposed to antibiotics is important, because this could give us insight into how advantageous phenotypes arise, and help identify the genomic basis of these phenotypes. The ability of bacteria to adapt to new environmental conditions arises from their short generation times and genomic variability, allowing rapid emergence of favorable mutations. Methods for investigating the effect of mutations on bacterial phenotype, such as knock-out strains and transposon mutagenesis, are often time-consuming, involve extensive sample manipulation, and often focus on single gene targets. In contrast, whole genome sequencing can rapidly identify suites of naturally occurring mutations, and also reveal potential synergy between different mutations. This study investigated how genetic and phenotypic diversity was generated within biofilms of a highly virulent strain of A. baumannii . We assessed the transcription profiles of biofilms grown in the presence and absence of sub-inhibitory concentration of antibiotics ciprofloxacin and tetracycline, and examined the genetic consequences of biofilm growth in the presence of antibiotics, identifying de novo mutations by using whole genome sequencing. Thus, we were able to link phenotypes with genotypes and with population level gene expression patterns in one experimental analysis, providing a holistic assessment of processes that occur in biofilms, and, subsequently, drive genomic changes under the exposure to sub-inhibitory concentration of antibiotics. To assess changes in antibiotic susceptibility, the MIC (minimum inhibitory concentration) levels of biofilm dispersal cells were assessed against the antibiotics in a broth microdilution assay, and compared to the MIC levels of initial planktonic cultures. The MIC broth microdilution assay tests the level of antibiotic resistance in the planktonic state, that is, the level of resistance determined by classical “cellular” antibiotic resistance mechanisms 5 and does not capture the additional resistance provided by biofilm mode of life. Additional resistance provided by the biofilm lifestyle (“biofilm tolerance”) is directly related to the ability to form biofilms, 5 which was tested separately. Thus, by using the broth microdilution MIC assay (to test “cellular” level resistance), and biofilm formation assays (to assess the ability to form biofilms), we were able to separate these two phenotypes, both of which can significantly contribute to the overall resilience of biofilms. Acinetobacter baumannii is intrinsically resistant to many antibiotics, and consequently ciprofloxacin and tetracycline were used in this study, due to the relatively low level of resistance of A. baumannii AB5075-UW to these two antibiotics. These antibiotics are chemically diverse and belong to different classes, with different modes", "role": "user" }, { "content": "Acinetobacter baumannii is a pathogen that creates serious problems in hospitals throughout the world. It causes opportunistic infections in the bloodstream, urinary tract, and other soft tissues, accounting for as much as 20 percent of infections spread in Intensive Care Units. As one of the pathogens involved in many multidrug-resistant infections caught in hospitals, it was top of the highest priority \"Critical\" group of antibiotic-resistant pathogens the World Health Organization rated in 2017 as needing further research. Unfortunately, Acinetobacter baumannii is one of the great survivors. It has an arsenal of tools to defend against antimicrobials, including the classical mechanisms of antibiotic resistance, along with an even more fundamental property—it forms biofilms. Acinetobacter baumannii biofilms can grow on a range of surfaces, including medical devices, making them persistent sources of contamination and infection. The National Institutes of Health estimates that biofilms are responsible for around four fifths of microbial infections in the body. In a paper just published in npj Biofilms and Microbiomes, Macquarie University's Anahit Penesyan and her colleagues have looked at the evolution of Acinetobacter baumannii's defence mechanisms in its biofilm state, when exposed to low levels of antibiotics. They are alarmingly impressive. The majority of bacteria don't just float around by themselves. They attach to each other, and to surfaces, forming so called biofilms, and becoming stronger as a whole than the sum of their parts. This added strength became even more sinister when the group exposed biofilms of Acinetobacter baumannii to low levels of two antibiotics—ciprofloxacin and tetracycline—for three days. These were chosen because the bacteria have only a low level of resistance to them, unlike some other antibiotics. By the end of three days, the bacteria were already demonstrating consistent increases in antibiotic resistance. Of random biofilm isolates exposed to ciprofloxacin, 93 percent showed at least two-fold increased resistance towards this antibiotic, with 76 percent of those having at least a four-fold increase in resistance. Some 80 percent of ciprofloxacin-exposed isolates also showed increased resistance to tetracycline, with one-third of them showing at least a four-fold increase. That means that these isolates would require double, quadruple, or even higher concentration of antibiotics for their effective control. This is often impossible and unsafe. Much the same thing happened with the biofilms exposed to tetracycline. More than half (53 percent) at least doubled their resistance to tetracycline, with eight showing four -fold increases. Nine of the tetracycline-exposed isolates also gained increased resistance to ciprofloxacin, again as much as four times greater. The team then tested the isolates for susceptibility to erythromycin—an antibiotic with a different structure and function from the antibiotics the biofilms had been exposed to. Many of the isolates that showed increased resistance towards ciprofloxacin and/or tetracycline were also resistant towards erythromycin. In other words, cells are becoming resistant to multiple antibiotics (multidrug resistant) when exposed to low levels of antibiotics in their natural, biofilm, state. The majority of biofilm derived cells also gained an increased capacity to form biofilms, thus further strengthening their resilience. These findings are a disturbing indication of what could be occurring in biofilms within infections, when they are exposed to antibiotics. They also have ramifications for antibiotic waste management. Low levels of antibiotics released into the environment may cause similar effects in biofilms growing in natural waterways, which may then spread antibiotic resistance still further. We need to think how we use antibiotics in the future, so we don't make superbugs an even greater threat. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Infections caused by Acinetobacter baumannii are increasingly antibiotic resistant, generating a significant public health problem. Like many bacteria, A. baumannii adopts a biofilm lifestyle that enhances its antibiotic resistance and environmental resilience. Biofilms represent the predominant mode of microbial life, but research into antibiotic resistance has mainly focused on planktonic cells. We investigated the dynamics of A. baumannii biofilms in the presence of antibiotics. A 3-day exposure of A. baumannii biofilms to sub-inhibitory concentrations of antibiotics had a profound effect, increasing biofilm formation and antibiotic resistance in the majority of biofilm dispersal isolates. Cells dispersing from biofilms were genome sequenced to identify mutations accumulating in their genomes, and network analysis linked these mutations to their phenotypes. Transcriptomics of biofilms confirmed the network analysis results, revealing novel gene functions of relevance to both resistance and biofilm formation. This approach is a rapid and objective tool for investigating resistance dynamics of biofilms. Introduction Acinetobacter baumannii is a Gram-negative pathogen found in hospitals worldwide. 1 It is responsible for opportunistic infections of the bloodstream, urinary tract, and other soft tissues, and can account for up to 20% of infections in Intensive Care Units, causing serious morbidity and mortality. 1 , 2 Acinetobacter baumannii belongs to a group of six pathogens responsible for many multidrug-resistant (MDR) nosocomial infections (the ESKAPE pathogens: Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter spp.). 3 In 2017, A. baumannii was listed at the top of the highest priority “Critical” group of antibiotic-resistant pathogens identified by the World Health Organization as in need of further research. 4 The success of this pathogen is due to a combination of cellular resistance mechanisms and the additional protection provided by its biofilm lifestyle. 5 Acinetobacter baumannii has an arsenal of tools to defend against antimicrobials, including classical mechanisms of antibiotic resistance, such as enzymatic inactivation of antibiotics, target and membrane modifications, and active export of drugs via membrane-localized drug efflux transporters. 6 , 7 , 8 These mechanisms have been extensively studied in planktonically grown A. baumannii . Transcriptomic and mutational studies under antibiotic challenge using A. baumannii planktonic cultures identified mutations and differentially expressed genes directly linked with these known mechanisms of resistance to particular antibiotics. 9 , 10 Resistance and pathogenicity of A. baumannii is enhanced by its ability to form biofilms. 5 Acinetobacter baumannii biofilms can form on various surfaces, including medical devices, where they are persistent sources of contamination and infection. 11 The National Institutes of Health (NIH) estimates that biofilms account for over 80% of microbial infections in the body. 12 Biofilms are a major obstacle to treatment because their cells can display up to a 1000-fold increase in antibiotic resistance compared to planktonic cells. 13 , 14 Biofilms provide additional resistance 5 (also referred to as “biofilm tolerance” 15 , 16 , 17 ) via biofilm-specific mechanisms such as the shielding effect of the biofilm matrix that leads to restricted penetration of antimicrobials, 18 the slower growth rate in deep layers of biofilms, 19 and the presence of persister cells. 20 Biofilms are recognized as the predominant form of bacterial life, with the majority of bacteria living as biofilm communities in diverse environments, including within host organisms. 15 , 21 Nevertheless, compared to the wealth of data collected using planktonic cultures during the history of microbiological research, the biofilm mode of life remains largely underexplored, leading to a growing interest in the ecology of microbial biofilms, and the factors involved in biofilm development and survival. In particular, understanding the processes that occur in biofilms when exposed to antibiotics is important, because this could give us insight into how advantageous phenotypes arise, and help identify the genomic basis of these phenotypes. The ability of bacteria to adapt to new environmental conditions arises from their short generation times and genomic variability, allowing rapid emergence of favorable mutations. Methods for investigating the effect of mutations on bacterial phenotype, such as knock-out strains and transposon mutagenesis, are often time-consuming, involve extensive sample manipulation, and often focus on single gene targets. In contrast, whole genome sequencing can rapidly identify suites of naturally occurring mutations, and also reveal potential synergy between different mutations. This study investigated how genetic and phenotypic diversity was generated within biofilms of a highly virulent strain of A. baumannii . We assessed the transcription profiles of biofilms grown in the presence and absence of sub-inhibitory concentration of antibiotics ciprofloxacin and tetracycline, and examined the genetic consequences of biofilm growth in the presence of antibiotics, identifying de novo mutations by using whole genome sequencing. Thus, we were able to link phenotypes with genotypes and with population level gene expression patterns in one experimental analysis, providing a holistic assessment of processes that occur in biofilms, and, subsequently, drive genomic changes under the exposure to sub-inhibitory concentration of antibiotics. To assess changes in antibiotic susceptibility, the MIC (minimum inhibitory concentration) levels of biofilm dispersal cells were assessed against the antibiotics in a broth microdilution assay, and compared to the MIC levels of initial planktonic cultures. The MIC broth microdilution assay tests the level of antibiotic resistance in the planktonic state, that is, the level of resistance determined by classical “cellular” antibiotic resistance mechanisms 5 and does not capture the additional resistance provided by biofilm mode of life. Additional resistance provided by the biofilm lifestyle (“biofilm tolerance”) is directly related to the ability to form biofilms, 5 which was tested separately. Thus, by using the broth microdilution MIC assay (to test “cellular” level resistance), and biofilm formation assays (to assess the ability to form biofilms), we were able to separate these two phenotypes, both of which can significantly contribute to the overall resilience of biofilms. Acinetobacter baumannii is intrinsically resistant to many antibiotics, and consequently ciprofloxacin and tetracycline were used in this study, due to the relatively low level of resistance of A. baumannii AB5075-UW to these two antibiotics. These antibiotics are chemically diverse and belong to different classes, with different modes<|im_end|> <|im_start|>assistant Acinetobacter baumannii is a pathogen that creates serious problems in hospitals throughout the world. It causes opportunistic infections in the bloodstream, urinary tract, and other soft tissues, accounting for as much as 20 percent of infections spread in Intensive Care Units. As one of the pathogens involved in many multidrug-resistant infections caught in hospitals, it was top of the highest priority "Critical" group of antibiotic-resistant pathogens the World Health Organization rated in 2017 as needing further research. Unfortunately, Acinetobacter baumannii is one of the great survivors. It has an arsenal of tools to defend against antimicrobials, including the classical mechanisms of antibiotic resistance, along with an even more fundamental property—it forms biofilms. Acinetobacter baumannii biofilms can grow on a range of surfaces, including medical devices, making them persistent sources of contamination and infection. The National Institutes of Health estimates that biofilms are responsible for around four fifths of microbial infections in the body. In a paper just published in npj Biofilms and Microbiomes, Macquarie University's Anahit Penesyan and her colleagues have looked at the evolution of Acinetobacter baumannii's defence mechanisms in its biofilm state, when exposed to low levels of antibiotics. They are alarmingly impressive. The majority of bacteria don't just float around by themselves. They attach to each other, and to surfaces, forming so called biofilms, and becoming stronger as a whole than the sum of their parts. This added strength became even more sinister when the group exposed biofilms of Acinetobacter baumannii to low levels of two antibiotics—ciprofloxacin and tetracycline—for three days. These were chosen because the bacteria have only a low level of resistance to them, unlike some other antibiotics. By the end of three days, the bacteria were already demonstrating consistent increases in antibiotic resistance. Of random biofilm isolates exposed to ciprofloxacin, 93 percent showed at least two-fold increased resistance towards this antibiotic, with 76 percent of those having at least a four-fold increase in resistance. Some 80 percent of ciprofloxacin-exposed isolates also showed increased resistance to tetracycline, with one-third of them showing at least a four-fold increase. That means that these isolates would require double, quadruple, or even higher concentration of antibiotics for their effective control. This is often impossible and unsafe. Much the same thing happened with the biofilms exposed to tetracycline. More than half (53 percent) at least doubled their resistance to tetracycline, with eight showing four -fold increases. Nine of the tetracycline-exposed isolates also gained increased resistance to ciprofloxacin, again as much as four times greater. The team then tested the isolates for susceptibility to erythromycin—an antibiotic with a different structure and function from the antibiotics the biofilms had been exposed to. Many of the isolates that showed increased resistance towards ciprofloxacin and/or tetracycline were also resistant towards erythromycin. In other words, cells are becoming resistant to multiple antibiotics (multidrug resistant) when exposed to low levels of antibiotics in their natural, biofilm, state. The majority of biofilm derived cells also gained an increased capacity to form biofilms, thus further strengthening their resilience. These findings are a disturbing indication of what could be occurring in biofilms within infections, when they are exposed to antibiotics. They also have ramifications for antibiotic waste management. Low levels of antibiotics released into the environment may cause similar effects in biofilms growing in natural waterways, which may then spread antibiotic resistance still further. We need to think how we use antibiotics in the future, so we don't make superbugs an even greater threat. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Electro-optic modulators translate high-speed electronic signals into the optical domain and are critical components in modern telecommunication networks 1 , 2 and microwave-photonic systems 3 , 4 . They are also expected to be building blocks for emerging applications such as quantum photonics 5 , 6 and non-reciprocal optics 7 , 8 . All of these applications require chip-scale electro-optic modulators that operate at voltages compatible with complementary metal–oxide–semiconductor (CMOS) technology, have ultra-high electro-optic bandwidths and feature very low optical losses. Integrated modulator platforms based on materials such as silicon, indium phosphide or polymers have not yet been able to meet these requirements simultaneously because of the intrinsic limitations of the materials used. On the other hand, lithium niobate electro-optic modulators, the workhorse of the optoelectronic industry for decades 9 , have been challenging to integrate on-chip because of difficulties in microstructuring lithium niobate. The current generation of lithium niobate modulators are bulky, expensive, limited in bandwidth and require high drive voltages, and thus are unable to reach the full potential of the material. Here we overcome these limitations and demonstrate monolithically integrated lithium niobate electro-optic modulators that feature a CMOS-compatible drive voltage, support data rates up to 210 gigabits per second and show an on-chip optical loss of less than 0.5 decibels. We achieve this by engineering the microwave and photonic circuits to achieve high electro-optical efficiencies, ultra-low optical losses and group-velocity matching simultaneously. Our scalable modulator devices could provide cost-effective, low-power and ultra-high-speed solutions for next-generation optical communication networks and microwave photonic systems. Furthermore, our approach could lead to large-scale ultra-low-loss photonic circuits that are reconfigurable on a picosecond timescale, enabling a wide range of quantum and classical applications 5 , 10 , 11 including feed-forward photonic quantum computation. Main Future photonic systems require modulators with a CMOS-compatible drive voltage, a large bandwidth, a low optical insertion loss, a high extinction ratio, excellent signal quality and compatibility with large-scale manufacturing. Because discrete lithium niobate (LN) modulators are difficult to integrate, many other photonic platforms compatible with microfabrication processes have been pursued instead, including those based on silicon 1 , 12 , 13 , indium phosphide 14 , 15 , polymers 16 , 17 and plasmonics 18 . These have shown excellent scalability and distinct performance merits, including the potential for integration with CMOS electronics (Si), low drive voltages (InP, polymer), ultra-high bandwidths (polymer, plasmonics) and small footprints (Si, plasmonics). Although the integration problem has been greatly alleviated in these platforms, a modulator that simultaneously meets all desired performance aspects remains elusive because of the non-ideal electro-optic properties of the underlying materials. The material properties of LN are well suited for realizing ultra-fast modulation, low-voltage operation and low optical losses at the same time. The strong electro-optic (Pockels) effect in LN leads to a linear change of its refractive index in response to an applied voltage, on femtosecond timescales 19 . Although it has been known for some time that microstructured LN devices can provide better modulator performance 20 , most commercial LN modulators are still based on titanium-indiffusion or proton-exchange waveguides, because LN is notoriously difficult to etch 9 . These waveguides typically have a low refractive index contrast Δ n of around 0.02 between core and cladding, resulting in a large optical mode size 21 . The weak optical confinement requires metal electrodes to be spaced far apart from the optical waveguide (about 10 µm), lowering the electro-optic efficiency. As a result, LN modulators today are much larger in size and require much higher drive voltages than the material is capable of supporting. In recent years, the LN-on-insulator platform has emerged as a promising candidate for integrated high-performance modulators. In this approach, a single-crystal, submicrometre-thick LN film is bonded on top of a low-index substrate (silicon dioxide, SiO 2 ), and waveguides are created by dry etching the LN device layer 22 . This has led to a range of LN photonic devices with high index contrast of >0.7 and tightly confined optical modes 23 , 24 , 25 , 26 , 27 , 28 , 29 . Electro-optic modulators with promising electro-optic efficiencies have been demonstrated 25 , 26 , 27 , 29 . However, the actual switching voltages, bandwidths and optical losses in these demonstrations still suffer from critical trade-offs, limited by non-ideal etching, reduced overlap between electrical and optical fields, and/or the inefficient microwave signal delivery. Whether it is possible to simultaneously achieve a low on/off switching voltage, an ultra-high bandwidth and a low optical loss in LN modulators has remained an outstanding question. Here we demonstrate monolithically integrated LN electro-optic modulators (Fig. 1 ) that overcome such trade-offs, featuring a switching voltage of 1.4 V while supporting very high bandwidths. Our integrated modulators operate in a travelling-wave Mach–Zehnder interferometer (MZI) configuration that uses highly confined co-propagating microwave and optical fields with matched group velocities and low propagation losses. A 50:50 Y-junction splits the input light into two LN optical waveguides that form the arms of the MZI. The optical waveguides run through the dielectric gaps of a ground–signal–ground coplanar microwave strip line (Fig. 1d ). As a result, the microwave electric field has opposite signs across the two LN waveguides, thus inducing (through the Pockels effect) an optical phase delay on one arm and an optical phase advance on the other. This optical phase difference results in constructive/destructive interference at the output 50:50 Y-junction, and thereby an amplitude modulation of the output optical signal (Fig. 1c ). An important figure of merit for MZI modulators is the half-wave voltage ( V π ), defined as the voltage required to induce a π-phase difference between the two modulator arms, changing the optical transmission from maximum to minimum. For a device with 20-mm-long microwave strip line electrodes, we measure a low V π of 1.4 V (Fig. 1c ), which allows the modulator to be directly driven by a CMOS circuit. Importantly, our devices also feature a high optical power extinction ratio of about", "role": "user" }, { "content": "Conventional lithium niobite modulators, the longtime workhorse of the optoelectronic industry, may soon go the way of the vacuum tube and floppy disc. Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences have developed a new method to fabricate and design integrated, on-chip modulators 100 times smaller and 20 times more efficient than current lithium niobite (LN) modulators. The research is described in Nature. \"This research demonstrates a fundamental technological breakthrough in integrated photonics,\" said Marko Loncar, the Tiantsai Lin Professor of Electrical Engineering at SEAS and senior author of the paper. \"Our platform could lead to large-scale, very fast and ultra-low-loss photonic circuits, enabling a wide range of applications for future quantum and classical photonic communication and computation.\" Harvard's Office of Technology Development (OTD) has worked closely with the Loncar Lab on the formation of a startup company, HyperLight, that intends to commercialize a portfolio of foundational intellectual property related to this research. Readying the technology toward the launch of HyperLight has been aided by funding from OTD's Physical Sciences & Engineering Accelerator, which provides translational funding for research projects that show potential for significant commercial impact. Lithium niobate modulators are the backbone of modern telecommunications, converting electronic data to optical information in fiber optic cables. However, conventional LN modulators are bulky, expensive and power hungry. These modulators require a drive voltage of 3 to 5 volts, significantly higher than that provided by typical CMOS circuitry, which provides about 1 volt. As a result, separate, power-consuming amplifiers are needed to drive the modulators, severely limiting chip-scale optoelectronic integration. Fiber-optical networks, the backbone of the internet, rely on high-fidelity information conversion from electrical to the optical domain. The researchers combined the best optical material with innovative nanofabrication and design approaches, to realize, energy-efficient, high-speed, low-loss, electro-optic converters for quantum and classical communications. Credit: Second Bay Studios/Harvard SEAS \"We show that by integrating lithium niobate on a small chip, the drive voltage can be reduced to a CMOS-compatible level,\" said Cheng Wang, co-first author of the paper, former Ph.D. student and postdoctoral fellow at SEAS, and currently Assistant Professor at City University of Hong Kong. \"Remarkably, these tiny modulators can also support data transmission rates up to 210 Gbit/s. It's like Antman—smaller, faster and better.\" \"Highly-integrated yet high-performance optical modulators are very important for the closer integration of optics and digital electronics, paving the way towards future fiber-in-fiber-out opto-electronic processing engines,\" said Peter Winzer, Director of Optical Transmission Research at Nokia Bell Labs, the industrial partner in this project, and coauthor of the paper. \"We see this new modulator technology as a promising candidate for such solutions.\" Lithium niobite is considered by many in the field to be difficult to work with on small scales, an obstacle that has so far ruled out practical integrated, on-chip applications. In previous research, Loncar and his team demonstrated a technique to fabricate high-performance lithium niobate microstructures using standard plasma etching to physically sculpt microresonators in thin lithium niobate films. Combining that technique with specially designed electrical components, the researchers can now design and fabricate an integrated, high-performance on-chip modulator. \"Previously, if you wanted to make modulators smaller and more integrated, you had to compromise their performance,\" said Mian Zhang, a postdoctoral fellow at SEAS and co-first author of the research. \"For example, existing integrated modulators can easily lose majority of the light as it propagates on the chip. In contrast, we have reduced losses by more than an order of magnitude. Essentially, we can control light without losing it.\" \"Because a modulator is such a fundamental component of communication technology—with a role equivalent to that of a transistor in computation technology—the applications are enormous,\" said Zhang. \"The fact that these modulators can be integrated with other components on the same platform could provide practical solutions for next-generation long distance optical networks, data center optical interconnects, wireless communications, radar, sensing and so on.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Electro-optic modulators translate high-speed electronic signals into the optical domain and are critical components in modern telecommunication networks 1 , 2 and microwave-photonic systems 3 , 4 . They are also expected to be building blocks for emerging applications such as quantum photonics 5 , 6 and non-reciprocal optics 7 , 8 . All of these applications require chip-scale electro-optic modulators that operate at voltages compatible with complementary metal–oxide–semiconductor (CMOS) technology, have ultra-high electro-optic bandwidths and feature very low optical losses. Integrated modulator platforms based on materials such as silicon, indium phosphide or polymers have not yet been able to meet these requirements simultaneously because of the intrinsic limitations of the materials used. On the other hand, lithium niobate electro-optic modulators, the workhorse of the optoelectronic industry for decades 9 , have been challenging to integrate on-chip because of difficulties in microstructuring lithium niobate. The current generation of lithium niobate modulators are bulky, expensive, limited in bandwidth and require high drive voltages, and thus are unable to reach the full potential of the material. Here we overcome these limitations and demonstrate monolithically integrated lithium niobate electro-optic modulators that feature a CMOS-compatible drive voltage, support data rates up to 210 gigabits per second and show an on-chip optical loss of less than 0.5 decibels. We achieve this by engineering the microwave and photonic circuits to achieve high electro-optical efficiencies, ultra-low optical losses and group-velocity matching simultaneously. Our scalable modulator devices could provide cost-effective, low-power and ultra-high-speed solutions for next-generation optical communication networks and microwave photonic systems. Furthermore, our approach could lead to large-scale ultra-low-loss photonic circuits that are reconfigurable on a picosecond timescale, enabling a wide range of quantum and classical applications 5 , 10 , 11 including feed-forward photonic quantum computation. Main Future photonic systems require modulators with a CMOS-compatible drive voltage, a large bandwidth, a low optical insertion loss, a high extinction ratio, excellent signal quality and compatibility with large-scale manufacturing. Because discrete lithium niobate (LN) modulators are difficult to integrate, many other photonic platforms compatible with microfabrication processes have been pursued instead, including those based on silicon 1 , 12 , 13 , indium phosphide 14 , 15 , polymers 16 , 17 and plasmonics 18 . These have shown excellent scalability and distinct performance merits, including the potential for integration with CMOS electronics (Si), low drive voltages (InP, polymer), ultra-high bandwidths (polymer, plasmonics) and small footprints (Si, plasmonics). Although the integration problem has been greatly alleviated in these platforms, a modulator that simultaneously meets all desired performance aspects remains elusive because of the non-ideal electro-optic properties of the underlying materials. The material properties of LN are well suited for realizing ultra-fast modulation, low-voltage operation and low optical losses at the same time. The strong electro-optic (Pockels) effect in LN leads to a linear change of its refractive index in response to an applied voltage, on femtosecond timescales 19 . Although it has been known for some time that microstructured LN devices can provide better modulator performance 20 , most commercial LN modulators are still based on titanium-indiffusion or proton-exchange waveguides, because LN is notoriously difficult to etch 9 . These waveguides typically have a low refractive index contrast Δ n of around 0.02 between core and cladding, resulting in a large optical mode size 21 . The weak optical confinement requires metal electrodes to be spaced far apart from the optical waveguide (about 10 µm), lowering the electro-optic efficiency. As a result, LN modulators today are much larger in size and require much higher drive voltages than the material is capable of supporting. In recent years, the LN-on-insulator platform has emerged as a promising candidate for integrated high-performance modulators. In this approach, a single-crystal, submicrometre-thick LN film is bonded on top of a low-index substrate (silicon dioxide, SiO 2 ), and waveguides are created by dry etching the LN device layer 22 . This has led to a range of LN photonic devices with high index contrast of >0.7 and tightly confined optical modes 23 , 24 , 25 , 26 , 27 , 28 , 29 . Electro-optic modulators with promising electro-optic efficiencies have been demonstrated 25 , 26 , 27 , 29 . However, the actual switching voltages, bandwidths and optical losses in these demonstrations still suffer from critical trade-offs, limited by non-ideal etching, reduced overlap between electrical and optical fields, and/or the inefficient microwave signal delivery. Whether it is possible to simultaneously achieve a low on/off switching voltage, an ultra-high bandwidth and a low optical loss in LN modulators has remained an outstanding question. Here we demonstrate monolithically integrated LN electro-optic modulators (Fig. 1 ) that overcome such trade-offs, featuring a switching voltage of 1.4 V while supporting very high bandwidths. Our integrated modulators operate in a travelling-wave Mach–Zehnder interferometer (MZI) configuration that uses highly confined co-propagating microwave and optical fields with matched group velocities and low propagation losses. A 50:50 Y-junction splits the input light into two LN optical waveguides that form the arms of the MZI. The optical waveguides run through the dielectric gaps of a ground–signal–ground coplanar microwave strip line (Fig. 1d ). As a result, the microwave electric field has opposite signs across the two LN waveguides, thus inducing (through the Pockels effect) an optical phase delay on one arm and an optical phase advance on the other. This optical phase difference results in constructive/destructive interference at the output 50:50 Y-junction, and thereby an amplitude modulation of the output optical signal (Fig. 1c ). An important figure of merit for MZI modulators is the half-wave voltage ( V π ), defined as the voltage required to induce a π-phase difference between the two modulator arms, changing the optical transmission from maximum to minimum. For a device with 20-mm-long microwave strip line electrodes, we measure a low V π of 1.4 V (Fig. 1c ), which allows the modulator to be directly driven by a CMOS circuit. Importantly, our devices also feature a high optical power extinction ratio of about<|im_end|> <|im_start|>assistant Conventional lithium niobite modulators, the longtime workhorse of the optoelectronic industry, may soon go the way of the vacuum tube and floppy disc. Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences have developed a new method to fabricate and design integrated, on-chip modulators 100 times smaller and 20 times more efficient than current lithium niobite (LN) modulators. The research is described in Nature. "This research demonstrates a fundamental technological breakthrough in integrated photonics," said Marko Loncar, the Tiantsai Lin Professor of Electrical Engineering at SEAS and senior author of the paper. "Our platform could lead to large-scale, very fast and ultra-low-loss photonic circuits, enabling a wide range of applications for future quantum and classical photonic communication and computation." Harvard's Office of Technology Development (OTD) has worked closely with the Loncar Lab on the formation of a startup company, HyperLight, that intends to commercialize a portfolio of foundational intellectual property related to this research. Readying the technology toward the launch of HyperLight has been aided by funding from OTD's Physical Sciences & Engineering Accelerator, which provides translational funding for research projects that show potential for significant commercial impact. Lithium niobate modulators are the backbone of modern telecommunications, converting electronic data to optical information in fiber optic cables. However, conventional LN modulators are bulky, expensive and power hungry. These modulators require a drive voltage of 3 to 5 volts, significantly higher than that provided by typical CMOS circuitry, which provides about 1 volt. As a result, separate, power-consuming amplifiers are needed to drive the modulators, severely limiting chip-scale optoelectronic integration. Fiber-optical networks, the backbone of the internet, rely on high-fidelity information conversion from electrical to the optical domain. The researchers combined the best optical material with innovative nanofabrication and design approaches, to realize, energy-efficient, high-speed, low-loss, electro-optic converters for quantum and classical communications. Credit: Second Bay Studios/Harvard SEAS "We show that by integrating lithium niobate on a small chip, the drive voltage can be reduced to a CMOS-compatible level," said Cheng Wang, co-first author of the paper, former Ph.D. student and postdoctoral fellow at SEAS, and currently Assistant Professor at City University of Hong Kong. "Remarkably, these tiny modulators can also support data transmission rates up to 210 Gbit/s. It's like Antman—smaller, faster and better." "Highly-integrated yet high-performance optical modulators are very important for the closer integration of optics and digital electronics, paving the way towards future fiber-in-fiber-out opto-electronic processing engines," said Peter Winzer, Director of Optical Transmission Research at Nokia Bell Labs, the industrial partner in this project, and coauthor of the paper. "We see this new modulator technology as a promising candidate for such solutions." Lithium niobite is considered by many in the field to be difficult to work with on small scales, an obstacle that has so far ruled out practical integrated, on-chip applications. In previous research, Loncar and his team demonstrated a technique to fabricate high-performance lithium niobate microstructures using standard plasma etching to physically sculpt microresonators in thin lithium niobate films. Combining that technique with specially designed electrical components, the researchers can now design and fabricate an integrated, high-performance on-chip modulator. "Previously, if you wanted to make modulators smaller and more integrated, you had to compromise their performance," said Mian Zhang, a postdoctoral fellow at SEAS and co-first author of the research. "For example, existing integrated modulators can easily lose majority of the light as it propagates on the chip. In contrast, we have reduced losses by more than an order of magnitude. Essentially, we can control light without losing it." "Because a modulator is such a fundamental component of communication technology—with a role equivalent to that of a transistor in computation technology—the applications are enormous," said Zhang. "The fact that these modulators can be integrated with other components on the same platform could provide practical solutions for next-generation long distance optical networks, data center optical interconnects, wireless communications, radar, sensing and so on." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The emotional-reactivity hypothesis proposes that problem-solving abilities can be constrained by temperament, within and across species. One way to test this hypothesis is with the predictions of the Yerkes–Dodson law. The law posits that arousal level, a component of temperament, affects problem solving in an inverted U-shaped relationship: Optimal performance is reached at intermediate levels of arousal and impeded by high and low levels. Thus, a powerful test of the emotional-reactivity hypothesis is to compare cognitive performance in dog populations that have been bred and trained based in part on their arousal levels. We therefore compared a group of pet dogs to a group of assistance dogs bred and trained for low arousal ( N = 106) on a task of inhibitory control involving a detour response. Consistent with the Yerkes–Dodson law, assistance dogs, which began the test with lower levels of baseline arousal, showed improvements when arousal was artificially increased. In contrast, pet dogs, which began the test with higher levels of baseline arousal, were negatively affected when their arousal was increased. Furthermore, the dogs’ baseline levels of arousal, as measured in their rate of tail wagging, differed by population in the expected directions. Low-arousal assistance dogs showed the most inhibition in a detour task when humans eagerly encouraged them, while more highly aroused pet dogs performed worst on the same task with strong encouragement. Our findings support the hypothesis that selection on temperament can have important implications for cognitive performance. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction Successful problem solving involves well-calibrated emotional and motivational input (Blair and Diamond 2008 ; Diamond 2010 ; Hare and Tomasello 2005a ; Tooby and Cosmides 2005 ). This idea is central to the emotional-reactivity hypothesis, which posits that selection on temperament influences problem-solving capabilities in diverse species (Hare and Tomasello 2005a , b ). For example, foxes that were selected over generations based on their approach behavior and emotional response to humans are more skilled at using human gestures than a control line bred without regard to their reaction to humans (Hare et al. 2005 ). The emotional-reactivity hypothesis has been proposed to explain shifts in problem solving in a range of taxa including dogs (Hare and Tomasello 2005a ), ferrets (Hernádi et al. 2012 ), bonobos (Hare et al. 2012 ), and even humans (Cieri et al. 2014 ). One largely untested prediction of the emotional-reactivity hypothesis is that the effect of temperamental differences on problem solving will be apparent even within species (e.g., Kagan and Snidman 2004 ; Melis et al. 2006 ). Dogs provide a particularly powerful test of this prediction given the history of selection that is thought to have focused on temperamental traits such as arousal or excitability (Miklósi 2007 ). This selection has created a diversity of temperamental profiles that might be explored by comparing subpopulations of dogs on cognitive tasks. Inhibitory control is one problem-solving skill that seems to be affected across taxa by levels of emotional arousal—a component of temperament (Hare et al. 2007 ; Rosati and Hare 2013 ; Wright et al. 2011 , 2012 ; Topál et al. 2009 )—and is also known to vary widely between individuals and species (MacLean et al. 2014 ; Moffitt et al. 2011 ; Bray et al. 2014 ). Previous research has shown that the relationship between arousal and problem solving is not always linear. It is theorized that while a higher level of arousal in simple tasks promotes learning, if the task is more cognitively complex increased arousal facilitates performance only to a certain point, beyond which it is detrimental (see Fig. 1 ). Thus, the Yerkes and Dodson ( 1908 ) law in its modern interpretation predicts an inverted U-shaped relationship between arousal level and achievement on complex tasks, with performance peaking at moderate arousal levels and suffering at both high and low levels (Duffy 1957 ; Hebb 1955 ; Schlosberg 1954 ). While the predictions of the Yerkes–Dodson law have not always held up (see Watters et al. 1997 ), there have been a number of instances across species—including humans—in which the U-shaped function between arousal and problem solving has been observed (rats: Broadhurst 1957 ; chicks: Cole 1911 ; cats: Dodson 1915 ; humans: Anderson 1994 ; van der Meere et al. 1995 ). Based on the Yerkes–Dodson law and the complex cognitions involved in exerting inhibitory control, one prediction is that dogs’ arousal will affect inhibitory control in an inverted U-shaped curve depending on the temperamental selection that different populations of dogs have undergone. Fig. 1 Predictions of the Yerkes–Dodson hypothesis. For a simple task, it posits a positive linear relationship between arousal level and task performance. For a complex task, it posits an inverted U-shaped relationship, wherein increasing arousal level is linked to stronger performance only up to a certain point, after which increasing arousal harms performance Full size image Pet and assistance dogs, two populations of dogs that vary systematically in level of formal training and artificial selection, provide one way to test this prediction. Pet dogs are attuned to human gestures, but generally receive no professional training (beyond basic obedience) or systematic genetic selection (other than that which occurs spontaneously in pet dog populations). Assistance dogs, on the other hand, may be hyper-attuned to human gestures as a result of both intensive training and intentional, highly controlled selection (e.g., Topál et al. 2006 ). Furthermore, as part of their training, many working dogs are required to perform acts that require inhibitory control, such as following commands while a cat walks around the training area or while ignoring scattered dog food. Failure on tests of inhibitory control has been linked to high aggression, decreased tolerance of close contact, and negative responses to novelty in dogs (Wright et al. 2011 ). All of these traits are highly discouraged in assistance dogs and could lead to release from training and/or breeding programs. We predicted that", "role": "user" }, { "content": "People aren't the only ones who perform better on tests or athletic events when they are just a little bit nervous—dogs do too. But in dogs as in people, the right amount of stress depends on disposition. A new study by researchers at Duke University finds that a little extra stress and stimulation makes hyper dogs crack under pressure but gives mellow dogs an edge. The findings appear online in the journal Animal Cognition. According to an idea in psychology called the Yerkes-Dodson law, a little stress can be a good thing, but only up to a point. A task that isn't demanding or challenging enough can make it hard to stay engaged and perform at one's peak. But when the pressure becomes too much to handle, performance is likely to suffer again. The idea is the relationship between stress and performance follows a Goldilocks model: Both people and animals function best when the level of stress is not too much, nor too little, but just right. \"When you're taking a test, for example, it helps to be a little bit anxious so you don't just blow it off,\" said study co-author Emily Bray, who was an undergraduate at Duke at the time of the study. \"But if you're too nervous, even if you study and you really know the material, you aren't going to perform at your best.\" Researchers first observed this pattern more than a hundred years ago in lab rats, but it has since been demonstrated in chickens, cats and humans. In a new study, a Duke team consisting of Bray and evolutionary anthropologists Evan MacLean and Brian Hare of Duke's Canine Cognition Center wanted to find out if the conditions that enable certain animals to do their best also depend on the animal's underlying temperament. In a series of experiments, the researchers challenged dogs to retrieve a meat jerky treat from a person standing behind a clear plastic barrier that was six feet wide and three feet tall. To get it right, the dogs had to resist the impulse to try to take the shortest path to reach the treat—which would only cause them to whack into the barrier and bump their heads against the plastic—and instead walk around the barrier to one of the open sides. In one set of trials, an experimenter stood behind the barrier holding a treat and called the dog's name in a calm, flat voice. In another set of trials, the experimenter enthusiastically waved the treat in the air and used an urgent, excited voice. The researchers tested 30 pet dogs, ranging in age from an eight-month-old Jack Russell terrier named Enzo to an 11-year-old Vizsla named Sienna. They also tested 76 assistance dogs at Canine Companions for Independence in Santa Rosa, California, a non-profit organization that breeds and trains assistance dogs for people with disabilities. The researchers studied video recordings of each dog and estimated their baseline temperament in terms of tail wags per minute. \"The service dogs were generally more cool in the face of stress or distraction, whereas the pet dogs tended to be more excitable and high-strung,\" Bray said. Both groups of dogs were able to solve the puzzle. But the optimal amount of stress and stimulation depended on each dog's disposition. For the dogs that were naturally calm and laid-back—measured by how quickly they tended to wag their tails—increasing the level of excitement and urgency boosted their ability to stay on task and get the treat. But for excitable dogs the pattern was reversed. Increasing the level of stimulation only made them take longer. In one high-arousal trial, a two-year-old spaniel named Charlie Brown lost it and shut down, barking and zipping around crazily until she almost ran out of time. \"In the first five trials she did fine and solved the puzzle quickly with no problems,\" Bray said. \"Then when the high-arousal trials started she choked. She just couldn't figure it out.\" \"Adding more excitement pushed the pet dogs over the edge and impaired their ability to perform at their peak,\" Bray said. The results will help researchers develop better tests to determine which dogs are likely to graduate from service dog training programs, for example. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The emotional-reactivity hypothesis proposes that problem-solving abilities can be constrained by temperament, within and across species. One way to test this hypothesis is with the predictions of the Yerkes–Dodson law. The law posits that arousal level, a component of temperament, affects problem solving in an inverted U-shaped relationship: Optimal performance is reached at intermediate levels of arousal and impeded by high and low levels. Thus, a powerful test of the emotional-reactivity hypothesis is to compare cognitive performance in dog populations that have been bred and trained based in part on their arousal levels. We therefore compared a group of pet dogs to a group of assistance dogs bred and trained for low arousal ( N = 106) on a task of inhibitory control involving a detour response. Consistent with the Yerkes–Dodson law, assistance dogs, which began the test with lower levels of baseline arousal, showed improvements when arousal was artificially increased. In contrast, pet dogs, which began the test with higher levels of baseline arousal, were negatively affected when their arousal was increased. Furthermore, the dogs’ baseline levels of arousal, as measured in their rate of tail wagging, differed by population in the expected directions. Low-arousal assistance dogs showed the most inhibition in a detour task when humans eagerly encouraged them, while more highly aroused pet dogs performed worst on the same task with strong encouragement. Our findings support the hypothesis that selection on temperament can have important implications for cognitive performance. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction Successful problem solving involves well-calibrated emotional and motivational input (Blair and Diamond 2008 ; Diamond 2010 ; Hare and Tomasello 2005a ; Tooby and Cosmides 2005 ). This idea is central to the emotional-reactivity hypothesis, which posits that selection on temperament influences problem-solving capabilities in diverse species (Hare and Tomasello 2005a , b ). For example, foxes that were selected over generations based on their approach behavior and emotional response to humans are more skilled at using human gestures than a control line bred without regard to their reaction to humans (Hare et al. 2005 ). The emotional-reactivity hypothesis has been proposed to explain shifts in problem solving in a range of taxa including dogs (Hare and Tomasello 2005a ), ferrets (Hernádi et al. 2012 ), bonobos (Hare et al. 2012 ), and even humans (Cieri et al. 2014 ). One largely untested prediction of the emotional-reactivity hypothesis is that the effect of temperamental differences on problem solving will be apparent even within species (e.g., Kagan and Snidman 2004 ; Melis et al. 2006 ). Dogs provide a particularly powerful test of this prediction given the history of selection that is thought to have focused on temperamental traits such as arousal or excitability (Miklósi 2007 ). This selection has created a diversity of temperamental profiles that might be explored by comparing subpopulations of dogs on cognitive tasks. Inhibitory control is one problem-solving skill that seems to be affected across taxa by levels of emotional arousal—a component of temperament (Hare et al. 2007 ; Rosati and Hare 2013 ; Wright et al. 2011 , 2012 ; Topál et al. 2009 )—and is also known to vary widely between individuals and species (MacLean et al. 2014 ; Moffitt et al. 2011 ; Bray et al. 2014 ). Previous research has shown that the relationship between arousal and problem solving is not always linear. It is theorized that while a higher level of arousal in simple tasks promotes learning, if the task is more cognitively complex increased arousal facilitates performance only to a certain point, beyond which it is detrimental (see Fig. 1 ). Thus, the Yerkes and Dodson ( 1908 ) law in its modern interpretation predicts an inverted U-shaped relationship between arousal level and achievement on complex tasks, with performance peaking at moderate arousal levels and suffering at both high and low levels (Duffy 1957 ; Hebb 1955 ; Schlosberg 1954 ). While the predictions of the Yerkes–Dodson law have not always held up (see Watters et al. 1997 ), there have been a number of instances across species—including humans—in which the U-shaped function between arousal and problem solving has been observed (rats: Broadhurst 1957 ; chicks: Cole 1911 ; cats: Dodson 1915 ; humans: Anderson 1994 ; van der Meere et al. 1995 ). Based on the Yerkes–Dodson law and the complex cognitions involved in exerting inhibitory control, one prediction is that dogs’ arousal will affect inhibitory control in an inverted U-shaped curve depending on the temperamental selection that different populations of dogs have undergone. Fig. 1 Predictions of the Yerkes–Dodson hypothesis. For a simple task, it posits a positive linear relationship between arousal level and task performance. For a complex task, it posits an inverted U-shaped relationship, wherein increasing arousal level is linked to stronger performance only up to a certain point, after which increasing arousal harms performance Full size image Pet and assistance dogs, two populations of dogs that vary systematically in level of formal training and artificial selection, provide one way to test this prediction. Pet dogs are attuned to human gestures, but generally receive no professional training (beyond basic obedience) or systematic genetic selection (other than that which occurs spontaneously in pet dog populations). Assistance dogs, on the other hand, may be hyper-attuned to human gestures as a result of both intensive training and intentional, highly controlled selection (e.g., Topál et al. 2006 ). Furthermore, as part of their training, many working dogs are required to perform acts that require inhibitory control, such as following commands while a cat walks around the training area or while ignoring scattered dog food. Failure on tests of inhibitory control has been linked to high aggression, decreased tolerance of close contact, and negative responses to novelty in dogs (Wright et al. 2011 ). All of these traits are highly discouraged in assistance dogs and could lead to release from training and/or breeding programs. We predicted that<|im_end|> <|im_start|>assistant People aren't the only ones who perform better on tests or athletic events when they are just a little bit nervous—dogs do too. But in dogs as in people, the right amount of stress depends on disposition. A new study by researchers at Duke University finds that a little extra stress and stimulation makes hyper dogs crack under pressure but gives mellow dogs an edge. The findings appear online in the journal Animal Cognition. According to an idea in psychology called the Yerkes-Dodson law, a little stress can be a good thing, but only up to a point. A task that isn't demanding or challenging enough can make it hard to stay engaged and perform at one's peak. But when the pressure becomes too much to handle, performance is likely to suffer again. The idea is the relationship between stress and performance follows a Goldilocks model: Both people and animals function best when the level of stress is not too much, nor too little, but just right. "When you're taking a test, for example, it helps to be a little bit anxious so you don't just blow it off," said study co-author Emily Bray, who was an undergraduate at Duke at the time of the study. "But if you're too nervous, even if you study and you really know the material, you aren't going to perform at your best." Researchers first observed this pattern more than a hundred years ago in lab rats, but it has since been demonstrated in chickens, cats and humans. In a new study, a Duke team consisting of Bray and evolutionary anthropologists Evan MacLean and Brian Hare of Duke's Canine Cognition Center wanted to find out if the conditions that enable certain animals to do their best also depend on the animal's underlying temperament. In a series of experiments, the researchers challenged dogs to retrieve a meat jerky treat from a person standing behind a clear plastic barrier that was six feet wide and three feet tall. To get it right, the dogs had to resist the impulse to try to take the shortest path to reach the treat—which would only cause them to whack into the barrier and bump their heads against the plastic—and instead walk around the barrier to one of the open sides. In one set of trials, an experimenter stood behind the barrier holding a treat and called the dog's name in a calm, flat voice. In another set of trials, the experimenter enthusiastically waved the treat in the air and used an urgent, excited voice. The researchers tested 30 pet dogs, ranging in age from an eight-month-old Jack Russell terrier named Enzo to an 11-year-old Vizsla named Sienna. They also tested 76 assistance dogs at Canine Companions for Independence in Santa Rosa, California, a non-profit organization that breeds and trains assistance dogs for people with disabilities. The researchers studied video recordings of each dog and estimated their baseline temperament in terms of tail wags per minute. "The service dogs were generally more cool in the face of stress or distraction, whereas the pet dogs tended to be more excitable and high-strung," Bray said. Both groups of dogs were able to solve the puzzle. But the optimal amount of stress and stimulation depended on each dog's disposition. For the dogs that were naturally calm and laid-back—measured by how quickly they tended to wag their tails—increasing the level of excitement and urgency boosted their ability to stay on task and get the treat. But for excitable dogs the pattern was reversed. Increasing the level of stimulation only made them take longer. In one high-arousal trial, a two-year-old spaniel named Charlie Brown lost it and shut down, barking and zipping around crazily until she almost ran out of time. "In the first five trials she did fine and solved the puzzle quickly with no problems," Bray said. "Then when the high-arousal trials started she choked. She just couldn't figure it out." "Adding more excitement pushed the pet dogs over the edge and impaired their ability to perform at their peak," Bray said. The results will help researchers develop better tests to determine which dogs are likely to graduate from service dog training programs, for example. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The catalytic CO hydrogenation is one of the most versatile large-scale chemical syntheses leading to variable chemical feedstock. While traditionally mainly methanol and long-chain hydrocarbons are produced by CO hydrogenation, here we show that the same reaction can be tuned to produce long-chain n -aldehydes, 1-alcohols and olefins, as well as n -paraffins over potassium-promoted CoMn catalysts. The sum selectivity of aldehydes and alcohols is usually >50 wt% whereof up to ∼ 97% can be n -aldehydes. While the product slate contains ∼ 60% n -aldehydes at / p CO =0.5, a 65/35% slate of paraffins/alcohols is obtained at a ratio of 9. A linear Anderson–Schulz–Flory behaviour, independent of the / p CO ratio, is found for the sum of C 4+ products. We advocate a synergistic interaction between a Mn 5 O 8 oxide and a bulk Co 2 C phase, promoted by the presence of potassium, to be responsible for the unique product spectra in our studies. Introduction In his seminar ‘Zwölf Jahre Kohlenforschung’ (Twelve Years of Carbon Research, 1926) at the Kaiser-Wilhelm-Institut für Kohlenforschung in Mülheim-Ruhr (today Max Planck Institute für Kohlenforschung) 1 , Fischer informed the Kuratorium about his incapacity of reproducing the 1913 patent by Badische Anilin and Soda Fabriken (BASF) claiming hydrocarbon chain initiation through CO hydrogenation to occur in an excess of carbon monoxide 2 . On the same occasion, Fischer reported that an excess of hydrogen was actually necessary for hydrocarbon chains to form. He was puzzled by the observation that, contrary to the BASF patent claim, the oily product fraction contained no hydrocarbons but oxygenates instead. In early pilot tests, this product fraction, which he coined ‘synthol’, turned out to have physical properties enabling its use as a transportation fuel. Mittasch (leading the research at BASF) 3 as well as Fischer and Tropsch 4 , 5 chose a potassium-promoted iron catalyst for their experiments. Although in the following decades >20,000 different catalysts were empirically screened, potassium-promoted supported iron catalysts stood out for their low-cost production and good performance until present days. Similarly, following Fischer’s original suggestion, process conditions were adjusted to establish H 2 /CO pressure ratios between 1 and 2, with the actual value mainly depending on the extent of the catalyst’s water gas shift activity (producing additional hydrogen according to CO+H 2 OCO 2 +H 2 ) and on the product classes envisaged in the synthesis reaction. Decades after the original discoveries by Mittasch, and Fischer and Tropsch, the influence of the H 2 /CO pressure on the synthesis kinetics for potassium-promoted iron catalysts was systematically investigated by Dry et al . 6 , and Matsumoto and Satterfield 7 . These authors established a first-order kinetic dependence on hydrogen and a hydrocarbon chain-lengthening probability insensitive to both the actual H 2 /CO ratio and the degree of potassium promotion. It seems that similar studies for other catalysts enabling paraffins, olefins and oxygenates formation were not conducted up to date. This is all the more surprising against the background that catalyst formulations with specific selectivities for these product classes were tailored in the more recent past 8 , 9 , 10 , 11 , 12 . Based on our previous investigations of the catalytic CO hydrogenation to long-chain alcohols over ternary CoCuMn catalysts, we demonstrate here the very strong influence of the H 2 /CO pressure ratio on the product spectrum. In particular, we provide results for a potassium-promoted CoMn (‘CoMnK’ or CoMnK for simplicity, to indicate the general composition) catalyst producing straight- and long-chain aldehydes, terminal alcohols and olefins, as well as n -paraffins while changing the H 2 /CO ratio from low to high, at otherwise constant chain-lengthening probability. While aldehydes are presently produced via homogeneous hydroformylation of terminal olefins on an industrial scale, with the possibility of reducing them to terminal alcohols, our results open the door for designing a one-pot heterogeneous process with varying H 2 /CO ratios to optimize the selectivities of either product class. Results Catalytic data The rationale behind using alkali-promoted CoMn was twofold. On one hand, alkali is generally being considered a structural promoter influencing the product selectivity and increasing the overall rates of Co-based catalysts 13 . On the other hand, mixed-metal Co–Mn catalysts were previously reported to produce olefins with high selectivity 14 , 15 , 16 , 17 . To our surprise, CoMn prepared via oxalate precursors (see Methods), either alkali-promoted or not, turned out to produce significant amounts of straight-chain oxygenates in terms of aldehydes and alcohols, besides olefins and paraffins. Supplementary Table 1 provides an overview of the selectivities obtained for binary CoMn catalysts. It is seen that up to ∼ 25% oxygenates are obtained, with little influence of the actual Co/Mn ratio. Interestingly, >75% of the oxygenate fraction are n -aldehydes. For comparison, ternary CoCuMn catalysts were found to produce up to 60% alcohols under similar reaction conditions, with insignificant aldehyde side fractions 18 , 19 . The occurrence of considerable aldehyde selectivity with binary CoMn catalysts prompted us to tune their performance by including alkali in the catalyst preparation. Catalysts with a Co/Mn atomic ratio of 2/1 and 4/1 were chosen for this purpose since both demonstrated (slightly) higher aldehyde versus alcohol selectivity than those with a smaller ratio. The results in Fig. 1 refer to a H 2 /CO pressure ratio of 1.5 and demonstrate the temperature dependence of product selectivities for CoMnK catalysts containing varying amounts of potassium in comparison with binary CoMn. Figure 1: Catalytic performance. Activity and selectivity of Co 2 Mn 1 K x and Co 4 Mn 1 K x ( x =0, 0.1 and 0.3) catalysts for CO hydrogenation. Catalytic tests were carried out at P =40 bar, H 2 /CO=1.5 and total gas flow=40 ml min −1 . The same batch of catalyst was subjected to conversion at different temperatures (sequential increase from low to high). The catalytic performance of Co 4 Mn 1 K 0.1 at 220 °C was reproduced at least five times with", "role": "user" }, { "content": "A Washington State University research team has used a simple, common industrial process in a new way to create chemicals used widely as fuel additives and as feedstock for plasticizers, detergents, lubricants and cosmetics. Using the Fischer-Tropsch process to make alcohols and aldehydes in large amounts could lower the cost and energy required to produce the chemicals and possibly provide cleaner manufacturing. The work is reported in today's issue of Nature Communications. A patent has been filed on the process by Norbert Kruse, WSU Voiland Distinguished Professor, and Yizhi Xiang, a postdoctoral fellow in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering. Kruse holds a joint appointment at the U.S. Department of Energy's Pacific Northwest National Laboratory in Richland, Wash. Fischer-Tropsch process provides petrochemical alternative The Fischer-Tropsch process is a chemical reaction that uses catalysts to convert two gases, carbon monoxide and hydrogen, to liquid fuels in a simple, one-step process. It has been used for almost a century to create liquid fuels, which are made of long chains of molecules containing only carbon and hydrogen. Current industrial processes to make alcohols and aldehydes require starting with a complex, petrochemical-based target molecule, an olefin, which is then converted to liquid chemicals in a complicated series of several steps. To make the alcohols and aldehydes in the one-step Fischer-Tropsch process, the WSU researchers used a catalyst made of cobalt, manganese and potassium. To form the liquid, the two gases react at the surface of the solid catalyst. \"The catalyst preparation is really important,\" Kruse said. \"And the chemistry aspect is wonderful: Starting with only two gases, we end up with a technically useful liquid that you usually obtain only after a number of steps in petrochemical refining. I think there is a good chance for industrial implementation.\" Both cobalt and manganese are abundantly available, and the entire process could be significantly less expensive than more complicated methods. Commercialization underway The researchers also determined for the first time that they can create different amounts of chemicals depending on the ratio of carbon monoxide and hydrogen gases. \"This has rarely been done so far,\" said Kruse. \"It was most intriguing to see how easily you can influence the relative amounts of chemicals you produce without changing the length of the hydrocarbon scaffold.\" The researchers have started working with industry partners to commercialize their method. Though it has been used for almost a century, researchers don't exactly understand how the Fischer-Tropsch process works at the molecular level. \"We are making progress and are working very hard on that,\" said Kruse. \"Possibly we can crack that nut.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The catalytic CO hydrogenation is one of the most versatile large-scale chemical syntheses leading to variable chemical feedstock. While traditionally mainly methanol and long-chain hydrocarbons are produced by CO hydrogenation, here we show that the same reaction can be tuned to produce long-chain n -aldehydes, 1-alcohols and olefins, as well as n -paraffins over potassium-promoted CoMn catalysts. The sum selectivity of aldehydes and alcohols is usually >50 wt% whereof up to ∼ 97% can be n -aldehydes. While the product slate contains ∼ 60% n -aldehydes at / p CO =0.5, a 65/35% slate of paraffins/alcohols is obtained at a ratio of 9. A linear Anderson–Schulz–Flory behaviour, independent of the / p CO ratio, is found for the sum of C 4+ products. We advocate a synergistic interaction between a Mn 5 O 8 oxide and a bulk Co 2 C phase, promoted by the presence of potassium, to be responsible for the unique product spectra in our studies. Introduction In his seminar ‘Zwölf Jahre Kohlenforschung’ (Twelve Years of Carbon Research, 1926) at the Kaiser-Wilhelm-Institut für Kohlenforschung in Mülheim-Ruhr (today Max Planck Institute für Kohlenforschung) 1 , Fischer informed the Kuratorium about his incapacity of reproducing the 1913 patent by Badische Anilin and Soda Fabriken (BASF) claiming hydrocarbon chain initiation through CO hydrogenation to occur in an excess of carbon monoxide 2 . On the same occasion, Fischer reported that an excess of hydrogen was actually necessary for hydrocarbon chains to form. He was puzzled by the observation that, contrary to the BASF patent claim, the oily product fraction contained no hydrocarbons but oxygenates instead. In early pilot tests, this product fraction, which he coined ‘synthol’, turned out to have physical properties enabling its use as a transportation fuel. Mittasch (leading the research at BASF) 3 as well as Fischer and Tropsch 4 , 5 chose a potassium-promoted iron catalyst for their experiments. Although in the following decades >20,000 different catalysts were empirically screened, potassium-promoted supported iron catalysts stood out for their low-cost production and good performance until present days. Similarly, following Fischer’s original suggestion, process conditions were adjusted to establish H 2 /CO pressure ratios between 1 and 2, with the actual value mainly depending on the extent of the catalyst’s water gas shift activity (producing additional hydrogen according to CO+H 2 OCO 2 +H 2 ) and on the product classes envisaged in the synthesis reaction. Decades after the original discoveries by Mittasch, and Fischer and Tropsch, the influence of the H 2 /CO pressure on the synthesis kinetics for potassium-promoted iron catalysts was systematically investigated by Dry et al . 6 , and Matsumoto and Satterfield 7 . These authors established a first-order kinetic dependence on hydrogen and a hydrocarbon chain-lengthening probability insensitive to both the actual H 2 /CO ratio and the degree of potassium promotion. It seems that similar studies for other catalysts enabling paraffins, olefins and oxygenates formation were not conducted up to date. This is all the more surprising against the background that catalyst formulations with specific selectivities for these product classes were tailored in the more recent past 8 , 9 , 10 , 11 , 12 . Based on our previous investigations of the catalytic CO hydrogenation to long-chain alcohols over ternary CoCuMn catalysts, we demonstrate here the very strong influence of the H 2 /CO pressure ratio on the product spectrum. In particular, we provide results for a potassium-promoted CoMn (‘CoMnK’ or CoMnK for simplicity, to indicate the general composition) catalyst producing straight- and long-chain aldehydes, terminal alcohols and olefins, as well as n -paraffins while changing the H 2 /CO ratio from low to high, at otherwise constant chain-lengthening probability. While aldehydes are presently produced via homogeneous hydroformylation of terminal olefins on an industrial scale, with the possibility of reducing them to terminal alcohols, our results open the door for designing a one-pot heterogeneous process with varying H 2 /CO ratios to optimize the selectivities of either product class. Results Catalytic data The rationale behind using alkali-promoted CoMn was twofold. On one hand, alkali is generally being considered a structural promoter influencing the product selectivity and increasing the overall rates of Co-based catalysts 13 . On the other hand, mixed-metal Co–Mn catalysts were previously reported to produce olefins with high selectivity 14 , 15 , 16 , 17 . To our surprise, CoMn prepared via oxalate precursors (see Methods), either alkali-promoted or not, turned out to produce significant amounts of straight-chain oxygenates in terms of aldehydes and alcohols, besides olefins and paraffins. Supplementary Table 1 provides an overview of the selectivities obtained for binary CoMn catalysts. It is seen that up to ∼ 25% oxygenates are obtained, with little influence of the actual Co/Mn ratio. Interestingly, >75% of the oxygenate fraction are n -aldehydes. For comparison, ternary CoCuMn catalysts were found to produce up to 60% alcohols under similar reaction conditions, with insignificant aldehyde side fractions 18 , 19 . The occurrence of considerable aldehyde selectivity with binary CoMn catalysts prompted us to tune their performance by including alkali in the catalyst preparation. Catalysts with a Co/Mn atomic ratio of 2/1 and 4/1 were chosen for this purpose since both demonstrated (slightly) higher aldehyde versus alcohol selectivity than those with a smaller ratio. The results in Fig. 1 refer to a H 2 /CO pressure ratio of 1.5 and demonstrate the temperature dependence of product selectivities for CoMnK catalysts containing varying amounts of potassium in comparison with binary CoMn. Figure 1: Catalytic performance. Activity and selectivity of Co 2 Mn 1 K x and Co 4 Mn 1 K x ( x =0, 0.1 and 0.3) catalysts for CO hydrogenation. Catalytic tests were carried out at P =40 bar, H 2 /CO=1.5 and total gas flow=40 ml min −1 . The same batch of catalyst was subjected to conversion at different temperatures (sequential increase from low to high). The catalytic performance of Co 4 Mn 1 K 0.1 at 220 °C was reproduced at least five times with<|im_end|> <|im_start|>assistant A Washington State University research team has used a simple, common industrial process in a new way to create chemicals used widely as fuel additives and as feedstock for plasticizers, detergents, lubricants and cosmetics. Using the Fischer-Tropsch process to make alcohols and aldehydes in large amounts could lower the cost and energy required to produce the chemicals and possibly provide cleaner manufacturing. The work is reported in today's issue of Nature Communications. A patent has been filed on the process by Norbert Kruse, WSU Voiland Distinguished Professor, and Yizhi Xiang, a postdoctoral fellow in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering. Kruse holds a joint appointment at the U.S. Department of Energy's Pacific Northwest National Laboratory in Richland, Wash. Fischer-Tropsch process provides petrochemical alternative The Fischer-Tropsch process is a chemical reaction that uses catalysts to convert two gases, carbon monoxide and hydrogen, to liquid fuels in a simple, one-step process. It has been used for almost a century to create liquid fuels, which are made of long chains of molecules containing only carbon and hydrogen. Current industrial processes to make alcohols and aldehydes require starting with a complex, petrochemical-based target molecule, an olefin, which is then converted to liquid chemicals in a complicated series of several steps. To make the alcohols and aldehydes in the one-step Fischer-Tropsch process, the WSU researchers used a catalyst made of cobalt, manganese and potassium. To form the liquid, the two gases react at the surface of the solid catalyst. "The catalyst preparation is really important," Kruse said. "And the chemistry aspect is wonderful: Starting with only two gases, we end up with a technically useful liquid that you usually obtain only after a number of steps in petrochemical refining. I think there is a good chance for industrial implementation." Both cobalt and manganese are abundantly available, and the entire process could be significantly less expensive than more complicated methods. Commercialization underway The researchers also determined for the first time that they can create different amounts of chemicals depending on the ratio of carbon monoxide and hydrogen gases. "This has rarely been done so far," said Kruse. "It was most intriguing to see how easily you can influence the relative amounts of chemicals you produce without changing the length of the hydrocarbon scaffold." The researchers have started working with industry partners to commercialize their method. Though it has been used for almost a century, researchers don't exactly understand how the Fischer-Tropsch process works at the molecular level. "We are making progress and are working very hard on that," said Kruse. "Possibly we can crack that nut." <|im_end|>

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2,077

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Ninety-six months of crime incident data were examined to determine the extent to which crime counts changed within the Philadelphia neighborhood of Fishtown after the opening of a new casino. Count modeling regression results indicate that the operation of the casino had no significant effect on violent street felonies, vehicle crime, drug crime or residential burglary in the surrounding community. Weighted displacement quotient analyses suggest that the operation of the casino may be associated with an increase in vehicle crime in the area surrounding the casino neighborhood, indicative of crime displacement. Drug and residential burglary offenses in the area surrounding the casino neighborhood decreased after the casino opened, suggestive of a diffusion of benefits possibly tied to a change in local police patrols. Net of unexamined police patrol changes and casino opening simultaneity effects, the current study is unable to identify a neighborhood level effect of the casino on crime. Additional research is necessary to examine localized effects of casinos on various offenses. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction Before the last decade the presence of casinos had been limited to a few well-known sites in the United States. Atlantic City (NJ), Reno and Las Vegas (NV), and numerous Indian reservations have been able to capitalize on this limited presence by becoming central hubs for gaming and associated industries. The American recession of the early 2000s as well as continued national (and international) economic woes have, however, caused many lawmakers to reconsider whether the added tax revenue of the gaming industry outweighs its perceived costs. For example, the Pennsylvania Gaming Control Board (2011b) was charged with the oversight of the casino industry and was the first such state organization created in 40 years. Since then, Pennsylvania has authorized the development of 10 gaming establishments within its borders. This move received substantial (though not unequivocal) support from local politicians and it is clear why; according to the Pennsylvania Gaming Control Board (2011a) , slot machines were responsible for US$2.2 billion in revenue for the state during the 2009–2010 fiscal year. Thus the desirability of casinos in cash-strapped states should come as no surprise. Notwithstanding expected monetary benefits, anti-casino interest groups have articulated potential costs that are expected to be associated with casino development. Among these include beliefs that gambling will precipitate a host of social problems such as alcoholism, gambling addiction and organized crime, and that the gambling industry will exploit the poor and elderly ( Casino-Free Philadelphia, 2012 ). Social and economic cost concerns have also been expressed by state-level governmental agencies ( Pennsylvania Intergovernmental Cooperation Authority, 2007 ). In Maryland, Attorney General Curran (1995) released a damning opinion of casinos, arguing that they would lead to substantial increases in violent, property, domestic, white collar and organized crime, as well as child abuse. The federal government also has weighed in on the effects of gambling on American society. In 1996 Congress authorized creation of the National Gambling Impact Study Commission (1999) . The Commission was charged to ‘ … conduct a comprehensive legal and factual study of the social and economic impacts of gambling on (A) Federal, state, local, and Native American tribal governments; and (B) communities and social institutions generally, including individuals, families, and businesses within such communities and institutions’ ( National Gambling Impact Study Commission, 1999 , pp. IV–2). Although it was hesitant to form conclusions on the casino/crime relationship, citing issues with current research, two points are noteworthy. First, the Commission’s review of research suggested that studies were disproportionately based on pathological gamblers – individuals that may engage in crime to fund their gambling habit. As such, crimes attributed to pathological gambling may be substantially different from those attributed to non-pathological gambling. Second, in order to accurately associate crime with the casino industry, one must distinguish the gaming industry from the larger tourism industry (see also Miller and Schwartz, 1998 ). Unfortunately, research to address the perceived disorder and crime-producing effects of casinos has been limited to the municipality and county levels, leaving our understanding of more micro-level neighborhood impacts limited. When the SugarHouse Casino opened its doors in September 2010, just outside of downtown Philadelphia and in the largest city in the United States to host a representative of the gaming industry ( Associated Press, 2010 ), we had an opportunity to examine the criminogenic impact of casinos within a more localized environmental context. The contributions of the current study are threefold. First, we examine the relationship between the location of an urban casino and its immediate surrounding neighborhood, rather than focusing on a larger areal unit such as the city or county. Second, we provide a new perspective on the casino/crime link by considering it within the context of Philadelphia. Urban casino research to date has overwhelmingly focused on cities historically known for their expansive gambling/entertainment districts. Philadelphia has no such district with legal gambling, which allows this research to avoid the need to theoretically or empirically disentangle the effect of tourism from any crime-generating effects of the casino. Third, the availability of geolocated crime data allows us to examine any changes in crime volume in the immediate neighborhood environment of the casino alongside potential displacement or diffusion of benefits effects ( Clarke and Weisburd, 1994 ). The remainder of the article is structured as follows. First, we review prior literature on casinos and crime, organized by spatial unit of analysis. Second, the study site is described. Third, a methodology for examining the relationship between casinos and neighborhood crime is presented. After results are outlined, we conclude with a discussion of the implications of neighborhood level investigations of the casinos and crime link. Literature Review City-level research The most common research on casinos and crime has focused on the effects of casino development on cities and towns in the Atlantic City (NJ) region. Albanese (1985) was among the first to investigate the role of casinos on urban crime, using", "role": "user" }, { "content": "Philadelphia's SugarHouse Casino opened its doors in September 2010 after years of protests from community members who feared that the casino would lead to an increase in neighborhood crime. However, a new study by researchers at Drexel University and Temple University reveals that these concerns were unfounded. The study, which used geolocated crime data to examine changes in crime volume in the immediate neighborhood of the casino since its opening, found that crime rates in the Fishtown neighborhood of Philadelphia were largely unaffected by the introduction of the gaming establishment. The researchers found that any potential significant crime increases either did not occur or were effectively controlled by a reassignment of existing local police officers. Entitled \"A Partial Test of the Impact of a Casino on Neighborhood Crime,\" the study was published online on June 30 by Palgrave MacMillan's Security Journal, a peer-reviewed journal for security researchers and professionals. It is expected to run in an upcoming print issue of the journal. The study was conducted by Lallen T. Johnson, PhD, an assistant professor of criminal justice in Drexel University's College of Arts and Sciences, and Jerry H. Ratcliffe, PhD, a professor and chair of the Department of Criminal Justice at Temple University. \"The arrival of the gaming industry to the city of Philadelphia was met with much controversy and protest,\" said Johnson. \"In particular, anti-casino community activists and organizations believed that gambling would lead to increased crime and disorder. Early discussions about the arrival of SugarHouse revolved around whether the added tax revenue would outweigh the social cost of the expected increased crime. Although reasonable concerns, our findings suggest that these negative expectations did not play out in this case.\" In order to examine neighborhood-level crime-causing effects of a casino in a localized urban environment, Johnson and Ratcliffe analyzed 96 months of crime incident data to determine the extent to which crime counts changed within the Fishtown neighborhood after the casino's opening. The researchers used the data to evaluate the effect of the new casino development on four crime types – violent street felonies, vehicle crime, residential burglary and drug crime – at the neighborhood level. \"Prior studies of casinos and crime have considered the influence of gaming establishments on entire cities or counties,\" Johnson said. \"This study, on the other hand, is the first to examine how casinos influence crime at the neighborhood level. This is particularly important considering that SugarHouse is situated near residential developments. The study also looked at whether crime was displaced to surrounding areas after opening.\" Key findings include:Violent street felonies increased at a rate slightly greater than violence in the control area; however, this increase was not statistically significant when examined in the context of the longer trend since 2004.Vehicle crime decreased in the casino area; however, there was substantial displacement and the reductions in vehicle crime were not statistically significant over the long term.Both residential burglary and drug crime decreased in the casino area (again though, not significantly from a statistical perspective) and there were reductions in these crimes in the buffer areas. In summary, there is no evidence that the opening and operation of the casino had a significantly detrimental effect on the immediate neighborhood in terms of violent street felonies, vehicle crime, residential burglary or drug crimes. There was evidence, however, that some vehicle crime – including vehicle thefts and thefts from vehicles – was displaced to the surrounding community. According to the researchers, there may be a number of explanations for these findings. First, as a 24-hour facility, the casino may inadvertently attract more individuals to the area. Potential offenders may, as a result, opt to commit crime elsewhere believing that the odds of detection have increased. Second, in anticipation of the casino opening, the 26th police district commander created a special patrol district that works closely with SugarHouse management. The strategic allocation of police resources may be partially responsible for suppressing crime in the area. \"It is important to revitalize urban areas without inadvertently creating criminal opportunities,\" Ratcliffe said. \"With no increases in violence, burglary or drug crime, we hope that the community and the police are reassured by these findings.\" In spite of the relatively positive results, it would be premature to generalize the findings of this study to other neighborhoods with casinos, according to the researchers. Instead, this study shows that is important to study potential linkages between casinos and crime at multiple levels of analysis, such as neighborhood, city, county and state. \"While our findings here do not settle the debate on casino and crime linkages, they do contribute to a growing body of knowledge and suggest a need for more neighborhood-level research,\" said Johnson. \"At the very least, the findings demonstrate that common community concerns regarding local crime conditions with the addition of a gaming establishment to the neighborhood were not borne out by the SugarHouse example.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Ninety-six months of crime incident data were examined to determine the extent to which crime counts changed within the Philadelphia neighborhood of Fishtown after the opening of a new casino. Count modeling regression results indicate that the operation of the casino had no significant effect on violent street felonies, vehicle crime, drug crime or residential burglary in the surrounding community. Weighted displacement quotient analyses suggest that the operation of the casino may be associated with an increase in vehicle crime in the area surrounding the casino neighborhood, indicative of crime displacement. Drug and residential burglary offenses in the area surrounding the casino neighborhood decreased after the casino opened, suggestive of a diffusion of benefits possibly tied to a change in local police patrols. Net of unexamined police patrol changes and casino opening simultaneity effects, the current study is unable to identify a neighborhood level effect of the casino on crime. Additional research is necessary to examine localized effects of casinos on various offenses. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction Before the last decade the presence of casinos had been limited to a few well-known sites in the United States. Atlantic City (NJ), Reno and Las Vegas (NV), and numerous Indian reservations have been able to capitalize on this limited presence by becoming central hubs for gaming and associated industries. The American recession of the early 2000s as well as continued national (and international) economic woes have, however, caused many lawmakers to reconsider whether the added tax revenue of the gaming industry outweighs its perceived costs. For example, the Pennsylvania Gaming Control Board (2011b) was charged with the oversight of the casino industry and was the first such state organization created in 40 years. Since then, Pennsylvania has authorized the development of 10 gaming establishments within its borders. This move received substantial (though not unequivocal) support from local politicians and it is clear why; according to the Pennsylvania Gaming Control Board (2011a) , slot machines were responsible for US$2.2 billion in revenue for the state during the 2009–2010 fiscal year. Thus the desirability of casinos in cash-strapped states should come as no surprise. Notwithstanding expected monetary benefits, anti-casino interest groups have articulated potential costs that are expected to be associated with casino development. Among these include beliefs that gambling will precipitate a host of social problems such as alcoholism, gambling addiction and organized crime, and that the gambling industry will exploit the poor and elderly ( Casino-Free Philadelphia, 2012 ). Social and economic cost concerns have also been expressed by state-level governmental agencies ( Pennsylvania Intergovernmental Cooperation Authority, 2007 ). In Maryland, Attorney General Curran (1995) released a damning opinion of casinos, arguing that they would lead to substantial increases in violent, property, domestic, white collar and organized crime, as well as child abuse. The federal government also has weighed in on the effects of gambling on American society. In 1996 Congress authorized creation of the National Gambling Impact Study Commission (1999) . The Commission was charged to ‘ … conduct a comprehensive legal and factual study of the social and economic impacts of gambling on (A) Federal, state, local, and Native American tribal governments; and (B) communities and social institutions generally, including individuals, families, and businesses within such communities and institutions’ ( National Gambling Impact Study Commission, 1999 , pp. IV–2). Although it was hesitant to form conclusions on the casino/crime relationship, citing issues with current research, two points are noteworthy. First, the Commission’s review of research suggested that studies were disproportionately based on pathological gamblers – individuals that may engage in crime to fund their gambling habit. As such, crimes attributed to pathological gambling may be substantially different from those attributed to non-pathological gambling. Second, in order to accurately associate crime with the casino industry, one must distinguish the gaming industry from the larger tourism industry (see also Miller and Schwartz, 1998 ). Unfortunately, research to address the perceived disorder and crime-producing effects of casinos has been limited to the municipality and county levels, leaving our understanding of more micro-level neighborhood impacts limited. When the SugarHouse Casino opened its doors in September 2010, just outside of downtown Philadelphia and in the largest city in the United States to host a representative of the gaming industry ( Associated Press, 2010 ), we had an opportunity to examine the criminogenic impact of casinos within a more localized environmental context. The contributions of the current study are threefold. First, we examine the relationship between the location of an urban casino and its immediate surrounding neighborhood, rather than focusing on a larger areal unit such as the city or county. Second, we provide a new perspective on the casino/crime link by considering it within the context of Philadelphia. Urban casino research to date has overwhelmingly focused on cities historically known for their expansive gambling/entertainment districts. Philadelphia has no such district with legal gambling, which allows this research to avoid the need to theoretically or empirically disentangle the effect of tourism from any crime-generating effects of the casino. Third, the availability of geolocated crime data allows us to examine any changes in crime volume in the immediate neighborhood environment of the casino alongside potential displacement or diffusion of benefits effects ( Clarke and Weisburd, 1994 ). The remainder of the article is structured as follows. First, we review prior literature on casinos and crime, organized by spatial unit of analysis. Second, the study site is described. Third, a methodology for examining the relationship between casinos and neighborhood crime is presented. After results are outlined, we conclude with a discussion of the implications of neighborhood level investigations of the casinos and crime link. Literature Review City-level research The most common research on casinos and crime has focused on the effects of casino development on cities and towns in the Atlantic City (NJ) region. Albanese (1985) was among the first to investigate the role of casinos on urban crime, using<|im_end|> <|im_start|>assistant Philadelphia's SugarHouse Casino opened its doors in September 2010 after years of protests from community members who feared that the casino would lead to an increase in neighborhood crime. However, a new study by researchers at Drexel University and Temple University reveals that these concerns were unfounded. The study, which used geolocated crime data to examine changes in crime volume in the immediate neighborhood of the casino since its opening, found that crime rates in the Fishtown neighborhood of Philadelphia were largely unaffected by the introduction of the gaming establishment. The researchers found that any potential significant crime increases either did not occur or were effectively controlled by a reassignment of existing local police officers. Entitled "A Partial Test of the Impact of a Casino on Neighborhood Crime," the study was published online on June 30 by Palgrave MacMillan's Security Journal, a peer-reviewed journal for security researchers and professionals. It is expected to run in an upcoming print issue of the journal. The study was conducted by Lallen T. Johnson, PhD, an assistant professor of criminal justice in Drexel University's College of Arts and Sciences, and Jerry H. Ratcliffe, PhD, a professor and chair of the Department of Criminal Justice at Temple University. "The arrival of the gaming industry to the city of Philadelphia was met with much controversy and protest," said Johnson. "In particular, anti-casino community activists and organizations believed that gambling would lead to increased crime and disorder. Early discussions about the arrival of SugarHouse revolved around whether the added tax revenue would outweigh the social cost of the expected increased crime. Although reasonable concerns, our findings suggest that these negative expectations did not play out in this case." In order to examine neighborhood-level crime-causing effects of a casino in a localized urban environment, Johnson and Ratcliffe analyzed 96 months of crime incident data to determine the extent to which crime counts changed within the Fishtown neighborhood after the casino's opening. The researchers used the data to evaluate the effect of the new casino development on four crime types – violent street felonies, vehicle crime, residential burglary and drug crime – at the neighborhood level. "Prior studies of casinos and crime have considered the influence of gaming establishments on entire cities or counties," Johnson said. "This study, on the other hand, is the first to examine how casinos influence crime at the neighborhood level. This is particularly important considering that SugarHouse is situated near residential developments. The study also looked at whether crime was displaced to surrounding areas after opening." Key findings include:Violent street felonies increased at a rate slightly greater than violence in the control area; however, this increase was not statistically significant when examined in the context of the longer trend since 2004.Vehicle crime decreased in the casino area; however, there was substantial displacement and the reductions in vehicle crime were not statistically significant over the long term.Both residential burglary and drug crime decreased in the casino area (again though, not significantly from a statistical perspective) and there were reductions in these crimes in the buffer areas. In summary, there is no evidence that the opening and operation of the casino had a significantly detrimental effect on the immediate neighborhood in terms of violent street felonies, vehicle crime, residential burglary or drug crimes. There was evidence, however, that some vehicle crime – including vehicle thefts and thefts from vehicles – was displaced to the surrounding community. According to the researchers, there may be a number of explanations for these findings. First, as a 24-hour facility, the casino may inadvertently attract more individuals to the area. Potential offenders may, as a result, opt to commit crime elsewhere believing that the odds of detection have increased. Second, in anticipation of the casino opening, the 26th police district commander created a special patrol district that works closely with SugarHouse management. The strategic allocation of police resources may be partially responsible for suppressing crime in the area. "It is important to revitalize urban areas without inadvertently creating criminal opportunities," Ratcliffe said. "With no increases in violence, burglary or drug crime, we hope that the community and the police are reassured by these findings." In spite of the relatively positive results, it would be premature to generalize the findings of this study to other neighborhoods with casinos, according to the researchers. Instead, this study shows that is important to study potential linkages between casinos and crime at multiple levels of analysis, such as neighborhood, city, county and state. "While our findings here do not settle the debate on casino and crime linkages, they do contribute to a growing body of knowledge and suggest a need for more neighborhood-level research," said Johnson. "At the very least, the findings demonstrate that common community concerns regarding local crime conditions with the addition of a gaming establishment to the neighborhood were not borne out by the SugarHouse example." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Glacier retreat poses risks and benefits for species of cultural and economic importance. One example is Pacific salmon ( Oncorhynchus spp.), supporting subsistence harvests, and commercial and recreational fisheries worth billions of dollars annually. Although decreases in summer streamflow and warming freshwater is reducing salmon habitat quality in parts of their range, glacier retreat is creating new streams and lakes that salmon can colonize. However, potential gains in future salmon habitat associated with glacier loss have yet to be quantified across the range of Pacific salmon. Here we project future gains in Pacific salmon freshwater habitat by linking a model of glacier mass change for 315 glaciers, forced by five different Global Climate Models, with a simple model of salmon stream habitat potential throughout the Pacific Mountain ranges of western North America. We project that by the year 2100 glacier retreat will create 6,146 (±1,619) km of new streams accessible for colonization by Pacific salmon, of which 1,930 (±569) km have the potential to be used for spawning and juvenile rearing, representing 0 to 27% gains within the 18 sub-regions we studied. These findings can inform proactive management and conservation of Pacific salmon in this era of rapid climate change. Introduction Climate change is driving rapid changes in Earth’s ecosystems with new challenges and opportunities in resource management. For example, the loss of Arctic ice is posing risks to culturally important species like polar bears 1 , but also creating frontiers for emerging fisheries 2 . One group of species being strongly impacted by climate change is migratory Pacific salmon ( Oncorhynchus spp) 3 . Although Pacific salmon abundances have shifted from region to region over decades to centuries in response to climatic variability 4 , ocean heat waves, low summer water flows, and excessively warm water temperatures are currently stressing many wild salmon populations 3 , 5 . At the same time, the warming of Arctic and subarctic freshwaters 6 and contemporary glacier retreat 7 , 8 are creating potential new frontiers for salmon. While glacier retreat can have a variety of direct and indirect impacts on salmon ecosystems 9 , 10 , 11 , 12 , over the next century retreat of glacier ice will create new streams that, if not too steep for salmon migration, can provide future salmon habitat. For example, pink salmon abundance grew to >5000 adult spawners within ~15 years of a new stream (~2 km) and lake system being created following glacier retreat in Glacier Bay, Alaska 8 . Although salmon colonization of recently deglaciated streams has been well documented in individual watersheds 8 , predicting future shifts in the distribution of productive salmon habitat remains a challenge, and there are no regional projections for the creation of new salmon habitat in response to retreating glaciers. Forecasting the location of emerging salmon habitat is imperative because, while declining glacier ice can present local opportunities for salmon, it is also creating new prospects for large-scale resource extraction industries such as mining, which have the potential to degrade these salmon habitat frontiers 13 , 14 , 15 , 16 . Understanding the timing and location of emerging salmon habitat frontiers throughout the Pacific Mountain ranges of western North America can inform forward-looking management decision-making and conservation planning. The ~46,000 glaciers in the Pacific mountain ranges of North America cover an area of ~81,000 km 2 , 17 , of which 80% fall within the range of Pacific salmon (Fig. 1a ). These glaciers are rapidly declining in volume, thickness, and area, accelerated by recent anthropogenic climate warming 18 , 19 , 20 . For example, between 2006 and 2016, glaciers in western Canada lost an average of 1% of their ice mass annually 21 and are projected to lose up to 80% of their ice volume by 2100 in some regions 22 . Fig. 1: Pacific salmon range in glacierized watersheds and how glaciers will create new streams. a Map showing the Pacific salmon range in North America (pink), and our study region (blue). Glacier outlines are in grey. The black box indicates the location of example focal area, shown in b Harriman Glacier, Prince William Sound, Alaska, showing approximate glacier retreat (for the benchmark years 2050 and 2100), future salmon-accessible streams (<10% stream gradient threshold over ~500 m; blue and black), and suitable habitat below a 0–2% stream gradient over ~500 m (blue). Thicker lines represent higher stream orders and narrower lines represent lower stream orders. Streams >10% stream gradient threshold are marked with an X and colored in red. Full size image Here we quantify emerging salmon streams created from glacier retreat, by using Digital Elevation Models within a Geographic Information Systems framework to derive a synthetic stream network for glacierized watersheds in the 623,000 km 2 region extending from southern British Columbia to southcentral Alaska (Fig. 1a ). Synthetic stream networks include both present-day and future salmon streams (Methods). Using stream gradient-based salmon migration thresholds, we identify which glaciers are accessible to salmon (Methods). For the accessible glaciers within the 18 sub-regions of our study region, we model the timing of glacier retreat 23 and derive future stream networks based on sub-glacial terrain (Fig. 1b ). Modeled glacier retreat was driven by temperature and precipitation projections from an ensemble of five Global Climate Models (GCM; Methods) forced by two climate emission scenarios (Representative Concentration Pathways, RCP), RCP4.5 and 8.5, under which global emissions are expected to peak at ~2050 and after 2100, respectively 24 . We present both scenarios but focus on the more moderate RCP4.5. Here, we show where and when glacier retreat will create thousands of kilometers of new streams accessible for colonization by Pacific salmon, many of which are potentially suitable for spawning and juvenile rearing. We quantify two dimensions of future salmon habitat: the total future salmon-accessible stream kilometers (kms) and, of this amount, the habitat suitable for spawning and juvenile rearing. First, we quantify the extent of the stream network colonizable by adult migrating salmon based", "role": "user" }, { "content": "Retreating glaciers in the Pacific mountains of western North America could produce around 6,150 kilometers of new Pacific salmon habitat by the year 2100, according to a new study. Scientists have 'peeled back the ice' from 46,000 glaciers between southern British Columbia and south-central Alaska to look at how much potential salmon habitat would be created when underlying bedrock is exposed and new streams flow over the landscape. Modeling glacier retreat under different climate change scenarios, researchers discovered that, under a moderate temperature increase, the glaciers could reveal potential new Pacific salmon habitat nearly equal to the length of the Mississippi River (6,275 km). Desirable for salmon, in this case, means low-gradient streams (less than 10% incline) connected to the ocean with retreating glaciers at their headwaters. The team discovered that 315 of the glaciers examined met this criteria. The international team, led by researchers at Simon Fraser University (Canada) with University of Birmingham (UK) and other organizations, published their findings today in Nature Communications. Lead author, Simon Fraser University spatial analyst Dr. Kara Pitman comments: \"We predict that most of the emerging salmon habitat will occur in Alaska and the transboundary region, at the British Columbia‒Alaska border, where large coastal glaciers still exist. The Gulf of Alaska sub-region is predicted to see the most gains—a 27% increase in salmon-accessible habitat by 2100. Exit Glacier, in Alaska, is one of hundreds of glaciers that are melting and retreating creating new salmon habitat. Credit: Alexander Milner. \"Once conditions stabilize in the newly-formed streams, salmon can colonize these areas quite quickly. It's a common misconception that all salmon return home to the streams they were born in. Most do, but some individuals will stray—migrating into new streams to spawn and, if conditions are favorable, the population can increase rapidly.\" Co-author Professor Alexander Milner from the University of Birmingham has researched glacial retreat and salmon populations in southeast Alaska for over three decades. His team have worked on Stonefly Creek in Glacier Bay where glacier retreat reveal a new stream in the late 1970s and he comments \"Colonization by salmon can occur relatively quickly after glacial retreat creates favorable spawning habitat in the new stream. For example, Stonefly Creek was colonized within 10 years by pink salmon that grew rapidly to more than 5,000 spawners. Other species also colonized including Coho and Sockeye salmon, especially where a lake is associated with the stream\" The researchers caution that while the newly created habitat is a positive for salmon in some locations; overall, climate change still poses grave challenges for some salmon populations. \"On one hand, this amount of new salmon habitat will provide local opportunities for some salmon populations,\" says Dr. Pitman. \"On the other hand, climate change and other human impacts continue to threaten salmon survival—via warming rivers, changes in stream flows, and poor ocean conditions. \"Climate change means we increasingly need to look to the future. We can't just protect current-day habitat for species but need to consider what habitats they might rely on in the future.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Glacier retreat poses risks and benefits for species of cultural and economic importance. One example is Pacific salmon ( Oncorhynchus spp.), supporting subsistence harvests, and commercial and recreational fisheries worth billions of dollars annually. Although decreases in summer streamflow and warming freshwater is reducing salmon habitat quality in parts of their range, glacier retreat is creating new streams and lakes that salmon can colonize. However, potential gains in future salmon habitat associated with glacier loss have yet to be quantified across the range of Pacific salmon. Here we project future gains in Pacific salmon freshwater habitat by linking a model of glacier mass change for 315 glaciers, forced by five different Global Climate Models, with a simple model of salmon stream habitat potential throughout the Pacific Mountain ranges of western North America. We project that by the year 2100 glacier retreat will create 6,146 (±1,619) km of new streams accessible for colonization by Pacific salmon, of which 1,930 (±569) km have the potential to be used for spawning and juvenile rearing, representing 0 to 27% gains within the 18 sub-regions we studied. These findings can inform proactive management and conservation of Pacific salmon in this era of rapid climate change. Introduction Climate change is driving rapid changes in Earth’s ecosystems with new challenges and opportunities in resource management. For example, the loss of Arctic ice is posing risks to culturally important species like polar bears 1 , but also creating frontiers for emerging fisheries 2 . One group of species being strongly impacted by climate change is migratory Pacific salmon ( Oncorhynchus spp) 3 . Although Pacific salmon abundances have shifted from region to region over decades to centuries in response to climatic variability 4 , ocean heat waves, low summer water flows, and excessively warm water temperatures are currently stressing many wild salmon populations 3 , 5 . At the same time, the warming of Arctic and subarctic freshwaters 6 and contemporary glacier retreat 7 , 8 are creating potential new frontiers for salmon. While glacier retreat can have a variety of direct and indirect impacts on salmon ecosystems 9 , 10 , 11 , 12 , over the next century retreat of glacier ice will create new streams that, if not too steep for salmon migration, can provide future salmon habitat. For example, pink salmon abundance grew to >5000 adult spawners within ~15 years of a new stream (~2 km) and lake system being created following glacier retreat in Glacier Bay, Alaska 8 . Although salmon colonization of recently deglaciated streams has been well documented in individual watersheds 8 , predicting future shifts in the distribution of productive salmon habitat remains a challenge, and there are no regional projections for the creation of new salmon habitat in response to retreating glaciers. Forecasting the location of emerging salmon habitat is imperative because, while declining glacier ice can present local opportunities for salmon, it is also creating new prospects for large-scale resource extraction industries such as mining, which have the potential to degrade these salmon habitat frontiers 13 , 14 , 15 , 16 . Understanding the timing and location of emerging salmon habitat frontiers throughout the Pacific Mountain ranges of western North America can inform forward-looking management decision-making and conservation planning. The ~46,000 glaciers in the Pacific mountain ranges of North America cover an area of ~81,000 km 2 , 17 , of which 80% fall within the range of Pacific salmon (Fig. 1a ). These glaciers are rapidly declining in volume, thickness, and area, accelerated by recent anthropogenic climate warming 18 , 19 , 20 . For example, between 2006 and 2016, glaciers in western Canada lost an average of 1% of their ice mass annually 21 and are projected to lose up to 80% of their ice volume by 2100 in some regions 22 . Fig. 1: Pacific salmon range in glacierized watersheds and how glaciers will create new streams. a Map showing the Pacific salmon range in North America (pink), and our study region (blue). Glacier outlines are in grey. The black box indicates the location of example focal area, shown in b Harriman Glacier, Prince William Sound, Alaska, showing approximate glacier retreat (for the benchmark years 2050 and 2100), future salmon-accessible streams (<10% stream gradient threshold over ~500 m; blue and black), and suitable habitat below a 0–2% stream gradient over ~500 m (blue). Thicker lines represent higher stream orders and narrower lines represent lower stream orders. Streams >10% stream gradient threshold are marked with an X and colored in red. Full size image Here we quantify emerging salmon streams created from glacier retreat, by using Digital Elevation Models within a Geographic Information Systems framework to derive a synthetic stream network for glacierized watersheds in the 623,000 km 2 region extending from southern British Columbia to southcentral Alaska (Fig. 1a ). Synthetic stream networks include both present-day and future salmon streams (Methods). Using stream gradient-based salmon migration thresholds, we identify which glaciers are accessible to salmon (Methods). For the accessible glaciers within the 18 sub-regions of our study region, we model the timing of glacier retreat 23 and derive future stream networks based on sub-glacial terrain (Fig. 1b ). Modeled glacier retreat was driven by temperature and precipitation projections from an ensemble of five Global Climate Models (GCM; Methods) forced by two climate emission scenarios (Representative Concentration Pathways, RCP), RCP4.5 and 8.5, under which global emissions are expected to peak at ~2050 and after 2100, respectively 24 . We present both scenarios but focus on the more moderate RCP4.5. Here, we show where and when glacier retreat will create thousands of kilometers of new streams accessible for colonization by Pacific salmon, many of which are potentially suitable for spawning and juvenile rearing. We quantify two dimensions of future salmon habitat: the total future salmon-accessible stream kilometers (kms) and, of this amount, the habitat suitable for spawning and juvenile rearing. First, we quantify the extent of the stream network colonizable by adult migrating salmon based<|im_end|> <|im_start|>assistant Retreating glaciers in the Pacific mountains of western North America could produce around 6,150 kilometers of new Pacific salmon habitat by the year 2100, according to a new study. Scientists have 'peeled back the ice' from 46,000 glaciers between southern British Columbia and south-central Alaska to look at how much potential salmon habitat would be created when underlying bedrock is exposed and new streams flow over the landscape. Modeling glacier retreat under different climate change scenarios, researchers discovered that, under a moderate temperature increase, the glaciers could reveal potential new Pacific salmon habitat nearly equal to the length of the Mississippi River (6,275 km). Desirable for salmon, in this case, means low-gradient streams (less than 10% incline) connected to the ocean with retreating glaciers at their headwaters. The team discovered that 315 of the glaciers examined met this criteria. The international team, led by researchers at Simon Fraser University (Canada) with University of Birmingham (UK) and other organizations, published their findings today in Nature Communications. Lead author, Simon Fraser University spatial analyst Dr. Kara Pitman comments: "We predict that most of the emerging salmon habitat will occur in Alaska and the transboundary region, at the British Columbia‒Alaska border, where large coastal glaciers still exist. The Gulf of Alaska sub-region is predicted to see the most gains—a 27% increase in salmon-accessible habitat by 2100. Exit Glacier, in Alaska, is one of hundreds of glaciers that are melting and retreating creating new salmon habitat. Credit: Alexander Milner. "Once conditions stabilize in the newly-formed streams, salmon can colonize these areas quite quickly. It's a common misconception that all salmon return home to the streams they were born in. Most do, but some individuals will stray—migrating into new streams to spawn and, if conditions are favorable, the population can increase rapidly." Co-author Professor Alexander Milner from the University of Birmingham has researched glacial retreat and salmon populations in southeast Alaska for over three decades. His team have worked on Stonefly Creek in Glacier Bay where glacier retreat reveal a new stream in the late 1970s and he comments "Colonization by salmon can occur relatively quickly after glacial retreat creates favorable spawning habitat in the new stream. For example, Stonefly Creek was colonized within 10 years by pink salmon that grew rapidly to more than 5,000 spawners. Other species also colonized including Coho and Sockeye salmon, especially where a lake is associated with the stream" The researchers caution that while the newly created habitat is a positive for salmon in some locations; overall, climate change still poses grave challenges for some salmon populations. "On one hand, this amount of new salmon habitat will provide local opportunities for some salmon populations," says Dr. Pitman. "On the other hand, climate change and other human impacts continue to threaten salmon survival—via warming rivers, changes in stream flows, and poor ocean conditions. "Climate change means we increasingly need to look to the future. We can't just protect current-day habitat for species but need to consider what habitats they might rely on in the future." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Interspecies hydrogen transfer in anoxic ecosystems is essential for the complete microbial breakdown of organic matter to methane. Acetogenic bacteria are key players in anaerobic food webs and have been considered as prime candidates for hydrogen cycling. We have tested this hypothesis by mutational analysis of the hydrogenase in the model acetogen Acetobacterium woodii . Hydrogenase-deletion mutants no longer grew on H 2 + CO 2 or organic substrates such as fructose, lactate, or ethanol. Heterotrophic growth could be restored by addition of molecular hydrogen to the culture, indicating that hydrogen is an intermediate in heterotrophic growth. Indeed, hydrogen production from fructose was detected in a stirred-tank reactor. The mutant grew well on organic substrates plus caffeate, an alternative electron acceptor that does not require molecular hydrogen but NADH as reductant. These data are consistent with the notion that molecular hydrogen is produced from organic substrates and then used as reductant for CO 2 reduction. Surprisingly, hydrogen cycling in A. woodii is different from the known modes of interspecies or intraspecies hydrogen cycling. Our data are consistent with a novel type of hydrogen cycling that connects an oxidative and reductive metabolic module in one bacterial cell, “intracellular syntrophy.” Introduction Molecular hydrogen is present only in trace concentrations (550 parts per billion) in the Earth’s atmosphere [ 1 ], but plays an important part in the global carbon cycle and is a major constituent of microbial metabolism. In anoxic ecosystems it is rapidly produced and consumed by microorganisms resulting in a large turnover [ 2 ]. Hydrogen connects different parts of the anaerobic food web and is usually produced by primary fermenters [ 3 ]. Fermentations typically yield between 1 and 4 mol of ATP per mol of sugar, and the maximum is only observed if electrons can be blown away into the environment as molecular hydrogen thus allowing the cells to make acetate according to Eq. ( 1 ) [ 4 ]: $${\\rm{C}}_{6}{\\rm{H}}_{12}{\\rm{O}}_{6} + {\\rm{2H}}_{2}{\\rm{O}} + {\\rm{4ADP}} + {\\rm{4P}}_{\\rm{i}}{\\longrightarrow}{\\rm{2CH}}_{3}{\\rm{COOH}} \\\\ + {\\rm{2CO}}_{2} + {\\rm{4H}}_{2} + {\\rm{4ATP}} \\,\\,\\, \\Delta{\\rm{G}}^{0\\prime} = −206.3 \\,\\,{\\rm{{kJ/mol}}}$$ (1) However, hydrogen formation from reduced pyridine nucleotides or flavins is energetically unfavourable and growth according to Eq. ( 1 ) requires removal of hydrogen by a syntrophic partner such as a sulfate reducing bacterium, a methanogenic archaeon or an acetogenic bacterium [ 5 , 6 , 7 , 8 ]. The latter produces acetate according to Eq. ( 2 ): $$4{\\rm{H}}_{2} + {\\rm{2CO}}_{2} + {\\rm{xADP}} + {\\rm{xP}}_{\\rm{i}}{\\longrightarrow} {\\rm{CH}}_{3}{\\rm{COOH}} \\\\ + {\\rm{2H}}_{2}{\\rm{O}} + {\\rm{xATP}}\\,\\,\\,\\Delta{\\rm{G}}^{0\\prime} = −95 \\,\\,{\\rm{{kJ/mol}}}$$ (2) Since acetogens grow by conversion of H 2 + CO 2 to acetate, the reaction has to be coupled to net synthesis of ATP [ 9 ]. Detailed studies in the acetogenic model organism Acetobacterium woodii estimated the amount of ATP to 0.3 mol per mol of acetate produced [ 9 ]. In contrast to methanogenic archaea, acetogenic bacteria do not only grow lithotrophically according to Eq. ( 2 ) but also by fermentation [ 10 ]. Acetogenesis is a modular metabolism with an oxidative and a reductive branch [ 11 ] (Fig. 1 ). In the oxidative branch, hydrogen (during lithotrophic growth) or an organic carbon and energy source (during heterotrophic growth) are oxidised. Electrons are carried over to the reductive branch (the Wood-Ljungdahl pathway [WLP]) in which 2 mol of CO 2 are reduced to acetate according to Eq. ( 2 ). Overall, fermentation of fructose to three molecules of acetate by a combination of Eqs. ( 1 ) and ( 2 ) gives the highest ATP yield in fermenting bacteria of 4.3 mol ATP/mol of sugar [ 11 ]. Fig. 1: The modularity of acetogenesis in A. woodii . Shown are the oxidation of fructose to acetate in the oxidative branch (left) and the reduction of CO 2 to acetate (right) in the reductive branch (WLP). Redox balancing is achieved by a third module, in which the Rnf complex and the electron-bifurcating hydrogenase produce the reductants required for the the WLP. Fd, ferredoxin; Fd 2− , reduced ferredoxin; THF, tetrahydrofolate; HDCR, hydrogen-dependent CO 2 reductase; CODH/ACS, carbon monoxide dehydrogenase/acetyl-CoA synthetase; Co-FeS-P, corronoid iron-sulfur protein. Full size image Electron carriers involved in transferring electrons from the oxidative to the reductive branch in acetogens are NADH, NADPH, or reduced ferredoxin [ 9 ]. A third module, the redox balance module, ensures that the different reduced electron carriers from the oxidative module are fed in and are converted to the specific redox carriers required by the WLP [ 11 ]. In the model acetogen A. woodii , 2 mol of NADH from glycolysis and 2 mol of reduced ferredoxin from conversion of pyruvate to acetyl-CoA are converted to 1 mol of hydrogen, 2 mol of NADH and 1 mol of reduced ferredoxin by the combined action of the Rnf complex and the electron-bifurcating hydrogenase [ 11 , 12 ]. NADH is used as reductant for the methylene-tetrahydrofolate (THF) reductase [ 13 ] and the methylene-THF dehydrogenase [ 14 ], and reduced ferredoxin is used by the CO dehydrogenase/acetyl-CoA synthase as electron donor for CO 2 reduction in the carbonyl branch of the WLP [ 15 , 16 ]. In contrast, the first enzyme used for CO 2 reduction in the methyl branch of A. woodii (Fig. 1 ), the hydrogen-dependent CO 2 reductase (HDCR), uses H 2 as reductant in vitro [ 17 ], indicating the need for electron transfer via hydrogen from the oxidative module (glycolysis) to the reductive module (CO 2 reduction). On the other hand, the purified HDCR can also accept electrons from reduced ferredoxin, albeit with 17-fold lower activities [ 17 ]. To address a potential hydrogen transfer from the oxidative to the reductive branch of the acetogenic metabolism, we have deleted the only hydrogenase in A. woodii and studied the phenotype of the mutant. Materials and methods Growth of A. woodii A. woodii DSM1030 was cultivated at 30 °C under anoxic conditions in complex medium as previously described [ 18 ]. When using the pyrE", "role": "user" }, { "content": "They make sauerkraut sour, turn milk into yogurt and cheese, and give rye bread its intensive flavour: bacteria that ferment nutrients instead of using oxygen to extract their energy. Acetobacterium woodii (short: A. woodii) is one of these anaerobic living microbes. Cheese and bread are not its line of business—it lives far from oxygen in the sediments on the floor of the ocean, and can also be found in sewage treatment plants and the intestines of termites. These biotopes are teeming with microbes that use the organic substances to their advantage in different ways. A number of bacteria ferment sugars, fatty acids and alcohols to acetic acid, also creating hydrogen (H2) in the process. In higher concentration, however, hydrogen inhibits the fermentation—too much hydrogen stops the fermentation reaction. For this reason, fermenting bacteria live together with microbes that depend on precisely this hydrogen—methanogens, for example, that create methane from hydrogen and carbon dioxide and thus gain energy. Both partners profit from this association—and are simultaneously so dependent on each other that neither one can survive without the other. A. woodii masters both disciplines of the anaerobic \"hydrogen association\": it can ferment organic substances into acetic acid, and can also form acetic acid from carbon dioxide and hydrogen. In doing so, A. woodii recycles the important hydrogen within its own cell, as has now been discovered by the microbiologists in Professor Volker Müller's team at the Institute for Molecular Biosciences at Goethe University Frankfurt. In the laboratory, the Frankfurt scientists turned off the gene for the enzyme that creates hydrogen in A. woodii, which is called hydrogenase. The result: the bacterium was only able to grow, for example in a medium with fructose, if hydrogen was added externally. Different additional tests confirmed that both paths for creating acetic acid are connected to hydrogen that does not leave the cell. \"Though the 'hydrogen recycling' we discovered, A. woodii possesses a maximum of metabolic flexibility,\" says the Frankfurt experimenter Dr. Anja Wiechmann. \"In one cycle, it can both create and use hydrogen itself, or utilise hydrogen from external sources. This makes it capable of living both from organic as well as solely from inorganic substances.\" Professor Volker Müller explains: \"Our findings have implications far beyond the study of Acetobacterium woodii. There have already been speculations that many ancient life forms possess the kind of metabolism that we have described in A. woodii. This is assumed, for example for the Asgard archaea that were just discovered a few years ago on the seabed off of California. Our investigations provide the first evidence that these paths of metabolism actually exist.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Interspecies hydrogen transfer in anoxic ecosystems is essential for the complete microbial breakdown of organic matter to methane. Acetogenic bacteria are key players in anaerobic food webs and have been considered as prime candidates for hydrogen cycling. We have tested this hypothesis by mutational analysis of the hydrogenase in the model acetogen Acetobacterium woodii . Hydrogenase-deletion mutants no longer grew on H 2 + CO 2 or organic substrates such as fructose, lactate, or ethanol. Heterotrophic growth could be restored by addition of molecular hydrogen to the culture, indicating that hydrogen is an intermediate in heterotrophic growth. Indeed, hydrogen production from fructose was detected in a stirred-tank reactor. The mutant grew well on organic substrates plus caffeate, an alternative electron acceptor that does not require molecular hydrogen but NADH as reductant. These data are consistent with the notion that molecular hydrogen is produced from organic substrates and then used as reductant for CO 2 reduction. Surprisingly, hydrogen cycling in A. woodii is different from the known modes of interspecies or intraspecies hydrogen cycling. Our data are consistent with a novel type of hydrogen cycling that connects an oxidative and reductive metabolic module in one bacterial cell, “intracellular syntrophy.” Introduction Molecular hydrogen is present only in trace concentrations (550 parts per billion) in the Earth’s atmosphere [ 1 ], but plays an important part in the global carbon cycle and is a major constituent of microbial metabolism. In anoxic ecosystems it is rapidly produced and consumed by microorganisms resulting in a large turnover [ 2 ]. Hydrogen connects different parts of the anaerobic food web and is usually produced by primary fermenters [ 3 ]. Fermentations typically yield between 1 and 4 mol of ATP per mol of sugar, and the maximum is only observed if electrons can be blown away into the environment as molecular hydrogen thus allowing the cells to make acetate according to Eq. ( 1 ) [ 4 ]: $${\rm{C}}_{6}{\rm{H}}_{12}{\rm{O}}_{6} + {\rm{2H}}_{2}{\rm{O}} + {\rm{4ADP}} + {\rm{4P}}_{\rm{i}}{\longrightarrow}{\rm{2CH}}_{3}{\rm{COOH}} \\ + {\rm{2CO}}_{2} + {\rm{4H}}_{2} + {\rm{4ATP}} \,\,\, \Delta{\rm{G}}^{0\prime} = −206.3 \,\,{\rm{{kJ/mol}}}$$ (1) However, hydrogen formation from reduced pyridine nucleotides or flavins is energetically unfavourable and growth according to Eq. ( 1 ) requires removal of hydrogen by a syntrophic partner such as a sulfate reducing bacterium, a methanogenic archaeon or an acetogenic bacterium [ 5 , 6 , 7 , 8 ]. The latter produces acetate according to Eq. ( 2 ): $$4{\rm{H}}_{2} + {\rm{2CO}}_{2} + {\rm{xADP}} + {\rm{xP}}_{\rm{i}}{\longrightarrow} {\rm{CH}}_{3}{\rm{COOH}} \\ + {\rm{2H}}_{2}{\rm{O}} + {\rm{xATP}}\,\,\,\Delta{\rm{G}}^{0\prime} = −95 \,\,{\rm{{kJ/mol}}}$$ (2) Since acetogens grow by conversion of H 2 + CO 2 to acetate, the reaction has to be coupled to net synthesis of ATP [ 9 ]. Detailed studies in the acetogenic model organism Acetobacterium woodii estimated the amount of ATP to 0.3 mol per mol of acetate produced [ 9 ]. In contrast to methanogenic archaea, acetogenic bacteria do not only grow lithotrophically according to Eq. ( 2 ) but also by fermentation [ 10 ]. Acetogenesis is a modular metabolism with an oxidative and a reductive branch [ 11 ] (Fig. 1 ). In the oxidative branch, hydrogen (during lithotrophic growth) or an organic carbon and energy source (during heterotrophic growth) are oxidised. Electrons are carried over to the reductive branch (the Wood-Ljungdahl pathway [WLP]) in which 2 mol of CO 2 are reduced to acetate according to Eq. ( 2 ). Overall, fermentation of fructose to three molecules of acetate by a combination of Eqs. ( 1 ) and ( 2 ) gives the highest ATP yield in fermenting bacteria of 4.3 mol ATP/mol of sugar [ 11 ]. Fig. 1: The modularity of acetogenesis in A. woodii . Shown are the oxidation of fructose to acetate in the oxidative branch (left) and the reduction of CO 2 to acetate (right) in the reductive branch (WLP). Redox balancing is achieved by a third module, in which the Rnf complex and the electron-bifurcating hydrogenase produce the reductants required for the the WLP. Fd, ferredoxin; Fd 2− , reduced ferredoxin; THF, tetrahydrofolate; HDCR, hydrogen-dependent CO 2 reductase; CODH/ACS, carbon monoxide dehydrogenase/acetyl-CoA synthetase; Co-FeS-P, corronoid iron-sulfur protein. Full size image Electron carriers involved in transferring electrons from the oxidative to the reductive branch in acetogens are NADH, NADPH, or reduced ferredoxin [ 9 ]. A third module, the redox balance module, ensures that the different reduced electron carriers from the oxidative module are fed in and are converted to the specific redox carriers required by the WLP [ 11 ]. In the model acetogen A. woodii , 2 mol of NADH from glycolysis and 2 mol of reduced ferredoxin from conversion of pyruvate to acetyl-CoA are converted to 1 mol of hydrogen, 2 mol of NADH and 1 mol of reduced ferredoxin by the combined action of the Rnf complex and the electron-bifurcating hydrogenase [ 11 , 12 ]. NADH is used as reductant for the methylene-tetrahydrofolate (THF) reductase [ 13 ] and the methylene-THF dehydrogenase [ 14 ], and reduced ferredoxin is used by the CO dehydrogenase/acetyl-CoA synthase as electron donor for CO 2 reduction in the carbonyl branch of the WLP [ 15 , 16 ]. In contrast, the first enzyme used for CO 2 reduction in the methyl branch of A. woodii (Fig. 1 ), the hydrogen-dependent CO 2 reductase (HDCR), uses H 2 as reductant in vitro [ 17 ], indicating the need for electron transfer via hydrogen from the oxidative module (glycolysis) to the reductive module (CO 2 reduction). On the other hand, the purified HDCR can also accept electrons from reduced ferredoxin, albeit with 17-fold lower activities [ 17 ]. To address a potential hydrogen transfer from the oxidative to the reductive branch of the acetogenic metabolism, we have deleted the only hydrogenase in A. woodii and studied the phenotype of the mutant. Materials and methods Growth of A. woodii A. woodii DSM1030 was cultivated at 30 °C under anoxic conditions in complex medium as previously described [ 18 ]. When using the pyrE<|im_end|> <|im_start|>assistant They make sauerkraut sour, turn milk into yogurt and cheese, and give rye bread its intensive flavour: bacteria that ferment nutrients instead of using oxygen to extract their energy. Acetobacterium woodii (short: A. woodii) is one of these anaerobic living microbes. Cheese and bread are not its line of business—it lives far from oxygen in the sediments on the floor of the ocean, and can also be found in sewage treatment plants and the intestines of termites. These biotopes are teeming with microbes that use the organic substances to their advantage in different ways. A number of bacteria ferment sugars, fatty acids and alcohols to acetic acid, also creating hydrogen (H2) in the process. In higher concentration, however, hydrogen inhibits the fermentation—too much hydrogen stops the fermentation reaction. For this reason, fermenting bacteria live together with microbes that depend on precisely this hydrogen—methanogens, for example, that create methane from hydrogen and carbon dioxide and thus gain energy. Both partners profit from this association—and are simultaneously so dependent on each other that neither one can survive without the other. A. woodii masters both disciplines of the anaerobic "hydrogen association": it can ferment organic substances into acetic acid, and can also form acetic acid from carbon dioxide and hydrogen. In doing so, A. woodii recycles the important hydrogen within its own cell, as has now been discovered by the microbiologists in Professor Volker Müller's team at the Institute for Molecular Biosciences at Goethe University Frankfurt. In the laboratory, the Frankfurt scientists turned off the gene for the enzyme that creates hydrogen in A. woodii, which is called hydrogenase. The result: the bacterium was only able to grow, for example in a medium with fructose, if hydrogen was added externally. Different additional tests confirmed that both paths for creating acetic acid are connected to hydrogen that does not leave the cell. "Though the 'hydrogen recycling' we discovered, A. woodii possesses a maximum of metabolic flexibility," says the Frankfurt experimenter Dr. Anja Wiechmann. "In one cycle, it can both create and use hydrogen itself, or utilise hydrogen from external sources. This makes it capable of living both from organic as well as solely from inorganic substances." Professor Volker Müller explains: "Our findings have implications far beyond the study of Acetobacterium woodii. There have already been speculations that many ancient life forms possess the kind of metabolism that we have described in A. woodii. This is assumed, for example for the Asgard archaea that were just discovered a few years ago on the seabed off of California. Our investigations provide the first evidence that these paths of metabolism actually exist." <|im_end|>

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2,255

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the past few years, a new state of quantum matter known as the time-reversal-invariant topological insulator has been predicted theoretically and realized experimentally. All of the topological insulators discovered so far in experiment are inversion symmetric 1 , 2 , 3 , 4 , 5 —except for strained HgTe, which has weak inversion asymmetry, a small bulk gap but no bulk charge polarization 6 . Strong inversion asymmetry in topological insulators would not only lead to many interesting phenomena, such as crystalline-surface-dependent topological electronic states, pyroelectricity and intrinsic topological p–n junctions, but would also serve as an ideal platform for the realization of topological magneto-electric effects 7 , 8 , which result from the modification of Maxwell equations in topological insulators. Here we report the discovery of a strong inversion asymmetric topological insulator phase in BiTeCl by angle-resolved photoemission spectroscopy, which reveals Dirac surface states and crystalline-surface-dependent electronic structures. Moreover, we observe a tenfold increase of the bulk energy gap in BiTeCl over the weak inversion asymmetric topological insulator HgTe, making it a promising platform for topological phenomena and possible applications at high temperature. Main Topological insulators represent a new state of quantum matter with a bulk energy gap and robust surface states formed by an odd number of Dirac fermions with helical spin texture. The gaplessness of the surface states is protected by the time-reversal symmetry. Depending on their crystal structure, topological insulators may or may not preserve inversion symmetry. Although the presence of inversion symmetry is helpful in identifying topological insulators owing to the existence of the parity criterion 9 , the search for inversion asymmetric topological insulators (IATIs) persists 8 , 10 , 11 , 12 , 13 as an effort to realize new topological phenomena in practical material systems. IATIs have many unusual properties. For example, in an IATI, the top and bottom crystal surfaces are in-equivalent, resulting in different surface electronic structures. If the charge carriers of different surface states are opposite ( Fig. 1a ), a natural topological p–n junction is formed ( Fig. 1a ), enabling chiral edge states in a magnetic field that can carry dissipationless transport 14 . Furthermore, when an IATI is driven to the topological phase transition towards a trivial insulator, Weyl semimetals can be realized at the phase transition with interesting topological properties 15 , 16 ; and the broken inversion symmetry may also lead to topological superconductivity if an IATI is driven to a superconducting phase 17 . IATIs are also ideal candidates for the realization of the topological magneto-electric effects 8 , 10 (TMEs), which requires breaking both the inversion and time-reversal symmetries. For a usual inversion symmetric topological insulator (ISTI), this demands opposite magnetization on opposite surfaces ( Fig. 1b,d ), posing a great challenge for the experimental realization. On the contrary, in an IATI, a uniform magnetic field (or ferromagnetic order) will be sufficient to induce the TME effects ( Fig. 1c,e ) as the inversion symmetry is naturally broken by the crystal structure. Figure 1: Introduction and applications of IATIs. a , Illustration of a topological p–n junction formed by top and bottom surfaces of a polar topological insulator. The different E F positions of the top and bottom Dirac cones are shown in the inset. b , c , Under a uniform magnetic field, an electric field E does not induce a magnetic moment in an ISTI ( b ), whereas it does introduce a magnetic moment M in an IATI ( c ). FM, ferromagnetic. d , e , Experimental set-up for realizing the TME effect in an ISTI ( d ) and an IATI ( e ). f , g , Crystal structures of inversion asymmetric compounds BiTeCl ( f ) and BiTeI ( g ); the two adjacent Te–Bi–Cl triple layers are laterally offset ( f ) whereas the two Te–Bi–I layers are not ( g ). h , i , Crystal structures of the IATIs compounds Bi 2 Te 3 ( h ) and TlBiSe 2 ( i ). Full size image So far, all topological insulators experimentally discovered preserve inversion symmetry—such as the Bi 1− x Sb x alloy 1 , V 2 – VI 3 family compounds (Bi 2 Se 3 , Bi 2 Te 3 and Sb 2 Te 3 ; refs 2 , 3 ) and III – V – VI 2 family compounds (for example, TlBiSe 2 ; refs 4 , 5 ), except for strained HgTe (ref. 6 ), which is inversion asymmetric owing to its zinc blende structure. However, the inversion asymmetry in HgTe is weak in the sense that the crystal shows no net charge polarization (as we will discuss later). In addition, the small bulk bandgap ( ∼ 20 meV) of HgTe induced by strain 6 severely limits the temperature under which new topological phenomena can be observed. Here, we studied two V – VI – VII compounds (BiTeCl and BiTeI) using angle-resolved photoemission spectroscopy (ARPES) to investigate their electronic structures. In both materials, we found that the electronic structures from opposite crystal surfaces (with halogen or chalcogen termination, respectively) are significantly different as a result of the strong inversion asymmetry. In fact, the difference is so pronounced that the charge carriers on the two surfaces become opposite types, leading to strong bulk charge polarization. Surprisingly, for BiTeCl, we observed a single surface Dirac cone inside the bulk energy gap, making it the first strong inversion asymmetric polar (and also pyroelectric) topological insulator candidate. Furthermore, the bulk energy gap observed in BiTeCl was ∼ 220 meV, showing a tenfold increase over that for strained HgTe (refs 6 , 18 ; ∼ 20 meV). For BiTeI, we observed no topological surface states; however, in addition to the Rashba splitting in its bulk conduction band (BCB) recently reported 19 , 20 , we found that the bulk valence band (BVB) also has Rashba splitting, suggesting that both n- and p-type BiTeI may be good candidates for spintronic applications. The", "role": "user" }, { "content": "A new compound developed at Tokyo Tech shows highly unusual conducting properties that could be used in future electronic components. Ordinary insulating solids, such as diamond, have energy bands that are fully occupied by electrons. The conducting band is so far away from the valence band in diamond that electrons do not have sufficient energy to move - the 'band gap' is large - therefore no electric current can be carried. In recent years, researchers have become interested in materials called topological insulators (TIs), which act as insulators on the inside, but are highly conductive on their surfaces. In TIs, an exceptionally strong spin-orbit interaction inverts the energy gap between occupied and empty states, so that electrons at the surface can flow across the gap. These properties are intrinsic to the material, meaning a TI remains conductive even if its surface is not perfect. Now, an international team of scientists from Japan, the UK and the USA, led by Takao Sasagawa at Tokyo Institute of Technology, have successfully developed a new TI from bismuth, tellurium and chlorine (BiTeCl). Their new TI is inversion asymmetric, meaning it has different electronic states, and therefore different polarities, on each crystal surface. As a result, it exhibits many topological effects that have not been seen experimentally before. \"The metallic surface state of a TI is similar to graphene in that the electron mobility is remarkably high due to zero-mass electrons, or Dirac fermions,\" explains Sasagawa. \" The Dirac fermions have a characteristic spin and in this context they can host a wide range of exotic quantum phenomena. Symmetry-breaking is the best way of inducing these fascinating topological effects.\" Fig. 2: Electronic structures of BiTeCl's top and bottom crystal surfaces observed by photoemission spectroscopy. Sasagawa and his team optimised their laboratory growing conditions to produce single crystals of BiTeCl. They then split each single crystal to obtain two different surfaces - one Te and one Cl - and observed their electronic structures using spectroscopy. The composition of the TI's top and bottom crystal surfaces are such that their charge carriers are opposite, leading to polarization. The TI can therefore be used as a diode, allowing current flow in only one direction. It also exhibits pyroelectric capabilities, meaning that it can generate a temporary voltage when heated or cooled. BiTeCl shows promise as a platform for other topological phenomena, and may have applications at high temperatures. The discovery could also have significant implications for the development of quantum-based technologies in future, as Sasagawa explains: \" We would like to discover a topological superconductor whose surface can host Majorana fermions - particles which are their own antiparticles, and could be used for the development of topological quantum computing.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the past few years, a new state of quantum matter known as the time-reversal-invariant topological insulator has been predicted theoretically and realized experimentally. All of the topological insulators discovered so far in experiment are inversion symmetric 1 , 2 , 3 , 4 , 5 —except for strained HgTe, which has weak inversion asymmetry, a small bulk gap but no bulk charge polarization 6 . Strong inversion asymmetry in topological insulators would not only lead to many interesting phenomena, such as crystalline-surface-dependent topological electronic states, pyroelectricity and intrinsic topological p–n junctions, but would also serve as an ideal platform for the realization of topological magneto-electric effects 7 , 8 , which result from the modification of Maxwell equations in topological insulators. Here we report the discovery of a strong inversion asymmetric topological insulator phase in BiTeCl by angle-resolved photoemission spectroscopy, which reveals Dirac surface states and crystalline-surface-dependent electronic structures. Moreover, we observe a tenfold increase of the bulk energy gap in BiTeCl over the weak inversion asymmetric topological insulator HgTe, making it a promising platform for topological phenomena and possible applications at high temperature. Main Topological insulators represent a new state of quantum matter with a bulk energy gap and robust surface states formed by an odd number of Dirac fermions with helical spin texture. The gaplessness of the surface states is protected by the time-reversal symmetry. Depending on their crystal structure, topological insulators may or may not preserve inversion symmetry. Although the presence of inversion symmetry is helpful in identifying topological insulators owing to the existence of the parity criterion 9 , the search for inversion asymmetric topological insulators (IATIs) persists 8 , 10 , 11 , 12 , 13 as an effort to realize new topological phenomena in practical material systems. IATIs have many unusual properties. For example, in an IATI, the top and bottom crystal surfaces are in-equivalent, resulting in different surface electronic structures. If the charge carriers of different surface states are opposite ( Fig. 1a ), a natural topological p–n junction is formed ( Fig. 1a ), enabling chiral edge states in a magnetic field that can carry dissipationless transport 14 . Furthermore, when an IATI is driven to the topological phase transition towards a trivial insulator, Weyl semimetals can be realized at the phase transition with interesting topological properties 15 , 16 ; and the broken inversion symmetry may also lead to topological superconductivity if an IATI is driven to a superconducting phase 17 . IATIs are also ideal candidates for the realization of the topological magneto-electric effects 8 , 10 (TMEs), which requires breaking both the inversion and time-reversal symmetries. For a usual inversion symmetric topological insulator (ISTI), this demands opposite magnetization on opposite surfaces ( Fig. 1b,d ), posing a great challenge for the experimental realization. On the contrary, in an IATI, a uniform magnetic field (or ferromagnetic order) will be sufficient to induce the TME effects ( Fig. 1c,e ) as the inversion symmetry is naturally broken by the crystal structure. Figure 1: Introduction and applications of IATIs. a , Illustration of a topological p–n junction formed by top and bottom surfaces of a polar topological insulator. The different E F positions of the top and bottom Dirac cones are shown in the inset. b , c , Under a uniform magnetic field, an electric field E does not induce a magnetic moment in an ISTI ( b ), whereas it does introduce a magnetic moment M in an IATI ( c ). FM, ferromagnetic. d , e , Experimental set-up for realizing the TME effect in an ISTI ( d ) and an IATI ( e ). f , g , Crystal structures of inversion asymmetric compounds BiTeCl ( f ) and BiTeI ( g ); the two adjacent Te–Bi–Cl triple layers are laterally offset ( f ) whereas the two Te–Bi–I layers are not ( g ). h , i , Crystal structures of the IATIs compounds Bi 2 Te 3 ( h ) and TlBiSe 2 ( i ). Full size image So far, all topological insulators experimentally discovered preserve inversion symmetry—such as the Bi 1− x Sb x alloy 1 , V 2 – VI 3 family compounds (Bi 2 Se 3 , Bi 2 Te 3 and Sb 2 Te 3 ; refs 2 , 3 ) and III – V – VI 2 family compounds (for example, TlBiSe 2 ; refs 4 , 5 ), except for strained HgTe (ref. 6 ), which is inversion asymmetric owing to its zinc blende structure. However, the inversion asymmetry in HgTe is weak in the sense that the crystal shows no net charge polarization (as we will discuss later). In addition, the small bulk bandgap ( ∼ 20 meV) of HgTe induced by strain 6 severely limits the temperature under which new topological phenomena can be observed. Here, we studied two V – VI – VII compounds (BiTeCl and BiTeI) using angle-resolved photoemission spectroscopy (ARPES) to investigate their electronic structures. In both materials, we found that the electronic structures from opposite crystal surfaces (with halogen or chalcogen termination, respectively) are significantly different as a result of the strong inversion asymmetry. In fact, the difference is so pronounced that the charge carriers on the two surfaces become opposite types, leading to strong bulk charge polarization. Surprisingly, for BiTeCl, we observed a single surface Dirac cone inside the bulk energy gap, making it the first strong inversion asymmetric polar (and also pyroelectric) topological insulator candidate. Furthermore, the bulk energy gap observed in BiTeCl was ∼ 220 meV, showing a tenfold increase over that for strained HgTe (refs 6 , 18 ; ∼ 20 meV). For BiTeI, we observed no topological surface states; however, in addition to the Rashba splitting in its bulk conduction band (BCB) recently reported 19 , 20 , we found that the bulk valence band (BVB) also has Rashba splitting, suggesting that both n- and p-type BiTeI may be good candidates for spintronic applications. The<|im_end|> <|im_start|>assistant A new compound developed at Tokyo Tech shows highly unusual conducting properties that could be used in future electronic components. Ordinary insulating solids, such as diamond, have energy bands that are fully occupied by electrons. The conducting band is so far away from the valence band in diamond that electrons do not have sufficient energy to move - the 'band gap' is large - therefore no electric current can be carried. In recent years, researchers have become interested in materials called topological insulators (TIs), which act as insulators on the inside, but are highly conductive on their surfaces. In TIs, an exceptionally strong spin-orbit interaction inverts the energy gap between occupied and empty states, so that electrons at the surface can flow across the gap. These properties are intrinsic to the material, meaning a TI remains conductive even if its surface is not perfect. Now, an international team of scientists from Japan, the UK and the USA, led by Takao Sasagawa at Tokyo Institute of Technology, have successfully developed a new TI from bismuth, tellurium and chlorine (BiTeCl). Their new TI is inversion asymmetric, meaning it has different electronic states, and therefore different polarities, on each crystal surface. As a result, it exhibits many topological effects that have not been seen experimentally before. "The metallic surface state of a TI is similar to graphene in that the electron mobility is remarkably high due to zero-mass electrons, or Dirac fermions," explains Sasagawa. " The Dirac fermions have a characteristic spin and in this context they can host a wide range of exotic quantum phenomena. Symmetry-breaking is the best way of inducing these fascinating topological effects." Fig. 2: Electronic structures of BiTeCl's top and bottom crystal surfaces observed by photoemission spectroscopy. Sasagawa and his team optimised their laboratory growing conditions to produce single crystals of BiTeCl. They then split each single crystal to obtain two different surfaces - one Te and one Cl - and observed their electronic structures using spectroscopy. The composition of the TI's top and bottom crystal surfaces are such that their charge carriers are opposite, leading to polarization. The TI can therefore be used as a diode, allowing current flow in only one direction. It also exhibits pyroelectric capabilities, meaning that it can generate a temporary voltage when heated or cooled. BiTeCl shows promise as a platform for other topological phenomena, and may have applications at high temperatures. The discovery could also have significant implications for the development of quantum-based technologies in future, as Sasagawa explains: " We would like to discover a topological superconductor whose surface can host Majorana fermions - particles which are their own antiparticles, and could be used for the development of topological quantum computing." <|im_end|>

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1116, 13, 220, 21, 7026, 902, 374, 47588, 97929, 56612, 311, 1202, 49601, 1529, 11178, 6070, 13, 4452, 11, 279, 47588, 54395, 33342, 304, 473, 70, 6777, 374, 7621, 304, 279, 5647, 430, 279, 26110, 5039, 912, 4272, 6900, 83245, 320, 300, 584, 690, 4358, 3010, 570, 763, 5369, 11, 279, 2678, 20155, 7200, 42510, 320, 12264, 120, 220, 508, 757, 53, 8, 315, 473, 70, 6777, 36572, 555, 26800, 220, 21, 35906, 13693, 279, 9499, 1234, 902, 502, 1948, 5848, 44247, 649, 387, 13468, 13, 5810, 11, 584, 20041, 1403, 650, 1389, 30768, 1389, 46069, 32246, 320, 37196, 6777, 5176, 323, 12371, 6777, 40, 8, 1701, 9392, 11849, 8905, 6685, 336, 7711, 66425, 51856, 320, 43893, 1600, 8, 311, 19874, 872, 14683, 14726, 13, 763, 2225, 7384, 11, 584, 1766, 430, 279, 14683, 14726, 505, 14329, 26110, 27529, 320, 4291, 15104, 11968, 477, 523, 17356, 11968, 35508, 11, 15947, 8, 527, 12207, 2204, 439, 264, 1121, 315, 279, 3831, 47588, 54395, 33342, 13, 763, 2144, 11, 279, 6811, 374, 779, 38617, 430, 279, 6900, 35991, 389, 279, 1403, 27529, 3719, 14329, 4595, 11, 6522, 311, 3831, 20155, 6900, 83245, 13, 8242, 49264, 11, 369, 12371, 6777, 5176, 11, 584, 13468, 264, 3254, 7479, 31194, 582, 22949, 4871, 279, 20155, 4907, 13225, 11, 3339, 433, 279, 1176, 3831, 47588, 97929, 25685, 320, 438, 1101, 4611, 299, 64465, 8, 1948, 5848, 1672, 10733, 9322, 13, 24296, 11, 279, 20155, 4907, 13225, 13468, 304, 12371, 6777, 5176, 574, 12264, 120, 220, 8610, 757, 53, 11, 9204, 264, 5899, 20557, 5376, 927, 430, 369, 73779, 473, 70, 6777, 320, 16541, 220, 21, 1174, 220, 972, 2652, 12264, 120, 220, 508, 757, 53, 570, 1789, 12371, 6777, 40, 11, 584, 13468, 912, 1948, 5848, 7479, 5415, 26, 4869, 11, 304, 5369, 311, 279, 60483, 4749, 45473, 304, 1202, 20155, 390, 23985, 7200, 320, 5002, 33, 8, 6051, 5068, 220, 777, 1174, 220, 508, 1174, 584, 1766, 430, 279, 20155, 1062, 768, 7200, 320, 33, 37974, 8, 1101, 706, 60483, 4749, 45473, 11, 23377, 430, 2225, 308, 12, 323, 281, 10827, 12371, 6777, 40, 1253, 387, 1695, 11426, 369, 12903, 376, 14338, 8522, 13, 578, 128257, 198, 128256, 78191, 198, 32, 502, 24549, 8040, 520, 27286, 17829, 5039, 7701, 19018, 31474, 6012, 430, 1436, 387, 1511, 304, 3938, 14683, 6956, 13, 99011, 1672, 15853, 82486, 11, 1778, 439, 22996, 11, 617, 4907, 21562, 430, 527, 7373, 25366, 555, 57678, 13, 578, 31474, 7200, 374, 779, 3117, 3201, 505, 279, 1062, 768, 7200, 304, 22996, 430, 57678, 656, 539, 617, 14343, 4907, 311, 3351, 482, 279, 364, 7198, 13225, 6, 374, 3544, 482, 9093, 912, 9249, 1510, 649, 387, 11953, 13, 763, 3293, 1667, 11, 12074, 617, 3719, 8173, 304, 7384, 2663, 1948, 5848, 1672, 42391, 320, 51, 3957, 705, 902, 1180, 439, 1672, 42391, 389, 279, 4871, 11, 719, 527, 7701, 6929, 535, 389, 872, 27529, 13, 763, 350, 3957, 11, 459, 48298, 3831, 12903, 27609, 4590, 16628, 304, 29263, 279, 4907, 13225, 1990, 25366, 323, 4384, 5415, 11, 779, 430, 57678, 520, 279, 7479, 649, 6530, 4028, 279, 13225, 13, 4314, 6012, 527, 47701, 311, 279, 3769, 11, 7438, 264, 39237, 8625, 6929, 535, 1524, 422, 1202, 7479, 374, 539, 4832, 13, 4800, 11, 459, 6625, 2128, 315, 14248, 505, 6457, 11, 279, 6560, 323, 279, 7427, 11, 6197, 555, 34390, 3524, 62189, 351, 14406, 520, 27286, 10181, 315, 12053, 11, 617, 7946, 8040, 264, 502, 39237, 505, 293, 2191, 952, 11, 3371, 324, 2411, 323, 85206, 320, 37196, 6777, 5176, 570, 11205, 502, 39237, 374, 47588, 97929, 11, 7438, 433, 706, 2204, 14683, 5415, 11, 323, 9093, 2204, 25685, 1385, 11, 389, 1855, 26110, 7479, 13, 1666, 264, 1121, 11, 433, 50829, 1690, 1948, 5848, 6372, 430, 617, 539, 1027, 3970, 9526, 750, 1603, 13, 330, 791, 46258, 7479, 1614, 315, 264, 39237, 374, 4528, 311, 66192, 304, 430, 279, 17130, 31139, 374, 49723, 1579, 4245, 311, 7315, 1474, 395, 57678, 11, 477, 31194, 582, 81682, 919, 1359, 15100, 62189, 351, 14406, 13, 330, 578, 31194, 582, 81682, 919, 617, 264, 29683, 12903, 323, 304, 420, 2317, 814, 649, 3552, 264, 7029, 2134, 315, 39418, 31228, 44247, 13, 11629, 33342, 55407, 374, 279, 1888, 1648, 315, 96811, 1521, 27387, 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315, 31228, 6108, 14645, 304, 3938, 11, 439, 62189, 351, 14406, 15100, 25, 330, 1226, 1053, 1093, 311, 7142, 264, 1948, 5848, 2307, 444, 36869, 6832, 7479, 649, 3552, 17559, 3444, 81682, 919, 482, 19252, 902, 527, 872, 1866, 3276, 575, 16641, 11, 323, 1436, 387, 1511, 369, 279, 4500, 315, 1948, 5848, 31228, 25213, 1210, 220, 128257, 198 ]

1,994

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not been demonstrated to be of substantial clinical benefit in patients with prostate cancer. To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy. Main Immune checkpoint therapies, including anti-CTLA-4 and anti-PD-1 therapies, that block T cell inhibitory pathways have led to durable antitumor responses and clinical benefit in a substantial number of patients with cancer 1 , 2 . However, prostate cancer has proven to be poorly responsive to immune checkpoint monotherapy 3 , 4 , 5 . To better understand the immune profile within prostate tumors and potential compensatory immune inhibitory pathways that may arise in the setting of immune checkpoint monotherapy, we conducted a clinical trial ( NCT01194271 ) with ipilimumab plus androgen-deprivation therapy (ADT) before surgery in patients with localized prostate cancer ( Supplementary Fig. 1a–c and Supplementary Tables 1 and 2 ). We compared post-treatment and baseline blood samples ( Supplementary Fig. 1a ), evaluating the levels of CD4 + and CD8 + T cells ( Supplementary Fig. 2a ), as well as those of T cell subsets expressing inducible costimulator (ICOS), OX40, 4-1BB, PD-1, CTLA-4, and FoxP3 ( Supplementary Fig. 2a,b ). We observed an increase in CD4 + and CD8 + T cells, including PD-1 + and ICOS + subsets, after ipilimumab therapy, which is similar to our previous findings with ipilimumab monotherapy in patients with melanoma and bladder cancer 6 , 7 , 8 . We also compared post-treatment tumor tissues ( Supplementary Fig. 1a ) to those of stage-matched untreated tumors from another cohort of patients ( Supplementary Fig. 1b ). Flow cytometric studies revealed a significantly higher frequency of CD4 + , CD8 + , and ICOS + T cells in the post-treatment tumors ( Fig. 1a ). Immunohistochemical (IHC) studies also demonstrated significant increases in tumor-infiltrating immune cells, including CD4 + , CD8 + , ICOS + , CD45RO + , granzyme-B (GrB) + , and CD68 + cells ( Supplementary Fig. 3 ). We found significantly greater immune cell infiltration in prostate tumors after ipilimumab therapy but not after ADT alone, although ADT monotherapy was associated with significantly higher levels of ICOS + and GrB + cells, which may represent an activated T cell subset ( Fig. 1b ). Taken together, our data suggest that the immunologic changes in post-treatment tumors were mostly due to ipilimumab therapy, as opposed to ADT. However, we cannot discount a possible synergistic effect between ipilimumab and ADT. Figure 1: Treatment with ipilimumab increases immune cell infiltration, as well as expression of PD-L1 and VISTA in prostate tumors. ( a ) Frequency of CD4 + , CD8 + , and ICOS + T cells in untreated ( n = 11) and treated ( n = 6) tumors. ( b ) IHC analyses of CD4 + , CD8 + , ICOS + , CD45RO + , and GrB + T cells, as well as CD68 + macrophages. ( c ) IHC of PD-L1, PD-1, and VISTA in tumor cells and tumor-infiltrating immune cells. In b and c , tumors are from three different cohorts of stage-matched patients: untreated ( n = 18), treated with ADT ( n = 10), and treated with ipilimumab (Ipi) + ADT ( n = 16). An asterisk represents patients who received high-dose steroids with surgery delay. ( d ) Frequency of PD-L1 expression on CD4 + T cells, CD8 + T cells, CD68 + macrophages, and tumor cells. ( e ) Frequency of VISTA expression on CD4 + T cells, CD8 + T cells, and CD68 + macrophages. In d and e , matched pre-treatment ( n = 10) and post-treatment ( n = 10) tumors are shown. ( f ) IHC staining of CD4 + and CD8 + T cells and CD68 + macrophages in stage-matched untreated ( n = 18) and ipilimumab- + ADT-treated ( n = 15) prostate tumors as compared to stage-matched untreated ( n = 18) and ipilimumab-treated ( n = 20) metastatic melanomas. Arrows indicate a significant difference in CD8 + T cells and CD68 + macrophages between untreated prostate tumors and untreated melanomas. ( g ) Frequency of PD-L1 expression on CD4 + T cells, CD8 + T cells, and CD68 + macrophages. ( h ) Frequency of VISTA expression on CD4 + T cells, CD8 + T cells, and CD68 + macrophages. In g and h , matched pre-treatment ( n = 10) and post-treatment ( n = 10) prostate tumors are compared to matched pre-treatment ( n = 10) and post-treatment ( n = 10) melanomas. Pt, patient. In d – h , the bars represent the mean of each group. P values were calculated using Welch's t -test. Source data Full size image We did not observe clinical responses consisting of pathologic complete response, as we did previously for patients with bladder cancer 8 . To identify potential mechanisms that might explain this lack of response, we performed an unbiased gene expression study and found that ipilimumab therapy resulted in significant changes in the expression of a total of 690 genes (false discovery rate (FDR) < 0.2; P < 0.028; log 2 (fold change) > 0.5)( Supplementary Table 3 ), most of which are related to immune responses ( Supplementary Fig. 4a ). We focused our analyses on a subset of genes that represent inhibitory immune checkpoints and identified increased PD-L1 and VISTA expression in post-treatment tumors ( Supplementary Fig. 4b ). Both PD-L1 and VISTA were previously reported as inhibitory molecules that can suppress murine and human T cell responses 9 , 10 . Here we found significantly greater protein expression of PD-1, PD-L1, and VISTA in prostate tumors after ipilimumab therapy (", "role": "user" }, { "content": "Prostate cancer, notoriously resistant to immunotherapy due to its immunologically cool nature, triggers two pathways to chill an immune attack after one immunotherapy drug fires up the immune system, researchers at The University of Texas MD Anderson Cancer Center report in Nature Medicine. Based on their findings, the researchers launched a clinical trial for stage IV prostate cancer in March combining two drugs that target separate brakes on the immune system. The checkpoint inhibitors largely failed individually against the disease. Their results also implicate for the first time on a human tumor a third brake called VISTA in potentially inhibiting immune response. \"We've known that prostate cancer is immunologically cold, or quiet, with very little penetration of the tumors or their surrounding microenvironment by immune cells,\" said study leader Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. \"Our study explored whether we could increase immune cell infiltration by combining the anti-hormonal drug Lupron with two rounds of the checkpoint inhibitor ipilimumab before surgery in patients with locally advanced prostate cancer,\" Sharma said. Immune checkpoint inhibitors treat T cells, white blood cells that are the immune system's targeted weapons, freeing them to attack tumors by blocking proteins on the T cells' surface that shut them down. Ipilimumab blocks CTLA4 on T cells, the first known immune checkpoint, unleashing them to attack. \"Untreated prostate cancer is largely a desert for T cells,\" said co-author Jim Allison, Ph.D., chair of Immunology. Ipilimumab brings T cells in, but activates PD-L1 Immune analysis of the surgically removed tumors showed high levels of penetration of the tumors by activated T cells. \"But we didn't see any complete responses among 16 prostate cancer patients, so we suspected other immune-inhibiting mechanisms had come into play,\" Sharma said. Genomic and immune analysis of the tumors found increased levels of immune-suppressing PD-L1 and VISTA. T cells and other immune cells found in the tumors also had both proteins elevated. PD-L1 connects with the immune checkpoint PD1 on T cells, activating PD1 to shut down the T cell. A number of drugs blocking PD1 are approved for advanced melanoma, Hodgkin lymphoma, lung, kidney, bladder and head and neck cancers. PD1 inhibitors don't work where there is no pre-existing T cell penetration of tumors. \"We concluded that driving T cells into the tumors would be step one, but then the next step would be to block PD-L1 and VISTA,\" Sharma said. These results underpin the immunotherapy combination clinical trial: ipilimumab to bring T cells into the tumor, and the PD1 inhibitor nivolumab to defeat the PD-L1/PD1 response that follows. The trial, led by Sharma, will enroll 90 patients at nine centers nationally. Six therapies approved for treating metastatic, castration-resistant prostate cancer extend survival but none provide durable responses. Nivolumab failed to provide any responses in a small clinical trial. While ipilimumab fell short of proving survival benefit in two phase III clinical trials, a small group of patients had long-term responses. Targeting VISTA VISTA has been shown to block immune response in mouse models of human cancer. And the team confirmed in lab studies that an antibody to knock down VISTA freed T cells to attack cancer cells. An inhibitor for VISTA is in phase I clinical trial to gauge safety and dose, but Sharma notes the drug could also be combined in prostate cancer clinical trials after the phase I is completed. The ligand that activates VISTA has not been identified, Allison said. The team's findings represent the first report of VISTA expression on T cells in human tumors. Unhelpful macrophages The researchers also found that white blood cells called macrophages - Latin for \"big eaters\"—are also affected by ipilimumab treatment. Macrophages engulf and digest microbes, bits of cellular debris, tumor cells and other odds and ends as part of immune response. They are also bipolar. In their M1 form, they actively assist immune response. In M2, they are in repair mode, helping post-immune recovery. The M2 mode promotes cancer growth and survival.Sharma, Allison and colleagues found that macrophages after ipilimumab treatment expressed lots of PD-L1 and VISTA and were in M2 mode. Serial immune monitoring \"This paper highlights the importance of studying immune response longitudinally,\" Sharma said. \"Observing immune response at one point in time doesn't reflect what's going on because the immune system is so dynamic. So baseline sampling in prostate tumors shows minimal immune infiltrate. You can change that with ipilimumab, but what else changes becomes incredibly important. \"Understanding these changes using post-treatment or on-treatment biopsies is important to develop rational combination strategies for these immune-modulating drugs,\" she said.The presurgical clinical trials, also called window of opportunity trials, allow researchers to learn a lot from a small number of patients to guide the design of larger trials, Sharma said. Immune monitoring of serial biopsies taken before, during and after treatment is a central aspect of MD Anderson's Immunotherapy Platform, which is co-led by Sharma and Allison and provides immune monitoring for 100 clinical trials. The platform is part of MD Anderson's Moon Shots Program to accelerate development of new treatment, prevention and early detection based on scientific advances. Patient response In the Lupron-ipilimumab trial, 17 patients participated in the trial, 16 completed treatment and surgery and one died of a cardiac complication before surgery. Six patients had their cancer progress and 10 were without evidence of progression for at least 3.5 years. All 16 remained alive 3.5 years after surgery. All 17 experienced an immune-related adverse event, with eight experiencing the most serious grade 3 or 4 side effects, including inflammation of the colon, pancreas or pituitary gland and elevated transaminase enzymes in the liver. All were treated with corticosteroids and other immune-suppressive drugs. The ipilimumab-nivolumab combination is in use in clinical trials for other cancers, most prominently for metastatic melanoma. In a 937-patient randomized trial, the combination provided an overall response rate of 57.7 percent, surpassing either drug alone in response rate and progression-free survival. And 55 percent of patients on the combination experienced a grade 3 or 4 adverse event related to treatment. The prostate combination trial has protocols for recognizing and treating immune-related adverse events. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not been demonstrated to be of substantial clinical benefit in patients with prostate cancer. To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy. Main Immune checkpoint therapies, including anti-CTLA-4 and anti-PD-1 therapies, that block T cell inhibitory pathways have led to durable antitumor responses and clinical benefit in a substantial number of patients with cancer 1 , 2 . However, prostate cancer has proven to be poorly responsive to immune checkpoint monotherapy 3 , 4 , 5 . To better understand the immune profile within prostate tumors and potential compensatory immune inhibitory pathways that may arise in the setting of immune checkpoint monotherapy, we conducted a clinical trial ( NCT01194271 ) with ipilimumab plus androgen-deprivation therapy (ADT) before surgery in patients with localized prostate cancer ( Supplementary Fig. 1a–c and Supplementary Tables 1 and 2 ). We compared post-treatment and baseline blood samples ( Supplementary Fig. 1a ), evaluating the levels of CD4 + and CD8 + T cells ( Supplementary Fig. 2a ), as well as those of T cell subsets expressing inducible costimulator (ICOS), OX40, 4-1BB, PD-1, CTLA-4, and FoxP3 ( Supplementary Fig. 2a,b ). We observed an increase in CD4 + and CD8 + T cells, including PD-1 + and ICOS + subsets, after ipilimumab therapy, which is similar to our previous findings with ipilimumab monotherapy in patients with melanoma and bladder cancer 6 , 7 , 8 . We also compared post-treatment tumor tissues ( Supplementary Fig. 1a ) to those of stage-matched untreated tumors from another cohort of patients ( Supplementary Fig. 1b ). Flow cytometric studies revealed a significantly higher frequency of CD4 + , CD8 + , and ICOS + T cells in the post-treatment tumors ( Fig. 1a ). Immunohistochemical (IHC) studies also demonstrated significant increases in tumor-infiltrating immune cells, including CD4 + , CD8 + , ICOS + , CD45RO + , granzyme-B (GrB) + , and CD68 + cells ( Supplementary Fig. 3 ). We found significantly greater immune cell infiltration in prostate tumors after ipilimumab therapy but not after ADT alone, although ADT monotherapy was associated with significantly higher levels of ICOS + and GrB + cells, which may represent an activated T cell subset ( Fig. 1b ). Taken together, our data suggest that the immunologic changes in post-treatment tumors were mostly due to ipilimumab therapy, as opposed to ADT. However, we cannot discount a possible synergistic effect between ipilimumab and ADT. Figure 1: Treatment with ipilimumab increases immune cell infiltration, as well as expression of PD-L1 and VISTA in prostate tumors. ( a ) Frequency of CD4 + , CD8 + , and ICOS + T cells in untreated ( n = 11) and treated ( n = 6) tumors. ( b ) IHC analyses of CD4 + , CD8 + , ICOS + , CD45RO + , and GrB + T cells, as well as CD68 + macrophages. ( c ) IHC of PD-L1, PD-1, and VISTA in tumor cells and tumor-infiltrating immune cells. In b and c , tumors are from three different cohorts of stage-matched patients: untreated ( n = 18), treated with ADT ( n = 10), and treated with ipilimumab (Ipi) + ADT ( n = 16). An asterisk represents patients who received high-dose steroids with surgery delay. ( d ) Frequency of PD-L1 expression on CD4 + T cells, CD8 + T cells, CD68 + macrophages, and tumor cells. ( e ) Frequency of VISTA expression on CD4 + T cells, CD8 + T cells, and CD68 + macrophages. In d and e , matched pre-treatment ( n = 10) and post-treatment ( n = 10) tumors are shown. ( f ) IHC staining of CD4 + and CD8 + T cells and CD68 + macrophages in stage-matched untreated ( n = 18) and ipilimumab- + ADT-treated ( n = 15) prostate tumors as compared to stage-matched untreated ( n = 18) and ipilimumab-treated ( n = 20) metastatic melanomas. Arrows indicate a significant difference in CD8 + T cells and CD68 + macrophages between untreated prostate tumors and untreated melanomas. ( g ) Frequency of PD-L1 expression on CD4 + T cells, CD8 + T cells, and CD68 + macrophages. ( h ) Frequency of VISTA expression on CD4 + T cells, CD8 + T cells, and CD68 + macrophages. In g and h , matched pre-treatment ( n = 10) and post-treatment ( n = 10) prostate tumors are compared to matched pre-treatment ( n = 10) and post-treatment ( n = 10) melanomas. Pt, patient. In d – h , the bars represent the mean of each group. P values were calculated using Welch's t -test. Source data Full size image We did not observe clinical responses consisting of pathologic complete response, as we did previously for patients with bladder cancer 8 . To identify potential mechanisms that might explain this lack of response, we performed an unbiased gene expression study and found that ipilimumab therapy resulted in significant changes in the expression of a total of 690 genes (false discovery rate (FDR) < 0.2; P < 0.028; log 2 (fold change) > 0.5)( Supplementary Table 3 ), most of which are related to immune responses ( Supplementary Fig. 4a ). We focused our analyses on a subset of genes that represent inhibitory immune checkpoints and identified increased PD-L1 and VISTA expression in post-treatment tumors ( Supplementary Fig. 4b ). Both PD-L1 and VISTA were previously reported as inhibitory molecules that can suppress murine and human T cell responses 9 , 10 . Here we found significantly greater protein expression of PD-1, PD-L1, and VISTA in prostate tumors after ipilimumab therapy (<|im_end|> <|im_start|>assistant Prostate cancer, notoriously resistant to immunotherapy due to its immunologically cool nature, triggers two pathways to chill an immune attack after one immunotherapy drug fires up the immune system, researchers at The University of Texas MD Anderson Cancer Center report in Nature Medicine. Based on their findings, the researchers launched a clinical trial for stage IV prostate cancer in March combining two drugs that target separate brakes on the immune system. The checkpoint inhibitors largely failed individually against the disease. Their results also implicate for the first time on a human tumor a third brake called VISTA in potentially inhibiting immune response. "We've known that prostate cancer is immunologically cold, or quiet, with very little penetration of the tumors or their surrounding microenvironment by immune cells," said study leader Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. "Our study explored whether we could increase immune cell infiltration by combining the anti-hormonal drug Lupron with two rounds of the checkpoint inhibitor ipilimumab before surgery in patients with locally advanced prostate cancer," Sharma said. Immune checkpoint inhibitors treat T cells, white blood cells that are the immune system's targeted weapons, freeing them to attack tumors by blocking proteins on the T cells' surface that shut them down. Ipilimumab blocks CTLA4 on T cells, the first known immune checkpoint, unleashing them to attack. "Untreated prostate cancer is largely a desert for T cells," said co-author Jim Allison, Ph.D., chair of Immunology. Ipilimumab brings T cells in, but activates PD-L1 Immune analysis of the surgically removed tumors showed high levels of penetration of the tumors by activated T cells. "But we didn't see any complete responses among 16 prostate cancer patients, so we suspected other immune-inhibiting mechanisms had come into play," Sharma said. Genomic and immune analysis of the tumors found increased levels of immune-suppressing PD-L1 and VISTA. T cells and other immune cells found in the tumors also had both proteins elevated. PD-L1 connects with the immune checkpoint PD1 on T cells, activating PD1 to shut down the T cell. A number of drugs blocking PD1 are approved for advanced melanoma, Hodgkin lymphoma, lung, kidney, bladder and head and neck cancers. PD1 inhibitors don't work where there is no pre-existing T cell penetration of tumors. "We concluded that driving T cells into the tumors would be step one, but then the next step would be to block PD-L1 and VISTA," Sharma said. These results underpin the immunotherapy combination clinical trial: ipilimumab to bring T cells into the tumor, and the PD1 inhibitor nivolumab to defeat the PD-L1/PD1 response that follows. The trial, led by Sharma, will enroll 90 patients at nine centers nationally. Six therapies approved for treating metastatic, castration-resistant prostate cancer extend survival but none provide durable responses. Nivolumab failed to provide any responses in a small clinical trial. While ipilimumab fell short of proving survival benefit in two phase III clinical trials, a small group of patients had long-term responses. Targeting VISTA VISTA has been shown to block immune response in mouse models of human cancer. And the team confirmed in lab studies that an antibody to knock down VISTA freed T cells to attack cancer cells. An inhibitor for VISTA is in phase I clinical trial to gauge safety and dose, but Sharma notes the drug could also be combined in prostate cancer clinical trials after the phase I is completed. The ligand that activates VISTA has not been identified, Allison said. The team's findings represent the first report of VISTA expression on T cells in human tumors. Unhelpful macrophages The researchers also found that white blood cells called macrophages - Latin for "big eaters"—are also affected by ipilimumab treatment. Macrophages engulf and digest microbes, bits of cellular debris, tumor cells and other odds and ends as part of immune response. They are also bipolar. In their M1 form, they actively assist immune response. In M2, they are in repair mode, helping post-immune recovery. The M2 mode promotes cancer growth and survival.Sharma, Allison and colleagues found that macrophages after ipilimumab treatment expressed lots of PD-L1 and VISTA and were in M2 mode. Serial immune monitoring "This paper highlights the importance of studying immune response longitudinally," Sharma said. "Observing immune response at one point in time doesn't reflect what's going on because the immune system is so dynamic. So baseline sampling in prostate tumors shows minimal immune infiltrate. You can change that with ipilimumab, but what else changes becomes incredibly important. "Understanding these changes using post-treatment or on-treatment biopsies is important to develop rational combination strategies for these immune-modulating drugs," she said.The presurgical clinical trials, also called window of opportunity trials, allow researchers to learn a lot from a small number of patients to guide the design of larger trials, Sharma said. Immune monitoring of serial biopsies taken before, during and after treatment is a central aspect of MD Anderson's Immunotherapy Platform, which is co-led by Sharma and Allison and provides immune monitoring for 100 clinical trials. The platform is part of MD Anderson's Moon Shots Program to accelerate development of new treatment, prevention and early detection based on scientific advances. Patient response In the Lupron-ipilimumab trial, 17 patients participated in the trial, 16 completed treatment and surgery and one died of a cardiac complication before surgery. Six patients had their cancer progress and 10 were without evidence of progression for at least 3.5 years. All 16 remained alive 3.5 years after surgery. All 17 experienced an immune-related adverse event, with eight experiencing the most serious grade 3 or 4 side effects, including inflammation of the colon, pancreas or pituitary gland and elevated transaminase enzymes in the liver. All were treated with corticosteroids and other immune-suppressive drugs. The ipilimumab-nivolumab combination is in use in clinical trials for other cancers, most prominently for metastatic melanoma. In a 937-patient randomized trial, the combination provided an overall response rate of 57.7 percent, surpassing either drug alone in response rate and progression-free survival. And 55 percent of patients on the combination experienced a grade 3 or 4 adverse event related to treatment. The prostate combination trial has protocols for recognizing and treating immune-related adverse events. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Questioning basic assumptions about the structure of space and time has greatly enhanced our understanding of nature. State-of-the-art atomic clocks 1 , 2 , 3 make it possible to precisely test fundamental symmetry properties of spacetime and search for physics beyond the standard model at low energies of just a few electronvolts 4 . Modern tests of Einstein’s theory of relativity try to measure so-far-undetected violations of Lorentz symmetry 5 ; accurately comparing the frequencies of optical clocks is a promising route to further improving such tests 6 . Here we experimentally demonstrate agreement between two single-ion optical clocks at the 10 −18 level, directly validating their uncertainty budgets, over a six-month comparison period. The ytterbium ions of the two clocks are confined in separate ion traps with quantization axes aligned along non-parallel directions. Hypothetical Lorentz symmetry violations 5 , 6 , 7 would lead to periodic modulations of the frequency offset as the Earth rotates and orbits the Sun. From the absence of such modulations at the 10 −19 level we deduce stringent limits of the order of 10 −21 on Lorentz symmetry violation parameters for electrons, improving previous limits 8 , 9 , 10 by two orders of magnitude. Such levels of precision will be essential for low-energy tests of future quantum gravity theories describing dynamics at the Planck scale 4 , which are expected to predict the magnitude of residual symmetry violations. Main The principle of relativity requires that all descriptions of nature are covariant under Lorentz transformations; that is, the laws of physics stay the same when transforming from one inertial reference frame to another. Consequently, the outcome of any experiment must be independent of the velocity and orientation of the inertial frame in which it is performed. The Michelson–Morley experiment with a rotatable optical interferometer was an early test of this observational symmetry, disproving the existence of a preferred reference-frame orientation for electromagnetic waves. Later, Kennedy and Thorndike 11 modified the Michelson–Morley setup to also establish velocity invariance. Strong interest in improved tests of Lorentz symmetry in different branches of physics persists 12 , motivated by theoretical suggestions that local Lorentz covariance may not be an exact symmetry at all energies up to the Planck energy and is violated in various models of quantum gravity 5 . The first spectroscopic tests of Lorentz symmetry were performed in nuclear magnetic resonance and excluded a dependence of the magnetic splitting of energy levels of the 7 Li nucleus on its orientation relative to the centre of our Galaxy at a level of about 1 p.p.m. 13 , 14 . The apparatus was fixed in the laboratory, rotating with Earth once per sidereal day. Related experiments have since been performed with different nuclei, providing sensitivity to Lorentz violations (LVs) for protons and neutrons. LV limits for photons have been improved continually through numerous tests with high-finesse optical cavities (see ref. 4 for a review). Such cavity measurements also lead to LV constraints for electrons 15 , 16 , which have been further advanced by astrophysical observations 8 and more recently by direct measurements with bound electrons in Dy atoms 9 and Ca + ions 10 , 17 . In parallel, the development of optical clocks has seen substantial progress over recent years. Laser spectroscopy with 10 −18 fractional frequency accuracy 1 , 2 , 3 and coherence times reaching tens of seconds are now within experimental reach 18 . Here we experimentally demonstrate a level of performance of single-ion clocks that is, to our knowledge, unprecedented, by showing persistent agreement of two 171 Yb + systems at the low-10 −18 level over the course of six months. Long-term comparisons between such excellent quantum timekeepers open new avenues for low-energy tests of fundamental physics 4 . Here, we exploit the pronounced LV susceptibility 19 of the non-spherical 2 F 7/2 clock state in Yb + and implement a high-precision spacetime anisotropy test with two ion clocks operating on the same optical transition but being oriented along different quantization axes. To systematically quantify our frequency measurements in terms of LV constraints we rely on a theoretical framework called standard model extension (SME), which provides a universal platform to compare all kinds of LV measurements 7 . The SME covers all standard model particles and can therefore identify LV in all branches of the standard model. Considering the electron sector, a hypothetical LV is quantified in the SME by adding a symmetry-breaking c μν tensor to the kinetic term in the standard model Lagrangian 20 . In the context of our clock-comparison experiment, this leads to a non-common-mode energy shift of bound electronic states described by the Hamiltonian 9 , 20 $${\\rm{\\delta }}H=-{C}_{0}^{(2)}\\frac{{{\\bf{p}}}^{2}-3{p}_{z}^{2}}{6m}\\equiv -\\frac{{C}_{0}^{(2)}{T}_{0}^{(2)}}{6m}$$ (1) where p is the momentum of a bound electron, p z its projection along the quantization axis and m the electron mass. The parameter \${C}_{0}^{(2)}={c}_{xx}+{c}_{yy}-2{c}_{zz}\$ contains spatial elements of the frame-dependent c μν tensor and \${T}_{0}^{(2)}\$ is the corresponding component of the quadrupole moment operator of the electronic momentum distribution. However, instead of analysing our experiment in the electron sector and deriving anisotropy limits for the electronic dispersion, one can also base the analysis on anisotropies in the photon-mediated Coulomb field, where the coefficients ( k F ) κλμν quantify corresponding Lorentz violations 21 . Accordingly, the electron and photon parts cannot be separated, and it is necessary to specify a particular coordinate choice to obtain unambiguous results. Here, we choose a coordinate system with a vanishing trace 22 , \${\\left({k}_{{\\rm{F}}}\\right)}_{\\mu \\alpha \\nu }^{\\alpha }=0\$ . By substituting c μν with $${c}_{\\mu \\nu }^{^{\\prime} }={c}_{\\mu \\nu }+\\frac{1}{2}{\\left({k}_{{\\rm{F}}}\\right)}_{\\mu \\alpha \\nu }^{\\alpha }$$ (2) the present constraints are valid for arbitrary coordinate choices and describe differential electron–photon anisotropies that can be interpreted to limit either sector 10 , 22 . To simplify the notation we omit primes from now on and always assume sector-combined tensor components. In atoms such as 171 Yb with nuclear spin I = 1/2, LV in the nuclear sector cannot produce quadrupole energy", "role": "user" }, { "content": "In his Special Theory of Relativity, Einstein formulated the hypothesis according to which the speed of light is always the same, no matter what the conditions are. It may, however, be possible that—according to theoretical models of quantum gravitation—this uniformity of space-time does not apply to particles. Physicists have now tested this hypothesis with a first long-term comparison of two optical ytterbium clocks at the Physikalisch-Technische Bundesanstalt (PTB). With these clocks, whose error amounts to only one second in ten billion years, it should be possible to measure even extremely small deviations of the movement of the electrons in ytterbium. But the scientists did not detect any change when the clocks were oriented differently in space. Due to this result, the current limit for testing the space-time symmetry by means of experiments has been drastically improved by a factor of 100. In addition to this, the extremely small systematic measurement uncertainty of the optical ytterbium clocks of less than 4 × 10-18 has been confirmed. The team consisting of physicists from PTB and from the University of Delaware has published its results in the current issue of Nature. It is one of the most famous physics experiments in history: As early as 1887, Michelson and Morley demonstrated what Einstein later expressed in the form of a theory. With the aid of a rotating interferometer, they compared the speed of light along two optical axes running vertically to each other. The result of this experiment became one of the fundamental statements of Einstein's Special Theory of Relativity: The speed of light is the same in all directions of space. Now one could ask: Does this symmetry of space (which was named after Hendrik Antoon Lorentz) also apply to the motion of material particles? Or are there any directions along which these particles move faster or more slowly although the energy remains the same? Especially for high energies of the particles, theoretical models of quantum gravitation predict a violation of the Lorentz symmetry. Now an experiment has been carried out with two atomic clocks in order to investigate this question with high accuracy. The frequencies of these atomic clocks are each controlled by the resonance frequency of a single Yb+ ion that is stored in a trap. While the electrons of the Yb+ ions have a spherically symmetric distribution in the ground state, in the excited state they exhibit a distinctly elongated wave function and therefore move mainly along one spatial direction. The orientation of the wave function is determined by a magnetic field applied inside the clock. The field orientation was chosen to be approximately at right angles in the two clocks. The clocks are firmly mounted in a laboratory and rotate together with the Earth once a day (more exactly: once in 23.9345 hours) relative to the fixed stars. If the electrons' speed depended on the orientation in space, this would thus result in a frequency difference between the two atomic clocks that would occur periodically, together with the Earth's rotation. To be able to differentiate such an effect clearly from any possible technical influences, the frequencies of the Yb+ clocks were compared for more than 1000 hours. During the experiment, no change between the two clocks was observed for the accessible range of period durations from a few minutes up to 80 hours. For the theoretical interpretation and calculations concerning the atomic structure of the Yb+ ion, PTB's team worked in collaboration with theoreticians from the University of Delaware (USA). The results that have now been obtained have improved the limits set in 2015 by researchers from the University of California, Berkeley with Ca+ ions drastically by a factor of 100. Averaged over the total measuring time, both clocks exhibited a relative frequency deviation of less than 3 × 10-18. This confirms the combined uncertainty of the clock that had previously been estimated to be 4 × 10-18. Furthermore, it is an important step in the characterization of optical atomic clocks at this level of accuracy. Only after roughly ten billion years would these clocks potentially deviate from each other by one second. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Questioning basic assumptions about the structure of space and time has greatly enhanced our understanding of nature. State-of-the-art atomic clocks 1 , 2 , 3 make it possible to precisely test fundamental symmetry properties of spacetime and search for physics beyond the standard model at low energies of just a few electronvolts 4 . Modern tests of Einstein’s theory of relativity try to measure so-far-undetected violations of Lorentz symmetry 5 ; accurately comparing the frequencies of optical clocks is a promising route to further improving such tests 6 . Here we experimentally demonstrate agreement between two single-ion optical clocks at the 10 −18 level, directly validating their uncertainty budgets, over a six-month comparison period. The ytterbium ions of the two clocks are confined in separate ion traps with quantization axes aligned along non-parallel directions. Hypothetical Lorentz symmetry violations 5 , 6 , 7 would lead to periodic modulations of the frequency offset as the Earth rotates and orbits the Sun. From the absence of such modulations at the 10 −19 level we deduce stringent limits of the order of 10 −21 on Lorentz symmetry violation parameters for electrons, improving previous limits 8 , 9 , 10 by two orders of magnitude. Such levels of precision will be essential for low-energy tests of future quantum gravity theories describing dynamics at the Planck scale 4 , which are expected to predict the magnitude of residual symmetry violations. Main The principle of relativity requires that all descriptions of nature are covariant under Lorentz transformations; that is, the laws of physics stay the same when transforming from one inertial reference frame to another. Consequently, the outcome of any experiment must be independent of the velocity and orientation of the inertial frame in which it is performed. The Michelson–Morley experiment with a rotatable optical interferometer was an early test of this observational symmetry, disproving the existence of a preferred reference-frame orientation for electromagnetic waves. Later, Kennedy and Thorndike 11 modified the Michelson–Morley setup to also establish velocity invariance. Strong interest in improved tests of Lorentz symmetry in different branches of physics persists 12 , motivated by theoretical suggestions that local Lorentz covariance may not be an exact symmetry at all energies up to the Planck energy and is violated in various models of quantum gravity 5 . The first spectroscopic tests of Lorentz symmetry were performed in nuclear magnetic resonance and excluded a dependence of the magnetic splitting of energy levels of the 7 Li nucleus on its orientation relative to the centre of our Galaxy at a level of about 1 p.p.m. 13 , 14 . The apparatus was fixed in the laboratory, rotating with Earth once per sidereal day. Related experiments have since been performed with different nuclei, providing sensitivity to Lorentz violations (LVs) for protons and neutrons. LV limits for photons have been improved continually through numerous tests with high-finesse optical cavities (see ref. 4 for a review). Such cavity measurements also lead to LV constraints for electrons 15 , 16 , which have been further advanced by astrophysical observations 8 and more recently by direct measurements with bound electrons in Dy atoms 9 and Ca + ions 10 , 17 . In parallel, the development of optical clocks has seen substantial progress over recent years. Laser spectroscopy with 10 −18 fractional frequency accuracy 1 , 2 , 3 and coherence times reaching tens of seconds are now within experimental reach 18 . Here we experimentally demonstrate a level of performance of single-ion clocks that is, to our knowledge, unprecedented, by showing persistent agreement of two 171 Yb + systems at the low-10 −18 level over the course of six months. Long-term comparisons between such excellent quantum timekeepers open new avenues for low-energy tests of fundamental physics 4 . Here, we exploit the pronounced LV susceptibility 19 of the non-spherical 2 F 7/2 clock state in Yb + and implement a high-precision spacetime anisotropy test with two ion clocks operating on the same optical transition but being oriented along different quantization axes. To systematically quantify our frequency measurements in terms of LV constraints we rely on a theoretical framework called standard model extension (SME), which provides a universal platform to compare all kinds of LV measurements 7 . The SME covers all standard model particles and can therefore identify LV in all branches of the standard model. Considering the electron sector, a hypothetical LV is quantified in the SME by adding a symmetry-breaking c μν tensor to the kinetic term in the standard model Lagrangian 20 . In the context of our clock-comparison experiment, this leads to a non-common-mode energy shift of bound electronic states described by the Hamiltonian 9 , 20 $${\rm{\delta }}H=-{C}_{0}^{(2)}\frac{{{\bf{p}}}^{2}-3{p}_{z}^{2}}{6m}\equiv -\frac{{C}_{0}^{(2)}{T}_{0}^{(2)}}{6m}$$ (1) where p is the momentum of a bound electron, p z its projection along the quantization axis and m the electron mass. The parameter ${C}_{0}^{(2)}={c}_{xx}+{c}_{yy}-2{c}_{zz}$ contains spatial elements of the frame-dependent c μν tensor and ${T}_{0}^{(2)}$ is the corresponding component of the quadrupole moment operator of the electronic momentum distribution. However, instead of analysing our experiment in the electron sector and deriving anisotropy limits for the electronic dispersion, one can also base the analysis on anisotropies in the photon-mediated Coulomb field, where the coefficients ( k F ) κλμν quantify corresponding Lorentz violations 21 . Accordingly, the electron and photon parts cannot be separated, and it is necessary to specify a particular coordinate choice to obtain unambiguous results. Here, we choose a coordinate system with a vanishing trace 22 , ${\left({k}_{{\rm{F}}}\right)}_{\mu \alpha \nu }^{\alpha }=0$ . By substituting c μν with $${c}_{\mu \nu }^{^{\prime} }={c}_{\mu \nu }+\frac{1}{2}{\left({k}_{{\rm{F}}}\right)}_{\mu \alpha \nu }^{\alpha }$$ (2) the present constraints are valid for arbitrary coordinate choices and describe differential electron–photon anisotropies that can be interpreted to limit either sector 10 , 22 . To simplify the notation we omit primes from now on and always assume sector-combined tensor components. In atoms such as 171 Yb with nuclear spin I = 1/2, LV in the nuclear sector cannot produce quadrupole energy<|im_end|> <|im_start|>assistant In his Special Theory of Relativity, Einstein formulated the hypothesis according to which the speed of light is always the same, no matter what the conditions are. It may, however, be possible that—according to theoretical models of quantum gravitation—this uniformity of space-time does not apply to particles. Physicists have now tested this hypothesis with a first long-term comparison of two optical ytterbium clocks at the Physikalisch-Technische Bundesanstalt (PTB). With these clocks, whose error amounts to only one second in ten billion years, it should be possible to measure even extremely small deviations of the movement of the electrons in ytterbium. But the scientists did not detect any change when the clocks were oriented differently in space. Due to this result, the current limit for testing the space-time symmetry by means of experiments has been drastically improved by a factor of 100. In addition to this, the extremely small systematic measurement uncertainty of the optical ytterbium clocks of less than 4 × 10-18 has been confirmed. The team consisting of physicists from PTB and from the University of Delaware has published its results in the current issue of Nature. It is one of the most famous physics experiments in history: As early as 1887, Michelson and Morley demonstrated what Einstein later expressed in the form of a theory. With the aid of a rotating interferometer, they compared the speed of light along two optical axes running vertically to each other. The result of this experiment became one of the fundamental statements of Einstein's Special Theory of Relativity: The speed of light is the same in all directions of space. Now one could ask: Does this symmetry of space (which was named after Hendrik Antoon Lorentz) also apply to the motion of material particles? Or are there any directions along which these particles move faster or more slowly although the energy remains the same? Especially for high energies of the particles, theoretical models of quantum gravitation predict a violation of the Lorentz symmetry. Now an experiment has been carried out with two atomic clocks in order to investigate this question with high accuracy. The frequencies of these atomic clocks are each controlled by the resonance frequency of a single Yb+ ion that is stored in a trap. While the electrons of the Yb+ ions have a spherically symmetric distribution in the ground state, in the excited state they exhibit a distinctly elongated wave function and therefore move mainly along one spatial direction. The orientation of the wave function is determined by a magnetic field applied inside the clock. The field orientation was chosen to be approximately at right angles in the two clocks. The clocks are firmly mounted in a laboratory and rotate together with the Earth once a day (more exactly: once in 23.9345 hours) relative to the fixed stars. If the electrons' speed depended on the orientation in space, this would thus result in a frequency difference between the two atomic clocks that would occur periodically, together with the Earth's rotation. To be able to differentiate such an effect clearly from any possible technical influences, the frequencies of the Yb+ clocks were compared for more than 1000 hours. During the experiment, no change between the two clocks was observed for the accessible range of period durations from a few minutes up to 80 hours. For the theoretical interpretation and calculations concerning the atomic structure of the Yb+ ion, PTB's team worked in collaboration with theoreticians from the University of Delaware (USA). The results that have now been obtained have improved the limits set in 2015 by researchers from the University of California, Berkeley with Ca+ ions drastically by a factor of 100. Averaged over the total measuring time, both clocks exhibited a relative frequency deviation of less than 3 × 10-18. This confirms the combined uncertainty of the clock that had previously been estimated to be 4 × 10-18. Furthermore, it is an important step in the characterization of optical atomic clocks at this level of accuracy. Only after roughly ten billion years would these clocks potentially deviate from each other by one second. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Scaling of Si-based nanoelectronics has reached the regime where device function is affected not only by the presence of individual dopants, but also by their positions in the crystal. Determination of the precise dopant location is an unsolved problem in applications from channel doping in ultrascaled transistors to quantum information processing. Here, we establish a metrology combining low-temperature scanning tunnelling microscopy (STM) imaging and a comprehensive quantum treatment of the dopant–STM system to pinpoint the exact coordinates of the dopant in the Si crystal. The technique is underpinned by the observation that STM images contain atomic-sized features in ordered patterns that are highly sensitive to the STM tip orbital and the absolute dopant lattice site. The demonstrated ability to determine the locations of P and As dopants to 5 nm depths will provide critical information for the design and optimization of nanoscale devices for classical and quantum computing applications. Main As we approach the ultimate regime of Feynman's vision 1 of nanotechnology based on atom-by-atom fabrication 2 , 3 , 4 , 5 , there is a critical need to match the advances in miniaturization with atomically precise metrology. In conventional complementary metal–oxide–semiconductor 6 and tunnelling field-effect 7 , 8 transistors, the key relationship between the doping profile and performance is dominated by the positions of just a few dopant atoms, which at present cannot be quantitatively determined. Beyond conventional nanoelectronic devices, in quantum processors based on P dopants in Si 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 the precise locations of the individual dopants is critical to the design and operation of spin-based quantum logic gates. Indirect approaches for locating subsurface dopant positions in Si devices can only achieve a precision of several nanometres 18 . Compared to previous studies on locating subsurface dopant positions in direct-bandgap semiconductors 19 , 20 , the Si–dopant system is inherently more challenging due to its indirect bandgap and the presence of valley effects leading to a non-monotonic dependence of the wavefunction on dopant depth. The key metrological challenge in Si-based ultrascaled applications is determining the position of dopant atoms in the Si crystal substrate with lattice-site precision, which will drastically transform our understanding at the most fundamental scale, leading to devices with optimized functionalities. In this Article, we present an atomically precise metrology and demonstrate the pinpointing of the position of subsurface P and As dopants in Si down to individual lattice sites. The experimental technique involves low-temperature scanning tunnelling microscopy (STM) imaging, as recently reported for As dopants in Si 21 . In ref. 21 , valley interference processes were studied based on certain features of the Fourier spectra of images, which can be understood qualitatively without atomistic details of the system 22 , 23 . However, precision metrology of dopant positions demands a quantitative understanding of the atomic-level details in real-space images. To meet this challenge, we have developed a fully quantum, large-volume treatment of the STM–dopant system, based on a state-of-the-art multi-million-atom tight-binding framework 24 , 25 , from which quantitative information about donor position can be extracted from STM images. We also measured STM images of P dopants with engineered depths to demonstrate the metrology procedure for both subsurface P and As dopants. A direct quantitative comparison with real-space STM images shows remarkable agreement, enabling the determination of each dopant's lattice location by uniquely reproducing the normalized tunnelling current image. The relatively large extent of the dopant electron wavefunction (Bohr radius of ∼ 2 nm) as well as high-frequency content arising from the silicon valley interference processes 21 result in the atomic-level features in the STM image, which are highly sensitive to both dopant position and details of the STM tip orbital involved. In all cases, we establish the STM tip state to be dominated by a d -type tip orbital, consistent with expectations for a W tip 26 . For each experimental STM image, a quantitative comparison with the images calculated at various dopant locations allows us to uniquely pinpoint the actual three-dimensional lattice site position of the dopant with respect to the surface dimer rows for depths down to about 36 lattice planes ( ∼ 5 nm). These results establish an STM-based metrology to determine the exact three-dimensional position of dopants in Si, as is required in modern nanoelectronics. The method is directly applicable to the fabrication of a quantum computer based on P atoms in Si 9 , and is more generally of relevance to ultrascaled nanoelectronic devices. Figure 1 presents an overview of our metrology technique. We first describe the STM–donor measurement set-up and the quantum mechanical treatment of the tunnelling current, as shown in Fig. 1a,b . Our data set includes P (P-1 and P-2) and As (As-1 and As-2) dopants. Although the image detail has a complex relationship with the quantum mechanics of the tip orbital configuration, the tip height above the sample, the exact dopant position with regard to the lattice plane depth, and the lateral position relative to the surface dimers, we explicitly show these dependencies for a specific example (P-1). Fourier space analysis provides further evidence of the correct tip orbital and surface reconstruction. By a direct quantitative (pixel-by-pixel) comparison with the experimental images (for example, as in Fig. 1c ), the precise dopant position can be located with a high degree of confidence for all four members of the data set. Figure 1: STM-based metrology for the exact position of subsurface dopants in silicon. a , Illustration of the STM set-up used to measure atomically resolved subsurface dopant images. The dopant charge density distribution (| Ψ D | 2 ) calculated from a tight-binding simulation over a large volume of the Si lattice is shown, colour-coded to highlight its variation as a function of distance from the dopant atom. A P dopant is positioned a few nanometres below the surface ( z = 0) and is highlighted in red. The 2 × 1 reconstruction results in the", "role": "user" }, { "content": ",, A map of electron wave function patterns, where the symmetry, brightness and size of features is directly related to the position of a phosphorus atom in silicon lattice. Credit: M.Usman/ University of Melbourne Quantum computers are expected to offer tremendous computational power for complex problems –currently intractable even on supercomputers—in the areas of drug design, data science, astronomy and materials chemistry among others. The high technological and strategic stakes mean major technology companies as well as ambitious start-ups and government-funded research centers are all in the race to build the world's first universal quantum computer. Building a quantum computer In contrast to today's classical computers, where information is encoded in bits (0 or 1), quantum computers process information stored in quantum bits (qubits). These are hosted by quantum mechanical objects like electrons, the negatively charged particles of an atom. Quantum states can also be binary and can be put in one of two possibilities, or effectively both at the same time—known as quantum superposition—offering an exponentially larger computational space with an increasing number of qubits. This unique data crunching power is further boosted by entanglement, another magical property of quantum mechanics where the state of one qubit is able to dictate the state of another qubit without any physical connection, making them all 1's for example. Einstein called it a 'spooky action at distance'. Different research groups in the world are pursuing different kinds of qubits, each having its own benefits and limitations. Some qubits offer potential for scalability, while others come with very long coherence times, that is the time for which quantum information can be robustly stored. Over the next decade, quantum computers will move beyond physics research laboratories. Credit: Connie Zhou/IBM Qubits in silicon are highly promising as they offer both. Therefore, these qubits are one of the front-runner candidates for the design and implementation of a large-scale quantum computer architecture. One way to implement large-scale quantum computer architecture in silicon is by placing individual phosphorus atoms on a two-dimensional grid. The single and two qubit logical operations are controlled by a grid of nanoelectronic wires, bearing some resemblance to classical logic gates for conventional microelectronic circuits. However, key to this scheme is ultra-precise placement of phosphorus atoms on the silicon grid. The challenges However, even with state-of-the-art fabrication technologies, placing phosphorus atoms at precise locations in silicon lattice is a very challenging task. Small variations, of the order of one atomic lattice site, in their positions are often observed and may have a huge impact on the efficiency of two qubit operations. The problem arises from the ultra-sensitive dependence of the exchange interaction between the electron qubits on phosphorus atoms in silicon. Exchange interaction is a fundamental quantum mechanical property where two sub-atomic particles such as electrons can interact in real space when their wave functions overlap and make interference patterns, much like the two traveling waves interfering on water surface. Exchange interaction between electrons on phosphorus atom qubits can be exploited to implement fast two-qubit gates, but any unknown variation can be detrimental to accuracy of quantum gate. Like logic gates in a conventional computer, the quantum gates are the building blocks of a quantum circuit. An artist’s impression of a large-scale quantum computer architecture based on phosphorus (P) atom qubits in silicon. The wave functions of electrons bound to P atom exhibit oscillations and constructive/destructive spatial overlaps of these wave functions give rise to large variations in interaction, introducing errors in quantum gates. Determination of Exact P atom positions could eliminate errors, paving the way for the ultimate goal of fault-tolerant universal quantum computing. Credit: M.Usman/ University of Melbourne For phosphorus qubits in silicon, even an uncertainty in the location of qubit atom of the order of one atomic lattice site can alter the corresponding exchange interaction by orders of magnitude, leading to errors in two-qubit gate operations. Such errors, accumulated over the large-scale architecture, may severely impede the efficiency of quantum computer, diminishing any quantum advantage expected due to the quantum mechanical properties of qubits. Finding exact coordinates of qubit atom So in 2016, we worked with the Center for Quantum Computation & Communication Technology researchers at the University of New South Wales, to develop a technique that could pinpoint exact locations of phosphorus atoms in silicon. The technique, reported in Nature Nanotechnology, was the first to use computed scanning tunneling microscope (STM) images of phosphorus atom wave functions to pinpoint their spatial locations in silicon. The images were calculated using a computational framework which allowed electronic calculations to be performed on millions of atoms utilizing Australia's national supercomputer facilities at the Pawsey supercomputing center. These calculations produced maps of electron wave function patterns, where the symmetry, brightness and size of features was directly related to the position of a phosphorus atom in silicon lattice, around which the electron was bound. A map of electron wave function patterns, where the symmetry, brightness and size of features is directly related to the position of a phosphorus atom in silicon lattice. Credit: M.Usman/ University of Melbourne The fact that each donor atom positions led to a distinct map, pinpointing of qubit atom locations, known as spatial metrology, with single lattice site precision was achieved. The technique worked very well at the individual qubit level. However, the next big challenge was to build a framework that could perform this exact atom spatial pinpointing with high speed and minimal human interaction coping with the requirements of a universal fault tolerant quantum computer. Machine learning Machine learning is an emerging area of research which is revolutionizing almost every field of research, from medical science to image processing, robotics, and material design. A carefully trained machine learning algorithm can process very large data sets with enormous efficiency. One branch of machine learning is known as convolutional neural network (CNN) – an extremely powerful tool for image recognition and classification problems. When a CNN is trained on thousands of sample images, it can precisely recognize unknown images (including noise) and perform classifications. Recognising that the principle underpinning the established spatial metrology of qubit atoms is basically recognizing and classifying feature maps of STM images, we decided to train a CNN on the computed STM images. The work is published in the NPJ Computational Materials journal. Computed scanning tunneling microscope (STM) images of phosphorus atoms qubits in silicon used to train a convolutional neural network (CNN), capable of autonomous and high-throughput qubit characterization with an exact atom precision in both, their spatial locations and atom count. Credit: M.Usman/ University of Melbourne The training involved 100,000 STM images and achieved a remarkable learning of above 99 percent for the CNN. We then tested the trained CNN for 17600 test images including blurring and asymmetry noise typically present in the realistic environments. The CNN classified the test images with an accuracy of above 98 percent, confirming that this machine learning-based technique could process qubit measurement data with high-throughput, high precision, and minimal human interaction. This technique also has the potential to scale up for qubits consisting of more than one phosphorus atoms, where the number of possible image configurations would exponentially increase. However, machine learning-based framework could readily include any number of possible configurations. In the coming years, as the number of qubits increase and size of quantum devices grow, qubit characterization via manual measurements is likely to be highly challenging and onerous. This work shows how machine learning techniques such as developed in this work could play a crucial role in this aspect of the realization of a full-scale fault-tolerant universal quantum computer—the ultimate goal of the global research effort. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Scaling of Si-based nanoelectronics has reached the regime where device function is affected not only by the presence of individual dopants, but also by their positions in the crystal. Determination of the precise dopant location is an unsolved problem in applications from channel doping in ultrascaled transistors to quantum information processing. Here, we establish a metrology combining low-temperature scanning tunnelling microscopy (STM) imaging and a comprehensive quantum treatment of the dopant–STM system to pinpoint the exact coordinates of the dopant in the Si crystal. The technique is underpinned by the observation that STM images contain atomic-sized features in ordered patterns that are highly sensitive to the STM tip orbital and the absolute dopant lattice site. The demonstrated ability to determine the locations of P and As dopants to 5 nm depths will provide critical information for the design and optimization of nanoscale devices for classical and quantum computing applications. Main As we approach the ultimate regime of Feynman's vision 1 of nanotechnology based on atom-by-atom fabrication 2 , 3 , 4 , 5 , there is a critical need to match the advances in miniaturization with atomically precise metrology. In conventional complementary metal–oxide–semiconductor 6 and tunnelling field-effect 7 , 8 transistors, the key relationship between the doping profile and performance is dominated by the positions of just a few dopant atoms, which at present cannot be quantitatively determined. Beyond conventional nanoelectronic devices, in quantum processors based on P dopants in Si 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 the precise locations of the individual dopants is critical to the design and operation of spin-based quantum logic gates. Indirect approaches for locating subsurface dopant positions in Si devices can only achieve a precision of several nanometres 18 . Compared to previous studies on locating subsurface dopant positions in direct-bandgap semiconductors 19 , 20 , the Si–dopant system is inherently more challenging due to its indirect bandgap and the presence of valley effects leading to a non-monotonic dependence of the wavefunction on dopant depth. The key metrological challenge in Si-based ultrascaled applications is determining the position of dopant atoms in the Si crystal substrate with lattice-site precision, which will drastically transform our understanding at the most fundamental scale, leading to devices with optimized functionalities. In this Article, we present an atomically precise metrology and demonstrate the pinpointing of the position of subsurface P and As dopants in Si down to individual lattice sites. The experimental technique involves low-temperature scanning tunnelling microscopy (STM) imaging, as recently reported for As dopants in Si 21 . In ref. 21 , valley interference processes were studied based on certain features of the Fourier spectra of images, which can be understood qualitatively without atomistic details of the system 22 , 23 . However, precision metrology of dopant positions demands a quantitative understanding of the atomic-level details in real-space images. To meet this challenge, we have developed a fully quantum, large-volume treatment of the STM–dopant system, based on a state-of-the-art multi-million-atom tight-binding framework 24 , 25 , from which quantitative information about donor position can be extracted from STM images. We also measured STM images of P dopants with engineered depths to demonstrate the metrology procedure for both subsurface P and As dopants. A direct quantitative comparison with real-space STM images shows remarkable agreement, enabling the determination of each dopant's lattice location by uniquely reproducing the normalized tunnelling current image. The relatively large extent of the dopant electron wavefunction (Bohr radius of ∼ 2 nm) as well as high-frequency content arising from the silicon valley interference processes 21 result in the atomic-level features in the STM image, which are highly sensitive to both dopant position and details of the STM tip orbital involved. In all cases, we establish the STM tip state to be dominated by a d -type tip orbital, consistent with expectations for a W tip 26 . For each experimental STM image, a quantitative comparison with the images calculated at various dopant locations allows us to uniquely pinpoint the actual three-dimensional lattice site position of the dopant with respect to the surface dimer rows for depths down to about 36 lattice planes ( ∼ 5 nm). These results establish an STM-based metrology to determine the exact three-dimensional position of dopants in Si, as is required in modern nanoelectronics. The method is directly applicable to the fabrication of a quantum computer based on P atoms in Si 9 , and is more generally of relevance to ultrascaled nanoelectronic devices. Figure 1 presents an overview of our metrology technique. We first describe the STM–donor measurement set-up and the quantum mechanical treatment of the tunnelling current, as shown in Fig. 1a,b . Our data set includes P (P-1 and P-2) and As (As-1 and As-2) dopants. Although the image detail has a complex relationship with the quantum mechanics of the tip orbital configuration, the tip height above the sample, the exact dopant position with regard to the lattice plane depth, and the lateral position relative to the surface dimers, we explicitly show these dependencies for a specific example (P-1). Fourier space analysis provides further evidence of the correct tip orbital and surface reconstruction. By a direct quantitative (pixel-by-pixel) comparison with the experimental images (for example, as in Fig. 1c ), the precise dopant position can be located with a high degree of confidence for all four members of the data set. Figure 1: STM-based metrology for the exact position of subsurface dopants in silicon. a , Illustration of the STM set-up used to measure atomically resolved subsurface dopant images. The dopant charge density distribution (| Ψ D | 2 ) calculated from a tight-binding simulation over a large volume of the Si lattice is shown, colour-coded to highlight its variation as a function of distance from the dopant atom. A P dopant is positioned a few nanometres below the surface ( z = 0) and is highlighted in red. The 2 × 1 reconstruction results in the<|im_end|> <|im_start|>assistant ,, A map of electron wave function patterns, where the symmetry, brightness and size of features is directly related to the position of a phosphorus atom in silicon lattice. Credit: M.Usman/ University of Melbourne Quantum computers are expected to offer tremendous computational power for complex problems –currently intractable even on supercomputers—in the areas of drug design, data science, astronomy and materials chemistry among others. The high technological and strategic stakes mean major technology companies as well as ambitious start-ups and government-funded research centers are all in the race to build the world's first universal quantum computer. Building a quantum computer In contrast to today's classical computers, where information is encoded in bits (0 or 1), quantum computers process information stored in quantum bits (qubits). These are hosted by quantum mechanical objects like electrons, the negatively charged particles of an atom. Quantum states can also be binary and can be put in one of two possibilities, or effectively both at the same time—known as quantum superposition—offering an exponentially larger computational space with an increasing number of qubits. This unique data crunching power is further boosted by entanglement, another magical property of quantum mechanics where the state of one qubit is able to dictate the state of another qubit without any physical connection, making them all 1's for example. Einstein called it a 'spooky action at distance'. Different research groups in the world are pursuing different kinds of qubits, each having its own benefits and limitations. Some qubits offer potential for scalability, while others come with very long coherence times, that is the time for which quantum information can be robustly stored. Over the next decade, quantum computers will move beyond physics research laboratories. Credit: Connie Zhou/IBM Qubits in silicon are highly promising as they offer both. Therefore, these qubits are one of the front-runner candidates for the design and implementation of a large-scale quantum computer architecture. One way to implement large-scale quantum computer architecture in silicon is by placing individual phosphorus atoms on a two-dimensional grid. The single and two qubit logical operations are controlled by a grid of nanoelectronic wires, bearing some resemblance to classical logic gates for conventional microelectronic circuits. However, key to this scheme is ultra-precise placement of phosphorus atoms on the silicon grid. The challenges However, even with state-of-the-art fabrication technologies, placing phosphorus atoms at precise locations in silicon lattice is a very challenging task. Small variations, of the order of one atomic lattice site, in their positions are often observed and may have a huge impact on the efficiency of two qubit operations. The problem arises from the ultra-sensitive dependence of the exchange interaction between the electron qubits on phosphorus atoms in silicon. Exchange interaction is a fundamental quantum mechanical property where two sub-atomic particles such as electrons can interact in real space when their wave functions overlap and make interference patterns, much like the two traveling waves interfering on water surface. Exchange interaction between electrons on phosphorus atom qubits can be exploited to implement fast two-qubit gates, but any unknown variation can be detrimental to accuracy of quantum gate. Like logic gates in a conventional computer, the quantum gates are the building blocks of a quantum circuit. An artist’s impression of a large-scale quantum computer architecture based on phosphorus (P) atom qubits in silicon. The wave functions of electrons bound to P atom exhibit oscillations and constructive/destructive spatial overlaps of these wave functions give rise to large variations in interaction, introducing errors in quantum gates. Determination of Exact P atom positions could eliminate errors, paving the way for the ultimate goal of fault-tolerant universal quantum computing. Credit: M.Usman/ University of Melbourne For phosphorus qubits in silicon, even an uncertainty in the location of qubit atom of the order of one atomic lattice site can alter the corresponding exchange interaction by orders of magnitude, leading to errors in two-qubit gate operations. Such errors, accumulated over the large-scale architecture, may severely impede the efficiency of quantum computer, diminishing any quantum advantage expected due to the quantum mechanical properties of qubits. Finding exact coordinates of qubit atom So in 2016, we worked with the Center for Quantum Computation & Communication Technology researchers at the University of New South Wales, to develop a technique that could pinpoint exact locations of phosphorus atoms in silicon. The technique, reported in Nature Nanotechnology, was the first to use computed scanning tunneling microscope (STM) images of phosphorus atom wave functions to pinpoint their spatial locations in silicon. The images were calculated using a computational framework which allowed electronic calculations to be performed on millions of atoms utilizing Australia's national supercomputer facilities at the Pawsey supercomputing center. These calculations produced maps of electron wave function patterns, where the symmetry, brightness and size of features was directly related to the position of a phosphorus atom in silicon lattice, around which the electron was bound. A map of electron wave function patterns, where the symmetry, brightness and size of features is directly related to the position of a phosphorus atom in silicon lattice. Credit: M.Usman/ University of Melbourne The fact that each donor atom positions led to a distinct map, pinpointing of qubit atom locations, known as spatial metrology, with single lattice site precision was achieved. The technique worked very well at the individual qubit level. However, the next big challenge was to build a framework that could perform this exact atom spatial pinpointing with high speed and minimal human interaction coping with the requirements of a universal fault tolerant quantum computer. Machine learning Machine learning is an emerging area of research which is revolutionizing almost every field of research, from medical science to image processing, robotics, and material design. A carefully trained machine learning algorithm can process very large data sets with enormous efficiency. One branch of machine learning is known as convolutional neural network (CNN) – an extremely powerful tool for image recognition and classification problems. When a CNN is trained on thousands of sample images, it can precisely recognize unknown images (including noise) and perform classifications. Recognising that the principle underpinning the established spatial metrology of qubit atoms is basically recognizing and classifying feature maps of STM images, we decided to train a CNN on the computed STM images. The work is published in the NPJ Computational Materials journal. Computed scanning tunneling microscope (STM) images of phosphorus atoms qubits in silicon used to train a convolutional neural network (CNN), capable of autonomous and high-throughput qubit characterization with an exact atom precision in both, their spatial locations and atom count. Credit: M.Usman/ University of Melbourne The training involved 100,000 STM images and achieved a remarkable learning of above 99 percent for the CNN. We then tested the trained CNN for 17600 test images including blurring and asymmetry noise typically present in the realistic environments. The CNN classified the test images with an accuracy of above 98 percent, confirming that this machine learning-based technique could process qubit measurement data with high-throughput, high precision, and minimal human interaction. This technique also has the potential to scale up for qubits consisting of more than one phosphorus atoms, where the number of possible image configurations would exponentially increase. However, machine learning-based framework could readily include any number of possible configurations. In the coming years, as the number of qubits increase and size of quantum devices grow, qubit characterization via manual measurements is likely to be highly challenging and onerous. This work shows how machine learning techniques such as developed in this work could play a crucial role in this aspect of the realization of a full-scale fault-tolerant universal quantum computer—the ultimate goal of the global research effort. <|im_end|>

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311, 4305, 3544, 13230, 31228, 6500, 18112, 304, 51692, 374, 555, 25012, 3927, 33088, 30969, 33299, 389, 264, 1403, 33520, 5950, 13, 578, 3254, 323, 1403, 2874, 60320, 20406, 7677, 527, 14400, 555, 264, 5950, 315, 20622, 4748, 772, 8535, 36108, 11, 18534, 1063, 70000, 311, 29924, 12496, 35634, 369, 21349, 8162, 19493, 8535, 46121, 13, 4452, 11, 1401, 311, 420, 13155, 374, 24955, 12, 10872, 1082, 22165, 315, 33088, 30969, 33299, 389, 279, 51692, 5950, 13, 578, 11774, 4452, 11, 1524, 449, 1614, 8838, 10826, 38921, 59251, 14645, 11, 25012, 33088, 30969, 33299, 520, 24473, 10687, 304, 51692, 55372, 374, 264, 1633, 17436, 3465, 13, 15344, 27339, 11, 315, 279, 2015, 315, 832, 25524, 55372, 2816, 11, 304, 872, 10093, 527, 3629, 13468, 323, 1253, 617, 264, 6908, 5536, 389, 279, 15374, 315, 1403, 2874, 60320, 7677, 13, 578, 3575, 48282, 505, 279, 24955, 57767, 44393, 315, 279, 9473, 16628, 1990, 279, 17130, 2874, 82502, 389, 33088, 30969, 33299, 304, 51692, 13, 19224, 16628, 374, 264, 16188, 31228, 22936, 3424, 1405, 1403, 1207, 12, 6756, 19252, 1778, 439, 57678, 649, 16681, 304, 1972, 3634, 994, 872, 12330, 5865, 28347, 323, 1304, 32317, 12912, 11, 1790, 1093, 279, 1403, 21646, 17301, 75387, 389, 3090, 7479, 13, 19224, 16628, 1990, 57678, 389, 33088, 30969, 19670, 2874, 82502, 649, 387, 51763, 311, 4305, 5043, 1403, 52708, 60320, 35634, 11, 719, 904, 9987, 23851, 649, 387, 65069, 311, 13708, 315, 31228, 18618, 13, 9086, 12496, 35634, 304, 264, 21349, 6500, 11, 279, 31228, 35634, 527, 279, 4857, 10215, 315, 264, 31228, 16622, 13, 1556, 10255, 753, 21455, 315, 264, 3544, 13230, 31228, 6500, 18112, 3196, 389, 33088, 30969, 320, 47, 8, 19670, 2874, 82502, 304, 51692, 13, 578, 12330, 5865, 315, 57678, 6965, 311, 393, 19670, 31324, 43524, 811, 323, 54584, 23365, 1257, 535, 29079, 77107, 315, 1521, 12330, 5865, 3041, 10205, 311, 3544, 27339, 304, 16628, 11, 33018, 6103, 304, 31228, 35634, 13, 36007, 367, 315, 75580, 393, 19670, 10093, 1436, 22472, 6103, 11, 82568, 279, 1648, 369, 279, 17139, 5915, 315, 14867, 2442, 22847, 519, 20789, 31228, 25213, 13, 16666, 25, 386, 13, 3642, 1543, 14, 3907, 315, 27535, 1789, 33088, 30969, 2874, 82502, 304, 51692, 11, 1524, 459, 27924, 304, 279, 3813, 315, 2874, 60320, 19670, 315, 279, 2015, 315, 832, 25524, 55372, 2816, 649, 11857, 279, 12435, 9473, 16628, 555, 10373, 315, 26703, 11, 6522, 311, 6103, 304, 1403, 52708, 60320, 18618, 7677, 13, 15483, 6103, 11, 41165, 927, 279, 3544, 13230, 18112, 11, 1253, 35906, 3242, 15686, 279, 15374, 315, 31228, 6500, 11, 84153, 904, 31228, 9610, 3685, 4245, 311, 279, 31228, 22936, 6012, 315, 2874, 82502, 13, 43897, 4839, 14259, 315, 2874, 60320, 19670, 2100, 304, 220, 679, 21, 11, 584, 6575, 449, 279, 5955, 369, 56413, 1219, 13623, 612, 31966, 12053, 12074, 520, 279, 3907, 315, 1561, 4987, 23782, 11, 311, 2274, 264, 15105, 430, 1436, 67638, 4839, 10687, 315, 33088, 30969, 33299, 304, 51692, 13, 578, 15105, 11, 5068, 304, 22037, 33242, 52536, 11, 574, 279, 1176, 311, 1005, 25157, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells. Introduction Evasion of apoptosis and avoidance of immune attack represent two key hallmarks of cancer 1 . Members of the inhibitor of apoptosis (IAP) gene family play important interconnecting roles in both of these characteristic pathways of tumorigenesis 2 , providing a critical nexus in the targeting of cancer. Small-molecule antagonists of the IAPs, known as Smac mimetic compounds (SMCs), are in clinical development for cancer therapy 3 . SMCs were found to exert immunological effects leading to the eradication of tumours 4 , 5 . Mechanistically, SMCs bind to cellular IAP 1 and 2 (cIAP1 and cIAP2), which induces the auto-ubiquitination and subsequent proteasomal-mediated degradation of these IAPs 6 . At higher doses, SMCs can antagonize X-linked IAP (XIAP), de-repressing the ability of XIAP to inhibit pro-apoptotic caspases. These three IAPs are E3 ubiquitin ligases that control diverse signalling pathways through post-translational ubiquitination reactions, including pathways central to immunity 7 . The SMC drug-sustained loss of IAPs has important consequences. First, SMC-mediated antagonism of the IAPs sensitizes cancer cells to death ligands originating from the immune system by switching tumour necrosis factor alpha (TNF-α) from a survival factor to a potent death factor, leading to death through the ripoptosome or the necrosome 8 , 9 . Second, the loss of the cIAPs activates the alternative nuclear factor kappa B (NF-κB) pathway through the stabilization of NF-κB-inducing kinsase (NIK) in cells 10 . NIK is a target of the cIAPs, wherein NIK is constitutively ubiquitinated and degraded. However, on binding of a TNF superfamily ligand to their cognate receptor, such as CD137 (aka, 4-1BB), the cIAPs are sequestered and degraded, thereby allowing for the accumulation of NIK and activation of the alternative NF-κB pathway 10 , 11 . In general, tumours are resistant to the induction of apoptosis due to the p53-mediated adaptations of the intrinsic mitochondrial cell death pathway to damaging DNA lesions and prior chemotherapy treatments 12 . In contrast, the extrinsic cell death pathway, which responds to death ligands from the immune system, is typically intact in cancer cells 12 . Thus, the extrinsic pathway provides an avenue to exploit for the induction of cancer cell death. However, tumours have evolved other means to suppress immune attack such as by upregulating T-cell co-inhibitory molecules, typified by Programmed death-ligand (PD-L1, a.k.a., CD274), on the cancer cell surface. The recent clinical successes for antibody-based biologics, called immune checkpoint inhibitors (ICIs), which target molecules like programmed cell death protein 1 (PD-1, a.k.a. CD279), have demonstrated remarkable efficacy 13 , 14 , 15 . ICIs overcome the countervailing immune checkpoint blockade and promote the immune system to attack tumour cells. However, these drugs are not without limitations: a notable example is the appearance of limiting toxicities related to the induction of autoimmunity. Here, we investigate the efficacy of targeting cIAP1 and cIAP2 with a SMC in combination with an immunotherapy agent for the treatment of glioblastoma. We demonstrate that SMCs and ICIs combine to form an effective immunotherapy for the treatment in mouse models of this deadly brain cancer, and for other cancers, such as mammary carcinoma and multiple myeloma/plasmacytoma. In addition to the synergy that we have found with innate immune stimulants, our results uncover a second important mechanism by which SMCs exert their anti-cancer effects, specifically through the potentiation of cytotoxic T-cell (CTL) activity against tumours, which is amplified with an ICI. Results Combining immunostimulatory agents for glioblastoma therapy We previously found that SMC-mediated death of cancer cell lines was potentiated with a type I IFN-inducing oncolytic virus, such as the attenuated rhabdovirus Vesicular stomatitis virus (VSVΔ51) 16 . VSVΔ51 infection lacks cytolytic activity for the tested glioma cell lines, presumably due the presence of a partial type I interferon (IFN) response 17 . Notably, cIAP2 (a mediator and an indicator of NF-κB activity) is upregulated in glioblastoma tumours, showing that cIAP2 promotes tumorigenesis and further drives therapeutic resistance 18 , 19 , 20 . We show here that cultured and primary glioblastoma cell lines are killed with SMC when combined with exogenous TNF-α, the oncolytic virus VSVΔ51 or with an infectious but non-replicating virus, VSVΔ51ΔG ( Fig. 1a,b ). We confirmed that the synergistic effects between the SMC, LCL161, and TNF-α is a general phenomena within this drug class, as we observed death of glioblastoma cells with the combination of TNF-α and different SMCs ( Supplementary Fig. 1 ). Furthermore, we also observed potentiation of SMC efficacy with the oncolytic rhabdoviruses, VSVΔ51 or Maraba-MG1, for human brain tumour-initiating cells (BTICs) ( Fig. 1c ). Non-replicating rhabdovirus particles (NRRPs), which retain their infectious and immunostimulatory properties without the ability to replicate 21 , similarly were found to synergize with SMCs to induce glioblastoma cell death ( Supplementary Fig. 2 ). Notably, only ∼ 50% of profiled cancer cell lines are sensitized to death in combination of SMC and TNF-α or TNF-related apoptosis-inducing ligand (TRAIL); the majority of resistant cell lines are further sensitized to death with the downregulation of the caspase-8 inhibitor, cFLIP (cellular FLICE-like inhibitory protein) 22 . Consistent with this previous finding, two glioblastoma lines that are", "role": "user" }, { "content": "A promising combination of immunotherapies delivers a one-two punch to brain cancer tumours with high cure rates in mice, scientific evidence published in Nature Communications today says. Researchers at the Children's Hospital of Eastern Ontario (CHEO) in Ottawa found that a combination of drugs known as SMAC Mimetics and immune checkpoint inhibitors (ICIs) amplifies kill rates of cancer tumour cells in laboratory testing. Researchers also discovered a new mechanism by which the combination promotes long-term immunity against glioblastoma tumours. The combination therapy also proved to be highly effective against breast cancer and multiple myeloma. \"These findings represent a significant evolution in our research and the field of immunotherapy. We are the first in the world to show the synergistic tumour-killing impact of combining SMAC Mimetics with immune checkpoint inhibitors for glioblastoma,\" said Dr. Robert Korneluk, distinguished professor at the University of Ottawa and senior scientist at the CHEO Research Institute. \"You could say it takes two to tango. We believe that it takes a combination strategy to impact cancer cure rates.\" In 2014, a team of scientists led by Dr. Korneluk discovered that combining SMAC Mimetics with immune stimulators or live virus therapies had a synergistic or amplified tumour-killing effect that was greater than either agent on its own. Today's news shows that SMAC Mimetics also have a powerful synergistic effect with ICIs, relatively new drugs that are showing great promise in the clinic. SMAC Mimetics known as LCL161 and Birinapant were combined with ICI antibodies targeting PD-1 and CTLA-4 immune checkpoints. Eric Lacasse, a scientist at the CHEO Research Institute, said: \"Two drug companies have initiated human clinical trials this year to assess the impact of this combination of SMAC Mimetics and ICIs on patients with a variety of cancers. Although it could be years before any clinical trials begin for adults or children with the deadly brain cancer, glioblastoma, we're looking forward to seeing how scientific evidence from these experimental treatments adds to our knowledge. It's an exciting, exploratory field and we hope we've hit a home run.\" Shawn Beug, lead author of the 2014 and 2017 papers, said: \"This research heightens our understanding of the mechanics behind this double-whammy effect, which both enhances the immune response and weakens tumour cells to immune attack. We're hoping that more oncologists and biotech companies test out this combination in clinical trials as we continue to decipher how SMAC Mimetics encourage the immune system to kill cancer cells.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells. Introduction Evasion of apoptosis and avoidance of immune attack represent two key hallmarks of cancer 1 . Members of the inhibitor of apoptosis (IAP) gene family play important interconnecting roles in both of these characteristic pathways of tumorigenesis 2 , providing a critical nexus in the targeting of cancer. Small-molecule antagonists of the IAPs, known as Smac mimetic compounds (SMCs), are in clinical development for cancer therapy 3 . SMCs were found to exert immunological effects leading to the eradication of tumours 4 , 5 . Mechanistically, SMCs bind to cellular IAP 1 and 2 (cIAP1 and cIAP2), which induces the auto-ubiquitination and subsequent proteasomal-mediated degradation of these IAPs 6 . At higher doses, SMCs can antagonize X-linked IAP (XIAP), de-repressing the ability of XIAP to inhibit pro-apoptotic caspases. These three IAPs are E3 ubiquitin ligases that control diverse signalling pathways through post-translational ubiquitination reactions, including pathways central to immunity 7 . The SMC drug-sustained loss of IAPs has important consequences. First, SMC-mediated antagonism of the IAPs sensitizes cancer cells to death ligands originating from the immune system by switching tumour necrosis factor alpha (TNF-α) from a survival factor to a potent death factor, leading to death through the ripoptosome or the necrosome 8 , 9 . Second, the loss of the cIAPs activates the alternative nuclear factor kappa B (NF-κB) pathway through the stabilization of NF-κB-inducing kinsase (NIK) in cells 10 . NIK is a target of the cIAPs, wherein NIK is constitutively ubiquitinated and degraded. However, on binding of a TNF superfamily ligand to their cognate receptor, such as CD137 (aka, 4-1BB), the cIAPs are sequestered and degraded, thereby allowing for the accumulation of NIK and activation of the alternative NF-κB pathway 10 , 11 . In general, tumours are resistant to the induction of apoptosis due to the p53-mediated adaptations of the intrinsic mitochondrial cell death pathway to damaging DNA lesions and prior chemotherapy treatments 12 . In contrast, the extrinsic cell death pathway, which responds to death ligands from the immune system, is typically intact in cancer cells 12 . Thus, the extrinsic pathway provides an avenue to exploit for the induction of cancer cell death. However, tumours have evolved other means to suppress immune attack such as by upregulating T-cell co-inhibitory molecules, typified by Programmed death-ligand (PD-L1, a.k.a., CD274), on the cancer cell surface. The recent clinical successes for antibody-based biologics, called immune checkpoint inhibitors (ICIs), which target molecules like programmed cell death protein 1 (PD-1, a.k.a. CD279), have demonstrated remarkable efficacy 13 , 14 , 15 . ICIs overcome the countervailing immune checkpoint blockade and promote the immune system to attack tumour cells. However, these drugs are not without limitations: a notable example is the appearance of limiting toxicities related to the induction of autoimmunity. Here, we investigate the efficacy of targeting cIAP1 and cIAP2 with a SMC in combination with an immunotherapy agent for the treatment of glioblastoma. We demonstrate that SMCs and ICIs combine to form an effective immunotherapy for the treatment in mouse models of this deadly brain cancer, and for other cancers, such as mammary carcinoma and multiple myeloma/plasmacytoma. In addition to the synergy that we have found with innate immune stimulants, our results uncover a second important mechanism by which SMCs exert their anti-cancer effects, specifically through the potentiation of cytotoxic T-cell (CTL) activity against tumours, which is amplified with an ICI. Results Combining immunostimulatory agents for glioblastoma therapy We previously found that SMC-mediated death of cancer cell lines was potentiated with a type I IFN-inducing oncolytic virus, such as the attenuated rhabdovirus Vesicular stomatitis virus (VSVΔ51) 16 . VSVΔ51 infection lacks cytolytic activity for the tested glioma cell lines, presumably due the presence of a partial type I interferon (IFN) response 17 . Notably, cIAP2 (a mediator and an indicator of NF-κB activity) is upregulated in glioblastoma tumours, showing that cIAP2 promotes tumorigenesis and further drives therapeutic resistance 18 , 19 , 20 . We show here that cultured and primary glioblastoma cell lines are killed with SMC when combined with exogenous TNF-α, the oncolytic virus VSVΔ51 or with an infectious but non-replicating virus, VSVΔ51ΔG ( Fig. 1a,b ). We confirmed that the synergistic effects between the SMC, LCL161, and TNF-α is a general phenomena within this drug class, as we observed death of glioblastoma cells with the combination of TNF-α and different SMCs ( Supplementary Fig. 1 ). Furthermore, we also observed potentiation of SMC efficacy with the oncolytic rhabdoviruses, VSVΔ51 or Maraba-MG1, for human brain tumour-initiating cells (BTICs) ( Fig. 1c ). Non-replicating rhabdovirus particles (NRRPs), which retain their infectious and immunostimulatory properties without the ability to replicate 21 , similarly were found to synergize with SMCs to induce glioblastoma cell death ( Supplementary Fig. 2 ). Notably, only ∼ 50% of profiled cancer cell lines are sensitized to death in combination of SMC and TNF-α or TNF-related apoptosis-inducing ligand (TRAIL); the majority of resistant cell lines are further sensitized to death with the downregulation of the caspase-8 inhibitor, cFLIP (cellular FLICE-like inhibitory protein) 22 . Consistent with this previous finding, two glioblastoma lines that are<|im_end|> <|im_start|>assistant A promising combination of immunotherapies delivers a one-two punch to brain cancer tumours with high cure rates in mice, scientific evidence published in Nature Communications today says. Researchers at the Children's Hospital of Eastern Ontario (CHEO) in Ottawa found that a combination of drugs known as SMAC Mimetics and immune checkpoint inhibitors (ICIs) amplifies kill rates of cancer tumour cells in laboratory testing. Researchers also discovered a new mechanism by which the combination promotes long-term immunity against glioblastoma tumours. The combination therapy also proved to be highly effective against breast cancer and multiple myeloma. "These findings represent a significant evolution in our research and the field of immunotherapy. We are the first in the world to show the synergistic tumour-killing impact of combining SMAC Mimetics with immune checkpoint inhibitors for glioblastoma," said Dr. Robert Korneluk, distinguished professor at the University of Ottawa and senior scientist at the CHEO Research Institute. "You could say it takes two to tango. We believe that it takes a combination strategy to impact cancer cure rates." In 2014, a team of scientists led by Dr. Korneluk discovered that combining SMAC Mimetics with immune stimulators or live virus therapies had a synergistic or amplified tumour-killing effect that was greater than either agent on its own. Today's news shows that SMAC Mimetics also have a powerful synergistic effect with ICIs, relatively new drugs that are showing great promise in the clinic. SMAC Mimetics known as LCL161 and Birinapant were combined with ICI antibodies targeting PD-1 and CTLA-4 immune checkpoints. Eric Lacasse, a scientist at the CHEO Research Institute, said: "Two drug companies have initiated human clinical trials this year to assess the impact of this combination of SMAC Mimetics and ICIs on patients with a variety of cancers. Although it could be years before any clinical trials begin for adults or children with the deadly brain cancer, glioblastoma, we're looking forward to seeing how scientific evidence from these experimental treatments adds to our knowledge. It's an exciting, exploratory field and we hope we've hit a home run." Shawn Beug, lead author of the 2014 and 2017 papers, said: "This research heightens our understanding of the mechanics behind this double-whammy effect, which both enhances the immune response and weakens tumour cells to immune attack. We're hoping that more oncologists and biotech companies test out this combination in clinical trials as we continue to decipher how SMAC Mimetics encourage the immune system to kill cancer cells." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Machine-assisted pathological recognition has been focused on supervised learning (SL) that suffers from a significant annotation bottleneck. We propose a semi-supervised learning (SSL) method based on the mean teacher architecture using 13,111 whole slide images of colorectal cancer from 8803 subjects from 13 independent centers. SSL (~3150 labeled, ~40,950 unlabeled; ~6300 labeled, ~37,800 unlabeled patches) performs significantly better than the SL. No significant difference is found between SSL (~6300 labeled, ~37,800 unlabeled) and SL (~44,100 labeled) at patch-level diagnoses (area under the curve (AUC): 0.980 ± 0.014 vs. 0.987 ± 0.008, P value = 0.134) and patient-level diagnoses (AUC: 0.974 ± 0.013 vs. 0.980 ± 0.010, P value = 0.117), which is close to human pathologists (average AUC: 0.969). The evaluation on 15,000 lung and 294,912 lymph node images also confirm SSL can achieve similar performance as that of SL with massive annotations. SSL dramatically reduces the annotations, which has great potential to effectively build expert-level pathological artificial intelligence platforms in practice. Introduction Colorectal cancer (CRC) is the second most common cause of cancer death in Europe and America 1 , 2 . Pathological diagnosis is one of the most authoritative methods for diagnosing CRC 3 , 4 , which requires a pathologist to visually examine digital full-scale whole slide images (WSI). The challenges stem from the complexity of WSI including large image sizes (>10,000 × 10,000 pixels), complex shapes, textures, and histological changes in nuclear staining 4 . Furthermore, there is a shortage of pathologists worldwide in stark contrast with the rapid accumulation of WSI data, and the daily workload of pathologists is intensive which could lead to unintended misdiagnose due to fatigue 5 . Hence, it is crucial to develop diagnosing strategies that are effective yet of low cost by leveraging recent artificial intelligence (AI) development. Deep learning provides an exciting opportunity to support and accelerate pathological analysis 6 , including lung 7 , 8 , breast 9 , lymph node 10 , and skin cancers 11 , 12 . Progress has been made in applying deep learning to CRC including classification 13 , tumor cell detection 14 , 15 , and outcome prediction 16 , 17 , 18 . We have developed a recognition system for CRC using supervised learning (SL), which achieved one of the highest diagnosis accuracies in cancer diagnosis with AI 19 . However, our earlier method was built upon learning from 62,919 labeled patches from 842 subjects, which were carefully selected and extensively labeled by pathologists. While SL with massive labeled data can achieve high diagnostic accuracy, the reality is that we often have only a small amount of labeled data and a much larger amount of unlabeled data in medical domains. Although unsupervised learning does not require any labeled data, its performance is still limited currently 20 , 21 . There are some other approaches for learning on the small amount of labeled data. For example, in transfer learning, the network is firstly trained in a big data set of source domain, and then trained in labeled medical images. However, the number of labeled images needed is still quite large 22 , 23 . The generative adversarial networks (GAN) can generate a large amount of data by learning the style from a limited data set 24 , 25 . These approaches may improve accuracy, but they only used limited labeled data sets, and large amounts of unlabeled data do appear in medical domains and clinical settings. Moreover, it would be difficult for GAN to simulate all possible features of the disease based on limited samples. The semi-supervised learning (SSL), a method that leverages both labeled and unlabeled data is supposed to provide a low-cost alternative in terms of the requirement of the laborious and sometimes impractical sample labeling 26 , 27 . Although SSL can improve the accuracy of natural images, its performance on medical images is unclear. Recently, some studies were proposed to determine whether SSL based on a small amount of labeled data and a large amount of unlabeled data can improve medical image analysis 28 , 29 , 30 , such as object detection 31 , data augmentation 32 , image segmentation 33 , 34 . However, only a very limited few studies have investigated if SSL can be applied to achieve satisfactory accuracy in pathological images 35 , where on a small data set of 115 WSIs, an SSL method of CRC recognition can achieve the best accuracy of 0.938 only at 7180 patches of 50 WSIs from one data center, suggesting the potential of SSL for pathological diagnosis on patch-level. However, to the best of our knowledge, the CRC recognition system of SSL has not been extensively validated on patient-level data set from multiple centers to assess the general utility of SSL. How to translate the patch-level prediction to WSI and patient-level diagnosis is not trivial. Because we and other groups have not been able to develop perfect patch-level models, the errors at patch-level may be easily magnified on WSI level diagnosis. For example, even though the imperfect patch-level model may yield reasonable prediction on positive (cancerous) WSIs, it also may yield high false-positive errors on the negative (non-caner) WSIs, because the false-positive errors at patch level will accumulate due to the testing of multiple patches in WSI. However, the patient-level diagnosis is required in the clinical applications of any AI system for cancer diagnosis. To fill this gap, we used 13,111 WSIs collected from 8803 subjects from 13 independent centers to develop a CRC semi-supervised model. We evaluated SSL by comparing its performance with that of prevailing SL and also with that of professional pathologists. To confirm that SSL can achieve excellent performance on pathological images and further demonstrate our main point that a reliable medical AI can be built with a small amount of labeled data plus other available unlabeled data, we evaluated it on two other types of cancer (lung cancer and lymphoma). The main contributions of this study are summarized as follows:", "role": "user" }, { "content": "Deep brain stimulation (DBS) has been demonstrated to be an effective treatment for many patients suffering with treatment-resistant depression, but exactly how it works is not known. Scientists worldwide are racing for objective biomarkers of DBS treatment efficacy so that this experimental approach can be optimized, approved and disseminated to those in need. New research published November 3 in Translational Psychiatry, presents new evidence that brief intraoperative exposure to therapeutic stimulation at the time of implantation surgery induces rapid and consistent electrophysiological brain state change—indexed by a decrease in beta power measured at the site of stimulation. These intraoperative brain state changes are seen in individual subjects and are correlated with a significant and sustained decrease in depressive symptoms outside of the operating room without additional stimulation, establishing reduction in beta power as a novel biomarker for DBS treatment optimization. The data presented are from a collaborative study at Emory University and the Icahn School of Medicine at Mount Sinai. Led by Helen S. Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and Founding Director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai, this research is part of an ongoing National Institutes of Health (NIH) BRAIN Initiative-funded grant. Deep brain stimulation is approved by the U.S. Food and Drug Administration to treat essential tremor, Parkinson's disease, epilepsy and obsessive-compulsive disorder. It is a neurosurgical procedure involving placement of a neurostimulator (sometimes referred to as a \"brain pacemaker\"), which sends high-frequency electrical impulses through implanted electrodes deep in the brain to specific areas responsible for the symptoms of each disorder. While still an experimental treatment, DBS of the subcallosal cingulate (SCC, Area 25), a brain area that has been implicated as playing a major role in depression, has been repeatedly demonstrated as a promising intervention for patients suffering from treatment-resistant depression.. Acute behavioral changes and long-term antidepressant response can be reliably elicited with stimulation of this well-defined, surgically-targeted depression circuit, using individualized neuroimaging guidance. While the clinical effectiveness of DBS over the course of six months of treatment has been repeatedly demonstrated, there are differences in the timeline of recovery across different patients. Understanding the mechanisms of these initial rapid and reproducible behavioral effects and their role in predicting the more critical long-term response trajectories will be key to effective treatment and future study design. \"What we found was that within minutes of stimulation inside the operating room, there was a change in the beta brain rhythm. Patients who showed larger changes then experienced greater relief from their depression in the week after surgery,\" said Allison C. Waters, Ph.D., Assistant Professor of Psychiatry, and Neuroscience, at Icahn Mount Sinai and co-first author of the paper. \"The beta rhythm is conventionally associated with the brain's determination of whether to stop or keep going with a course of action, which is why neurologists target beta with DBS to treat disorders of movement. We haven't had a clear signal to target with DBS for depression, but now we can speculate as to how the beta signal might function in this context: a release of the brake that generates fatigue and slowness, or interrupting a habitual cycle of negative self-focused thought.\" \"We were able to leverage machine learning and explainable artificial intelligence approaches to explore unknown (hidden) changes in brain state that would explain the obvious behavioral changes previously observed,\" said Mohammad Sendi, MSc, Ph.D. candidate in the Biomedical Engineering Department of Emory University and Georgia Institute of Technology and co-first author of the paper. Eight treatment-resistant depression patients underwent electrophysiological recording in the operating room during their DBS lead implantation surgeries. Using patient-specific tractography models prior to surgery, investigators identified the \"optimal\" target within the SCC for lead placement. Stimulation was then delivered in the operating room over the course of an hour while local field potentials (LFPs)—electrical signals between neurons deep in the brain—were simultaneously recorded. A machine learning classification method was subsequently used to discriminate between intracranial LFPs recorded at baseline (stimulation-naïve) and after the first exposure to stimulation inside the operating room. Spectral inputs (theta, 4-8Hz; alpha, 9-121Hz; beta, 13-30Hz) to the model were then evaluated for importance to classifier success and tested as predictors of the antidepressant response. A decline in depression scores by 45.6 percent was observed after one week and this early antidepressant response correlated with a decrease in the SCC LFP beta power, which most contributed to classifier success. \"We generally think of depression treatment as taking weeks to months to show stable and meaningful changes in core clinical features of the illness,\" said Dr. Mayberg. \"This study shows reproducible and consistent changes in a brain readout over the first minutes of optimized stimulation in the operating room in individual patients. This provides new mechanistic understanding of the 'depression switch' that moves a patient from a state of sustained mental pain and immobility to relief and the renewed capacity to move and engage.\" \"This research provides individuals who have struggled with depression a sense of hope through advancements in existing technology,\" said John Ngai, Ph.D., Director of the NIH BRAIN Initiative. \"We are making immense strides in better understanding debilitating brain and mental health conditions through these discoveries and look forward to seeing how deep-brain stimulation will continue to improve people's lives.\" Studies that continue to track these brain state biomarkers during ongoing DBS therapy are ongoing at the Nash Family Center for Advanced Therapeutics at Mount Sinai West in New York. Phase II of this 5-year NIH BRAIN Initiative grant is currently recruiting new subjects. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Machine-assisted pathological recognition has been focused on supervised learning (SL) that suffers from a significant annotation bottleneck. We propose a semi-supervised learning (SSL) method based on the mean teacher architecture using 13,111 whole slide images of colorectal cancer from 8803 subjects from 13 independent centers. SSL (~3150 labeled, ~40,950 unlabeled; ~6300 labeled, ~37,800 unlabeled patches) performs significantly better than the SL. No significant difference is found between SSL (~6300 labeled, ~37,800 unlabeled) and SL (~44,100 labeled) at patch-level diagnoses (area under the curve (AUC): 0.980 ± 0.014 vs. 0.987 ± 0.008, P value = 0.134) and patient-level diagnoses (AUC: 0.974 ± 0.013 vs. 0.980 ± 0.010, P value = 0.117), which is close to human pathologists (average AUC: 0.969). The evaluation on 15,000 lung and 294,912 lymph node images also confirm SSL can achieve similar performance as that of SL with massive annotations. SSL dramatically reduces the annotations, which has great potential to effectively build expert-level pathological artificial intelligence platforms in practice. Introduction Colorectal cancer (CRC) is the second most common cause of cancer death in Europe and America 1 , 2 . Pathological diagnosis is one of the most authoritative methods for diagnosing CRC 3 , 4 , which requires a pathologist to visually examine digital full-scale whole slide images (WSI). The challenges stem from the complexity of WSI including large image sizes (>10,000 × 10,000 pixels), complex shapes, textures, and histological changes in nuclear staining 4 . Furthermore, there is a shortage of pathologists worldwide in stark contrast with the rapid accumulation of WSI data, and the daily workload of pathologists is intensive which could lead to unintended misdiagnose due to fatigue 5 . Hence, it is crucial to develop diagnosing strategies that are effective yet of low cost by leveraging recent artificial intelligence (AI) development. Deep learning provides an exciting opportunity to support and accelerate pathological analysis 6 , including lung 7 , 8 , breast 9 , lymph node 10 , and skin cancers 11 , 12 . Progress has been made in applying deep learning to CRC including classification 13 , tumor cell detection 14 , 15 , and outcome prediction 16 , 17 , 18 . We have developed a recognition system for CRC using supervised learning (SL), which achieved one of the highest diagnosis accuracies in cancer diagnosis with AI 19 . However, our earlier method was built upon learning from 62,919 labeled patches from 842 subjects, which were carefully selected and extensively labeled by pathologists. While SL with massive labeled data can achieve high diagnostic accuracy, the reality is that we often have only a small amount of labeled data and a much larger amount of unlabeled data in medical domains. Although unsupervised learning does not require any labeled data, its performance is still limited currently 20 , 21 . There are some other approaches for learning on the small amount of labeled data. For example, in transfer learning, the network is firstly trained in a big data set of source domain, and then trained in labeled medical images. However, the number of labeled images needed is still quite large 22 , 23 . The generative adversarial networks (GAN) can generate a large amount of data by learning the style from a limited data set 24 , 25 . These approaches may improve accuracy, but they only used limited labeled data sets, and large amounts of unlabeled data do appear in medical domains and clinical settings. Moreover, it would be difficult for GAN to simulate all possible features of the disease based on limited samples. The semi-supervised learning (SSL), a method that leverages both labeled and unlabeled data is supposed to provide a low-cost alternative in terms of the requirement of the laborious and sometimes impractical sample labeling 26 , 27 . Although SSL can improve the accuracy of natural images, its performance on medical images is unclear. Recently, some studies were proposed to determine whether SSL based on a small amount of labeled data and a large amount of unlabeled data can improve medical image analysis 28 , 29 , 30 , such as object detection 31 , data augmentation 32 , image segmentation 33 , 34 . However, only a very limited few studies have investigated if SSL can be applied to achieve satisfactory accuracy in pathological images 35 , where on a small data set of 115 WSIs, an SSL method of CRC recognition can achieve the best accuracy of 0.938 only at 7180 patches of 50 WSIs from one data center, suggesting the potential of SSL for pathological diagnosis on patch-level. However, to the best of our knowledge, the CRC recognition system of SSL has not been extensively validated on patient-level data set from multiple centers to assess the general utility of SSL. How to translate the patch-level prediction to WSI and patient-level diagnosis is not trivial. Because we and other groups have not been able to develop perfect patch-level models, the errors at patch-level may be easily magnified on WSI level diagnosis. For example, even though the imperfect patch-level model may yield reasonable prediction on positive (cancerous) WSIs, it also may yield high false-positive errors on the negative (non-caner) WSIs, because the false-positive errors at patch level will accumulate due to the testing of multiple patches in WSI. However, the patient-level diagnosis is required in the clinical applications of any AI system for cancer diagnosis. To fill this gap, we used 13,111 WSIs collected from 8803 subjects from 13 independent centers to develop a CRC semi-supervised model. We evaluated SSL by comparing its performance with that of prevailing SL and also with that of professional pathologists. To confirm that SSL can achieve excellent performance on pathological images and further demonstrate our main point that a reliable medical AI can be built with a small amount of labeled data plus other available unlabeled data, we evaluated it on two other types of cancer (lung cancer and lymphoma). The main contributions of this study are summarized as follows:<|im_end|> <|im_start|>assistant Deep brain stimulation (DBS) has been demonstrated to be an effective treatment for many patients suffering with treatment-resistant depression, but exactly how it works is not known. Scientists worldwide are racing for objective biomarkers of DBS treatment efficacy so that this experimental approach can be optimized, approved and disseminated to those in need. New research published November 3 in Translational Psychiatry, presents new evidence that brief intraoperative exposure to therapeutic stimulation at the time of implantation surgery induces rapid and consistent electrophysiological brain state change—indexed by a decrease in beta power measured at the site of stimulation. These intraoperative brain state changes are seen in individual subjects and are correlated with a significant and sustained decrease in depressive symptoms outside of the operating room without additional stimulation, establishing reduction in beta power as a novel biomarker for DBS treatment optimization. The data presented are from a collaborative study at Emory University and the Icahn School of Medicine at Mount Sinai. Led by Helen S. Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and Founding Director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai, this research is part of an ongoing National Institutes of Health (NIH) BRAIN Initiative-funded grant. Deep brain stimulation is approved by the U.S. Food and Drug Administration to treat essential tremor, Parkinson's disease, epilepsy and obsessive-compulsive disorder. It is a neurosurgical procedure involving placement of a neurostimulator (sometimes referred to as a "brain pacemaker"), which sends high-frequency electrical impulses through implanted electrodes deep in the brain to specific areas responsible for the symptoms of each disorder. While still an experimental treatment, DBS of the subcallosal cingulate (SCC, Area 25), a brain area that has been implicated as playing a major role in depression, has been repeatedly demonstrated as a promising intervention for patients suffering from treatment-resistant depression.. Acute behavioral changes and long-term antidepressant response can be reliably elicited with stimulation of this well-defined, surgically-targeted depression circuit, using individualized neuroimaging guidance. While the clinical effectiveness of DBS over the course of six months of treatment has been repeatedly demonstrated, there are differences in the timeline of recovery across different patients. Understanding the mechanisms of these initial rapid and reproducible behavioral effects and their role in predicting the more critical long-term response trajectories will be key to effective treatment and future study design. "What we found was that within minutes of stimulation inside the operating room, there was a change in the beta brain rhythm. Patients who showed larger changes then experienced greater relief from their depression in the week after surgery," said Allison C. Waters, Ph.D., Assistant Professor of Psychiatry, and Neuroscience, at Icahn Mount Sinai and co-first author of the paper. "The beta rhythm is conventionally associated with the brain's determination of whether to stop or keep going with a course of action, which is why neurologists target beta with DBS to treat disorders of movement. We haven't had a clear signal to target with DBS for depression, but now we can speculate as to how the beta signal might function in this context: a release of the brake that generates fatigue and slowness, or interrupting a habitual cycle of negative self-focused thought." "We were able to leverage machine learning and explainable artificial intelligence approaches to explore unknown (hidden) changes in brain state that would explain the obvious behavioral changes previously observed," said Mohammad Sendi, MSc, Ph.D. candidate in the Biomedical Engineering Department of Emory University and Georgia Institute of Technology and co-first author of the paper. Eight treatment-resistant depression patients underwent electrophysiological recording in the operating room during their DBS lead implantation surgeries. Using patient-specific tractography models prior to surgery, investigators identified the "optimal" target within the SCC for lead placement. Stimulation was then delivered in the operating room over the course of an hour while local field potentials (LFPs)—electrical signals between neurons deep in the brain—were simultaneously recorded. A machine learning classification method was subsequently used to discriminate between intracranial LFPs recorded at baseline (stimulation-naïve) and after the first exposure to stimulation inside the operating room. Spectral inputs (theta, 4-8Hz; alpha, 9-121Hz; beta, 13-30Hz) to the model were then evaluated for importance to classifier success and tested as predictors of the antidepressant response. A decline in depression scores by 45.6 percent was observed after one week and this early antidepressant response correlated with a decrease in the SCC LFP beta power, which most contributed to classifier success. "We generally think of depression treatment as taking weeks to months to show stable and meaningful changes in core clinical features of the illness," said Dr. Mayberg. "This study shows reproducible and consistent changes in a brain readout over the first minutes of optimized stimulation in the operating room in individual patients. This provides new mechanistic understanding of the 'depression switch' that moves a patient from a state of sustained mental pain and immobility to relief and the renewed capacity to move and engage." "This research provides individuals who have struggled with depression a sense of hope through advancements in existing technology," said John Ngai, Ph.D., Director of the NIH BRAIN Initiative. "We are making immense strides in better understanding debilitating brain and mental health conditions through these discoveries and look forward to seeing how deep-brain stimulation will continue to improve people's lives." Studies that continue to track these brain state biomarkers during ongoing DBS therapy are ongoing at the Nash Family Center for Advanced Therapeutics at Mount Sinai West in New York. Phase II of this 5-year NIH BRAIN Initiative grant is currently recruiting new subjects. <|im_end|>

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73828, 315, 6401, 320, 15259, 39, 8, 74863, 691, 38756, 50701, 13500, 13, 18682, 8271, 41959, 374, 12054, 555, 279, 549, 815, 13, 12369, 323, 26166, 17128, 311, 4322, 7718, 18659, 269, 11, 62145, 596, 8624, 11, 70655, 323, 84132, 63250, 58921, 19823, 13, 1102, 374, 264, 18247, 82, 57673, 10537, 16239, 22165, 315, 264, 18247, 54754, 10733, 320, 57753, 14183, 311, 439, 264, 330, 54160, 23744, 59775, 4063, 902, 22014, 1579, 79412, 20314, 87633, 1555, 95956, 80390, 5655, 304, 279, 8271, 311, 3230, 5789, 8647, 369, 279, 13803, 315, 1855, 19823, 13, 6104, 2103, 459, 22772, 6514, 11, 6078, 50, 315, 279, 1207, 5531, 2353, 278, 272, 287, 6468, 320, 3624, 34, 11, 12299, 220, 914, 705, 264, 8271, 3158, 430, 706, 1027, 69702, 439, 5737, 264, 3682, 3560, 304, 18710, 11, 706, 1027, 19352, 21091, 439, 264, 26455, 21623, 369, 6978, 16066, 505, 6514, 47056, 18710, 497, 6515, 1088, 36695, 4442, 323, 1317, 9860, 65211, 519, 2077, 649, 387, 57482, 95360, 1639, 449, 41959, 315, 420, 1664, 39817, 11, 12274, 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2133, 449, 264, 3388, 315, 1957, 11, 902, 374, 3249, 18247, 848, 1705, 2218, 13746, 449, 6078, 50, 311, 4322, 24673, 315, 7351, 13, 1226, 9167, 956, 1047, 264, 2867, 8450, 311, 2218, 449, 6078, 50, 369, 18710, 11, 719, 1457, 584, 649, 64601, 439, 311, 1268, 279, 13746, 8450, 2643, 734, 304, 420, 2317, 25, 264, 4984, 315, 279, 35718, 430, 27983, 36709, 323, 1776, 785, 434, 11, 477, 12956, 287, 264, 84820, 11008, 315, 8389, 659, 52373, 3463, 1210, 330, 1687, 1051, 3025, 311, 33164, 5780, 6975, 323, 10552, 481, 21075, 11478, 20414, 311, 13488, 9987, 320, 6397, 8, 4442, 304, 8271, 1614, 430, 1053, 10552, 279, 8196, 36695, 4442, 8767, 13468, 1359, 1071, 65552, 11244, 72, 11, 386, 3407, 11, 2405, 920, 13, 9322, 304, 279, 12371, 61860, 17005, 6011, 315, 5867, 683, 3907, 323, 16272, 10181, 315, 12053, 323, 1080, 38043, 3229, 315, 279, 5684, 13, 36944, 6514, 47056, 18710, 6978, 55093, 4135, 22761, 1065, 41314, 14975, 304, 279, 10565, 3130, 2391, 872, 6078, 50, 3063, 46460, 367, 68823, 13, 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2,508

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The vertical dimensions of complex nanostructures determine the functions of diverse nanotechnologies. In this paper, we investigate the unknown limits of such structure–function relationships at subnanometer scales. We begin with a quantitative evaluation of measurement uncertainty from atomic force microscopy, which propagates through our investigation from ion beam fabrication to fluorescent particle characterization. We use a focused beam of gallium ions to subtractively pattern silicon surfaces, and silicon nitride and silicon dioxide films. Our study of material responses quantifies the atomic limits of forming complex topographies with subnanometer resolution of vertical features over a wide range of vertical and lateral dimensions. Our results demonstrate the underutilized capability of this standard system for rapid prototyping of subnanometer structures in hard materials. We directly apply this unprecedented dimensional control to fabricate nanofluidic devices for the analytical separation of colloidal nanoparticles by size exclusion. Optical microscopy of single nanoparticles within such reference materials establishes a subnanometer limit of the fluidic manipulation of particulate matter and enables critical-dimension particle tracking with subnanometer accuracy. After calibrating for optical interference within our multifunctional devices, which also enables device metrology and integrated spectroscopy, we reveal an unexpected relationship between nanoparticle size and emission intensity for common fluorescent probes. Emission intensity increases supervolumetrically with nanoparticle diameter and then decreases as nanoparticles with different diameters photobleach to similar values of terminal intensity. We propose a simple model to empirically interpret these surprising results. Our investigation enables new control and study of structure–function relationships at subnanometer scales. Introduction Structure determines function in nanotechnologies of all dimensionalities, including those with nanoscale vertical dimensions and similar or larger lateral dimensions. Control of the vertical dimensions of such nanostructures enables the fabrication of functional devices in diverse domains of nanotechnology. In this paper, we dramatically advance both the structural and functional aspects of this fundamental relationship, and we couple them so closely as to essentially integrate the subnanometer structure and function of complex devices. First, we investigate the unknown limits of controlling the vertical dimensions of silicius materials at atomic scales with a focused beam of gallium ions, quantifying subnanometer resolution over a wide range of vertical and lateral dimensions. Then, we apply this unprecedented control, fabricating nanofluidic devices that enable dimensional and optical metrology of single nanoparticles in liquids with record accuracy and precision. Since Feynman envisioned the focused ion beam as a foundation of nanotechnology, 1 it has become extremely useful due to its unique capability to directly pattern hard materials with nanoscale resolution in three dimensions. 2–7 This capability obviates lithographic pattern transfer and facilitates rapid prototyping of functional nanostructures. While many studies have used a focused ion beam to precisely control the lateral dimensions of nanostructures, 2,8 few have precisely controlled their vertical dimensions, 9–13 and none have quantified the related limits of dimensional control or demonstrated devices functioning near these limits. To do so requires a comprehensive investigation that integrates nanoscale fabrication, characterization, and application, as we report here. We study the unknown limits of the subtractive processing of silicon, silicon nitride, and silicon dioxide by a focused beam of gallium ions, investigating the different responses of these diverse materials at atomic scales. In the context of fabricating devices for practical applications, we identify design rules for rapid prototyping of complex patterns with subnanometer resolution of vertical dimensions over a wide range of vertical and lateral dimensions. Remarkably, using this standard system, some aspects of our vertical dimensional control extend below 0.1 nm. In this way, our investigation enables new control and study of structure–function relationships at subnanometer scales. We demonstrate an application that requires and motivates this dimensional control. We fabricate nanofluidic devices for the analytical separation of nanoparticles by size exclusion, and track nanoparticles by optical microscopy within such reference materials to measure their size distribution. In this way, we establish a subnanometer limit of the fluidic manipulation of particulate matter, and enable critical-dimension particle tracking with subnanometer accuracy. In comparison to other fluidic methods of manipulating and measuring nanoparticles, 14–18 which generally involve tracking particle motion or sensing device occlusion, our method is more direct and capable of resolving smaller nanoparticles. Moreover, our method is optimal for quantitative measurement of the optical properties of nanoparticles, which are among their most important properties and depend on their dimensions. Our measurements reveal an unexpected nonvolumetric relationship between the size and emission intensity of nanoparticles which commonly serve as fluorescent probes. 19 These results are highly relevant to the many users of such nanoparticles in biological and other applications, 20 and establish a firm foundation for future applications of our method such as in quality control of nanoparticle manufacturing. Further, in this measurement, we calibrate for optical interference effects within our complex devices, enabling future measurements of device dimensions by optical microscopy and on-chip integration of spectroscopic optics. Results and discussion Uncertainty evaluation Considering our goal of quantifying the limits of subnanometer structure and function, a rigorous evaluation of measurement uncertainty is a prerequisite. We measure the vertical dimensions of surface features with an atomic force microscope, which we calibrate with a submicrometer reference material with a step depth of 183.6 nm ± 0.9 nm that is NIST traceable. 21,22 We report all uncertainties as a confidence interval of 95% or we note otherwise. A quartic polynomial linearizes the sensor response with negligible error, resulting in a systematic uncertainty of 0.5% for all depths. We test this submicrometer calibration at subnanometer scales by measuring highly ordered pyrolytic graphite as an atomic reference material with a monolayer thickness of 0.335 nm, adding negligible absolute uncertainty of 0.006 nm, as Fig. S1 † shows. We identify two other sources of measurement uncertainty that are significant. First, we quantify the variation in roughness of milled silicon (100) from different measurement parameters, as Fig. S2 † shows, resulting in additional absolute uncertainty of 0.07 nm. We report surface roughness quantities as root-mean-square values. All other materials in our study show lesser variation in roughness from different measurement parameters. Second, for each", "role": "user" }, { "content": "Like sandblasting at the nanometer scale, focused beams of ions ablate hard materials to form intricate three-dimensional patterns. The beams can create tiny features in the lateral dimensions—length and width, but to create the next generation of nanometer-scale devices, the energetic ions must precisely control the features in the vertical dimension—depth. Now, researchers at the National Institute of Standards and Technology (NIST) have demonstrated that a standard ion-beam technique can be fine-tuned to make structures with depths controlled to within the diameter of a single silicon atom. Taking advantage of that newly demonstrated precision, the NIST team used this standard machining technique to fabricate devices that allow precise measurement of the size of nanoparticles in a liquid. The nanofluidic devices, which have the potential for mass production, could become a new laboratory standard for determining nanoparticle size. Such measurements could expedite quality control in industrial applications of nanoparticles. \"We have tested and advanced what is possible to make and measure below one nanometer,\" said NIST researcher Samuel Stavis. He and his colleagues from NIST and the Maryland NanoCenter at the University of Maryland in College Park reported their findings in a recent issue of Lab on a Chip. Although engineers have for years used ion beams to fix defects in integrated circuits and machine tiny parts in optical and mechanical systems, those applications did not require the depth control the team has now reported. To realize the full potential of the process, the team explored several ways of using a focused beam of gallium ions to mill the surfaces of silicon, silicon nitride and silicon dioxide—materials that are common for the fabrication of nanoscale devices used in electronics, optics and mechanics. The researchers used an atomic force microscope, which features a sensitive probe to measure the depth of the topography formed by the ion beam. Careful measurements were important to testing the limits of the ion-beam technique. The facilities at NIST enabled the team to undertake both tasks—precision fabrication and precision measurement. Fluorescent nanoparticles separate by size in a nanofluidic staircase machined with subnanometer precision. Credit: NIST The team applied the new capability to improve the measurement of the size of nanoparticles. Using a gallium ion beam, the researchers machined staircase patterns in silicon dioxide and then enclosed them to control the flow of fluid at the nanoscale. In some devices, the researchers machined a staircase with a step size of 1.1 nanometers; they machined others with a step size of 0.6 nanometers—just a few atoms in depth. The steps of the staircase pattern precisely separated nanoparticles immersed in water according to their size. Nanoparticles flowed in to the deepest step at the bottom of the staircase, but only the smaller ones could ascend towards the shallowest step at the top; larger nanoparticles could not fit through and remain trapped at the bottom set of steps. Fluorescent dye within the nanoparticles enabled the team to record their location with an optical microscope and match that location to the known depth of the staircase. Comparing the nanoparticle sizes indicated by this method with the sizes measured using electron microscopy revealed a match that was accurate to within one nanometer. This good agreement of the different measurements suggests that the devices can serve not only as a particle separator but as a reference material for measuring the sizes of nanoparticles. Manufacturers who routinely perform quality control on nanoparticles—determining not only their average size, but how many of the nanoparticles are slightly smaller or larger than average from batch to batch—could benefit from the new technique. The newly fabricated devices, in combination with an inexpensive optical microscope to pinpoint the locations of nanoparticles, offer a potentially faster and more economical route than other measurement techniques, Stavis noted. The team is now investigating how the devices could serve as master molds for the mass production of inexpensive replicas. Because the nanoparticles were measured with an optical microscope, the NIST team could also explore the relationship between the size of nanoparticles and another key property—their brightness. Clarifying that relationship is important for understanding the properties of such nanoparticles as quantum dots for color displays, gold nanoparticles for biomedical sensors, and other nanoparticles for drug delivery. The team detailed their process so that researchers at NIST can readily take advantage of and adapt the process for their own work. Several customers of NIST's nanotechnology user facility, the Center for Nanoscale Science and Technology, where the work was conducted, have expressed interest in adapting the technology for measuring both the size and brightness of nanoparticles in these consumer products. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The vertical dimensions of complex nanostructures determine the functions of diverse nanotechnologies. In this paper, we investigate the unknown limits of such structure–function relationships at subnanometer scales. We begin with a quantitative evaluation of measurement uncertainty from atomic force microscopy, which propagates through our investigation from ion beam fabrication to fluorescent particle characterization. We use a focused beam of gallium ions to subtractively pattern silicon surfaces, and silicon nitride and silicon dioxide films. Our study of material responses quantifies the atomic limits of forming complex topographies with subnanometer resolution of vertical features over a wide range of vertical and lateral dimensions. Our results demonstrate the underutilized capability of this standard system for rapid prototyping of subnanometer structures in hard materials. We directly apply this unprecedented dimensional control to fabricate nanofluidic devices for the analytical separation of colloidal nanoparticles by size exclusion. Optical microscopy of single nanoparticles within such reference materials establishes a subnanometer limit of the fluidic manipulation of particulate matter and enables critical-dimension particle tracking with subnanometer accuracy. After calibrating for optical interference within our multifunctional devices, which also enables device metrology and integrated spectroscopy, we reveal an unexpected relationship between nanoparticle size and emission intensity for common fluorescent probes. Emission intensity increases supervolumetrically with nanoparticle diameter and then decreases as nanoparticles with different diameters photobleach to similar values of terminal intensity. We propose a simple model to empirically interpret these surprising results. Our investigation enables new control and study of structure–function relationships at subnanometer scales. Introduction Structure determines function in nanotechnologies of all dimensionalities, including those with nanoscale vertical dimensions and similar or larger lateral dimensions. Control of the vertical dimensions of such nanostructures enables the fabrication of functional devices in diverse domains of nanotechnology. In this paper, we dramatically advance both the structural and functional aspects of this fundamental relationship, and we couple them so closely as to essentially integrate the subnanometer structure and function of complex devices. First, we investigate the unknown limits of controlling the vertical dimensions of silicius materials at atomic scales with a focused beam of gallium ions, quantifying subnanometer resolution over a wide range of vertical and lateral dimensions. Then, we apply this unprecedented control, fabricating nanofluidic devices that enable dimensional and optical metrology of single nanoparticles in liquids with record accuracy and precision. Since Feynman envisioned the focused ion beam as a foundation of nanotechnology, 1 it has become extremely useful due to its unique capability to directly pattern hard materials with nanoscale resolution in three dimensions. 2–7 This capability obviates lithographic pattern transfer and facilitates rapid prototyping of functional nanostructures. While many studies have used a focused ion beam to precisely control the lateral dimensions of nanostructures, 2,8 few have precisely controlled their vertical dimensions, 9–13 and none have quantified the related limits of dimensional control or demonstrated devices functioning near these limits. To do so requires a comprehensive investigation that integrates nanoscale fabrication, characterization, and application, as we report here. We study the unknown limits of the subtractive processing of silicon, silicon nitride, and silicon dioxide by a focused beam of gallium ions, investigating the different responses of these diverse materials at atomic scales. In the context of fabricating devices for practical applications, we identify design rules for rapid prototyping of complex patterns with subnanometer resolution of vertical dimensions over a wide range of vertical and lateral dimensions. Remarkably, using this standard system, some aspects of our vertical dimensional control extend below 0.1 nm. In this way, our investigation enables new control and study of structure–function relationships at subnanometer scales. We demonstrate an application that requires and motivates this dimensional control. We fabricate nanofluidic devices for the analytical separation of nanoparticles by size exclusion, and track nanoparticles by optical microscopy within such reference materials to measure their size distribution. In this way, we establish a subnanometer limit of the fluidic manipulation of particulate matter, and enable critical-dimension particle tracking with subnanometer accuracy. In comparison to other fluidic methods of manipulating and measuring nanoparticles, 14–18 which generally involve tracking particle motion or sensing device occlusion, our method is more direct and capable of resolving smaller nanoparticles. Moreover, our method is optimal for quantitative measurement of the optical properties of nanoparticles, which are among their most important properties and depend on their dimensions. Our measurements reveal an unexpected nonvolumetric relationship between the size and emission intensity of nanoparticles which commonly serve as fluorescent probes. 19 These results are highly relevant to the many users of such nanoparticles in biological and other applications, 20 and establish a firm foundation for future applications of our method such as in quality control of nanoparticle manufacturing. Further, in this measurement, we calibrate for optical interference effects within our complex devices, enabling future measurements of device dimensions by optical microscopy and on-chip integration of spectroscopic optics. Results and discussion Uncertainty evaluation Considering our goal of quantifying the limits of subnanometer structure and function, a rigorous evaluation of measurement uncertainty is a prerequisite. We measure the vertical dimensions of surface features with an atomic force microscope, which we calibrate with a submicrometer reference material with a step depth of 183.6 nm ± 0.9 nm that is NIST traceable. 21,22 We report all uncertainties as a confidence interval of 95% or we note otherwise. A quartic polynomial linearizes the sensor response with negligible error, resulting in a systematic uncertainty of 0.5% for all depths. We test this submicrometer calibration at subnanometer scales by measuring highly ordered pyrolytic graphite as an atomic reference material with a monolayer thickness of 0.335 nm, adding negligible absolute uncertainty of 0.006 nm, as Fig. S1 † shows. We identify two other sources of measurement uncertainty that are significant. First, we quantify the variation in roughness of milled silicon (100) from different measurement parameters, as Fig. S2 † shows, resulting in additional absolute uncertainty of 0.07 nm. We report surface roughness quantities as root-mean-square values. All other materials in our study show lesser variation in roughness from different measurement parameters. Second, for each<|im_end|> <|im_start|>assistant Like sandblasting at the nanometer scale, focused beams of ions ablate hard materials to form intricate three-dimensional patterns. The beams can create tiny features in the lateral dimensions—length and width, but to create the next generation of nanometer-scale devices, the energetic ions must precisely control the features in the vertical dimension—depth. Now, researchers at the National Institute of Standards and Technology (NIST) have demonstrated that a standard ion-beam technique can be fine-tuned to make structures with depths controlled to within the diameter of a single silicon atom. Taking advantage of that newly demonstrated precision, the NIST team used this standard machining technique to fabricate devices that allow precise measurement of the size of nanoparticles in a liquid. The nanofluidic devices, which have the potential for mass production, could become a new laboratory standard for determining nanoparticle size. Such measurements could expedite quality control in industrial applications of nanoparticles. "We have tested and advanced what is possible to make and measure below one nanometer," said NIST researcher Samuel Stavis. He and his colleagues from NIST and the Maryland NanoCenter at the University of Maryland in College Park reported their findings in a recent issue of Lab on a Chip. Although engineers have for years used ion beams to fix defects in integrated circuits and machine tiny parts in optical and mechanical systems, those applications did not require the depth control the team has now reported. To realize the full potential of the process, the team explored several ways of using a focused beam of gallium ions to mill the surfaces of silicon, silicon nitride and silicon dioxide—materials that are common for the fabrication of nanoscale devices used in electronics, optics and mechanics. The researchers used an atomic force microscope, which features a sensitive probe to measure the depth of the topography formed by the ion beam. Careful measurements were important to testing the limits of the ion-beam technique. The facilities at NIST enabled the team to undertake both tasks—precision fabrication and precision measurement. Fluorescent nanoparticles separate by size in a nanofluidic staircase machined with subnanometer precision. Credit: NIST The team applied the new capability to improve the measurement of the size of nanoparticles. Using a gallium ion beam, the researchers machined staircase patterns in silicon dioxide and then enclosed them to control the flow of fluid at the nanoscale. In some devices, the researchers machined a staircase with a step size of 1.1 nanometers; they machined others with a step size of 0.6 nanometers—just a few atoms in depth. The steps of the staircase pattern precisely separated nanoparticles immersed in water according to their size. Nanoparticles flowed in to the deepest step at the bottom of the staircase, but only the smaller ones could ascend towards the shallowest step at the top; larger nanoparticles could not fit through and remain trapped at the bottom set of steps. Fluorescent dye within the nanoparticles enabled the team to record their location with an optical microscope and match that location to the known depth of the staircase. Comparing the nanoparticle sizes indicated by this method with the sizes measured using electron microscopy revealed a match that was accurate to within one nanometer. This good agreement of the different measurements suggests that the devices can serve not only as a particle separator but as a reference material for measuring the sizes of nanoparticles. Manufacturers who routinely perform quality control on nanoparticles—determining not only their average size, but how many of the nanoparticles are slightly smaller or larger than average from batch to batch—could benefit from the new technique. The newly fabricated devices, in combination with an inexpensive optical microscope to pinpoint the locations of nanoparticles, offer a potentially faster and more economical route than other measurement techniques, Stavis noted. The team is now investigating how the devices could serve as master molds for the mass production of inexpensive replicas. Because the nanoparticles were measured with an optical microscope, the NIST team could also explore the relationship between the size of nanoparticles and another key property—their brightness. Clarifying that relationship is important for understanding the properties of such nanoparticles as quantum dots for color displays, gold nanoparticles for biomedical sensors, and other nanoparticles for drug delivery. The team detailed their process so that researchers at NIST can readily take advantage of and adapt the process for their own work. Several customers of NIST's nanotechnology user facility, the Center for Nanoscale Science and Technology, where the work was conducted, have expressed interest in adapting the technology for measuring both the size and brightness of nanoparticles in these consumer products. <|im_end|>

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2,243

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Resting-state functional magnetic resonance imaging (MRI) has yielded seemingly disparate insights into large-scale organization of the human brain. The brain’s large-scale organization can be divided into two broad categories: zero-lag representations of functional connectivity structure and time-lag representations of traveling wave or propagation structure. In this study, we sought to unify observed phenomena across these two categories in the form of three low-frequency spatiotemporal patterns composed of a mixture of standing and traveling wave dynamics. We showed that a range of empirical phenomena, including functional connectivity gradients, the task-positive/task-negative anti-correlation pattern, the global signal, time-lag propagation patterns, the quasiperiodic pattern and the functional connectome network structure, are manifestations of these three spatiotemporal patterns. These patterns account for much of the global spatial structure that underlies functional connectivity analyses and unifies phenomena in resting-state functional MRI previously thought distinct. Main Since the discovery of spontaneous low-frequency blood oxygenation level dependent (BOLD) fluctuations in the 1990s 1 , increasingly complex analytic techniques have been applied to understand the spatial and temporal structure of these brain signals. A notable feature of these signals is their organization into global patterns that span across functional systems for cognition, perception and action 2 , 3 , 4 . Here we distinguish between two characterizations of this global structure: zero-lag synchrony and time-lag synchrony between brain regions. Zero-lag synchrony is defined as instantaneous statistical dependence between two time courses or the correlation between two BOLD signals with no time-lag. The zero-lag analysis approach has identified several global patterns spanning across functional networks that have generated sustained research interest: the global signal 5 , the task-positive/task-negative pattern 6 and the principal functional connectivity (FC) gradient 2 . Time-lag synchrony is defined as the statistical dependence between two time courses, where one time course is delayed in time. Two prominent global patterns with coherent time-lag structure have emerged. Short spontaneous global propagation BOLD fluctuations that extend across cortical and subcortical brain regions (~0–2 seconds) are known as lag projections 7 . This propagation pattern varies according to experimental manipulations of task demands and sensory inputs, suggesting that at least some of this structure is uncoupled from hemodynamic delays 7 . A pseudo-periodic spatiotemporal pattern at a longer time scale (~20 seconds), known as the ‘quasi-periodic pattern’ (QPP), involves an alteration in BOLD amplitudes between the task-positive (TP) and default mode networks (DMNs). The shift in BOLD amplitudes between TP and DMN regions is marked by a large-scale propagation of BOLD activity between the two networks. There may be an underlying unity to these representations that has heretofore remained overlooked. We hypothesized that the vast majority of widely used zero-lag and time-lag representations of intrinsic functional brain organization capture different aspects of a small number of spatiotemporal patterns that exhibit both zero-lag and time-lag structure. Our specific hypotheses were that (1) global patterns of zero-lag and time-lag synchrony are describing different facets of the same underlying spatiotemporal patterns and (2) a small set of spatiotemporal patterns can explain a large number of previous findings in the literature describing spontaneous BOLD signal fluctuations. Three lines of evidence support the first hypothesis. First, time-lag representations have a spatial distribution that precisely maps to the spatial weights of the principal FC gradient 8 , 9 , 10 . Second, the cortical global signal spatial topography is not entirely constituted by zero-lag spatial structure but has time-lag structure 10 , 11 . Third, removal of time-lag synchronous patterns, such as the QPP, from spontaneous BOLD fluctuations substantially alters patterns of zero-lag synchrony in FC network representations 12 . These findings suggest that there may be a common pattern of global BOLD activity that unifies these zero-lag and time-lag representations. To develop intuitions on the proposed relationship between zero-lag and time-lag synchrony patterns, we use the concepts of ‘standing’ and ‘traveling’ waves 13 , 14 . Standing waves refer to stationary oscillations exhibiting no time-lagged statistical dependencies across space (of the kind captured by FC analyses). Traveling waves refer to oscillations in a spatial field with non-zero time-lag statistical dependence across space (of the kind captured by the QPP and lag projection algorithm). We suggest that global BOLD spatiotemporal patterns consist of a mixture of standing and traveling wave spatial structure. Zero-lag analyses capture the standing wave structure of these patterns, whereas time-lag analyses capture the traveling wave structure of these patterns. To capture these patterns in a single latent representation, we use a complex-valued extension of a popular dimension reduction technique: complex principal component analysis (CPCA). In support of the second hypothesis, we begin with the observation that the resting-state functional MRI (fMRI) literature reveals very similar patterns of global BOLD activity across analytic approaches, including FC gradients 2 , co-activation patterns (CAPs) 15 , independent component analysis (ICA) 16 and other latent brain state methods 17 as well as seed-based correlation analyses 6 . We propose that these similar patterns across analysis methods are descriptions of the same underlying spatiotemporal patterns proposed in our first hypothesis. To test the second hypothesis, we compared a systematic survey of zero-lag and time-lag analyses to a set of spatiotemporal patterns derived from CPCA. Our analyses revealed that three spatiotemporal patterns constitute the dominant large-scale spatial structure in spontaneous low-frequency BOLD fluctuations. With these three patterns, we can unify a range of previous findings in resting-state fMRI, including lag projections 7 , the QPP 18 , the topography of the global signal 19 , the task-positive/task-negative pattern 6 , the principal FC gradient 2 and FC network structure. We demonstrate that all of these previous observations are manifestations of three spatiotemporal patterns captured within a unifying framework capable of modeling standing and traveling oscillatory BOLD phenomena. This novel framework allows for a parsimonious description of global functional brain organization that can inspire new hypotheses about the mechanisms underlying coordination of spontaneous activity across the brain. Results Standing and traveling wave simulation We posit that the relative mixture of standing and traveling waves in cortical BOLD signals", "role": "user" }, { "content": "UCLA researchers and colleagues at Emory University and other research centers have combined data simulation and experimental observation to bridge a gap between two major properties of large-scale organization of the human brain—stationary and traveling waves of activity. \"Functional magnetic resonance imaging suggests the brain has a globally coherent spatial structure, but there is not yet consensus among scientists on the proper way to catalog this structure. We show that a small number of spatiotemporal patterns can do the job,\" said Lucina Uddin, professor of psychiatry and biobehavioral sciences and director of the Brain Connectivity and Cognition Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior. Taylor Bolt, the lab's statistician and the study's first author, said, \"We showed that a wide range of previously observed empirical phenomena are manifestations of three main spatiotemporal patterns.\" The study centers on spontaneous low-frequency blood-oxygenation-level dependent (BOLD) fluctuations, a phenomenon discovered in the 1990s. Spontaneous fluctuations have been subjected to increasingly complex analytic techniques, leading to a large landscape of competing descriptions of large-scale functional brain organization. Some researchers have highlighted the simultaneous synchrony of brain regions across the cortex—what the authors refer to as \"standing\" or \"stationary\" wave structure. Other researchers have highlighted the time-lag synchrony of brain regions across the cortex—what the authors refer to as \"propagatory\" or \"traveling\" wave structure. There has been \"little attempt to synthesize findings across different approaches,\" the researchers said. Uddin likened the lack of consensus to the Indian parable of the blind men and the elephant, where each man encounters one part of the animal and comes up with a description that is different from all the others. \"The parable teaches us the perils of missing the 'big picture' due to our own limited observations,\" she said. Hypothesizing that stationary and traveling wave representations \"of intrinsic functional brain organization are capturing different aspects of a small number of spatiotemporal patterns,\" the authors found that a range of previous observations could be unified in a framework modeling both standing and traveling wave structure. The investigators said their findings provide a \"description of global functional brain organization that can inspire new hypotheses about the mechanisms underlying coordination of activity across the brain.\" The study was published in July 28, 2022 issue of Nature Neuroscience. Uddin and Jason Nomi, an assistant researcher at the UCLA Semel Institute for Neuroscience and Human Behavior, collaborated on the study with an international team including senior author Shella Keilholz, of Emory University in the United States; Dr. Danilo Bzdok, of McGill University in Canada; Jorge Salas and Catie Chang, of Vanderbilt University in the U.S.; and Thomas Yeo, of the National University of Singapore. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Resting-state functional magnetic resonance imaging (MRI) has yielded seemingly disparate insights into large-scale organization of the human brain. The brain’s large-scale organization can be divided into two broad categories: zero-lag representations of functional connectivity structure and time-lag representations of traveling wave or propagation structure. In this study, we sought to unify observed phenomena across these two categories in the form of three low-frequency spatiotemporal patterns composed of a mixture of standing and traveling wave dynamics. We showed that a range of empirical phenomena, including functional connectivity gradients, the task-positive/task-negative anti-correlation pattern, the global signal, time-lag propagation patterns, the quasiperiodic pattern and the functional connectome network structure, are manifestations of these three spatiotemporal patterns. These patterns account for much of the global spatial structure that underlies functional connectivity analyses and unifies phenomena in resting-state functional MRI previously thought distinct. Main Since the discovery of spontaneous low-frequency blood oxygenation level dependent (BOLD) fluctuations in the 1990s 1 , increasingly complex analytic techniques have been applied to understand the spatial and temporal structure of these brain signals. A notable feature of these signals is their organization into global patterns that span across functional systems for cognition, perception and action 2 , 3 , 4 . Here we distinguish between two characterizations of this global structure: zero-lag synchrony and time-lag synchrony between brain regions. Zero-lag synchrony is defined as instantaneous statistical dependence between two time courses or the correlation between two BOLD signals with no time-lag. The zero-lag analysis approach has identified several global patterns spanning across functional networks that have generated sustained research interest: the global signal 5 , the task-positive/task-negative pattern 6 and the principal functional connectivity (FC) gradient 2 . Time-lag synchrony is defined as the statistical dependence between two time courses, where one time course is delayed in time. Two prominent global patterns with coherent time-lag structure have emerged. Short spontaneous global propagation BOLD fluctuations that extend across cortical and subcortical brain regions (~0–2 seconds) are known as lag projections 7 . This propagation pattern varies according to experimental manipulations of task demands and sensory inputs, suggesting that at least some of this structure is uncoupled from hemodynamic delays 7 . A pseudo-periodic spatiotemporal pattern at a longer time scale (~20 seconds), known as the ‘quasi-periodic pattern’ (QPP), involves an alteration in BOLD amplitudes between the task-positive (TP) and default mode networks (DMNs). The shift in BOLD amplitudes between TP and DMN regions is marked by a large-scale propagation of BOLD activity between the two networks. There may be an underlying unity to these representations that has heretofore remained overlooked. We hypothesized that the vast majority of widely used zero-lag and time-lag representations of intrinsic functional brain organization capture different aspects of a small number of spatiotemporal patterns that exhibit both zero-lag and time-lag structure. Our specific hypotheses were that (1) global patterns of zero-lag and time-lag synchrony are describing different facets of the same underlying spatiotemporal patterns and (2) a small set of spatiotemporal patterns can explain a large number of previous findings in the literature describing spontaneous BOLD signal fluctuations. Three lines of evidence support the first hypothesis. First, time-lag representations have a spatial distribution that precisely maps to the spatial weights of the principal FC gradient 8 , 9 , 10 . Second, the cortical global signal spatial topography is not entirely constituted by zero-lag spatial structure but has time-lag structure 10 , 11 . Third, removal of time-lag synchronous patterns, such as the QPP, from spontaneous BOLD fluctuations substantially alters patterns of zero-lag synchrony in FC network representations 12 . These findings suggest that there may be a common pattern of global BOLD activity that unifies these zero-lag and time-lag representations. To develop intuitions on the proposed relationship between zero-lag and time-lag synchrony patterns, we use the concepts of ‘standing’ and ‘traveling’ waves 13 , 14 . Standing waves refer to stationary oscillations exhibiting no time-lagged statistical dependencies across space (of the kind captured by FC analyses). Traveling waves refer to oscillations in a spatial field with non-zero time-lag statistical dependence across space (of the kind captured by the QPP and lag projection algorithm). We suggest that global BOLD spatiotemporal patterns consist of a mixture of standing and traveling wave spatial structure. Zero-lag analyses capture the standing wave structure of these patterns, whereas time-lag analyses capture the traveling wave structure of these patterns. To capture these patterns in a single latent representation, we use a complex-valued extension of a popular dimension reduction technique: complex principal component analysis (CPCA). In support of the second hypothesis, we begin with the observation that the resting-state functional MRI (fMRI) literature reveals very similar patterns of global BOLD activity across analytic approaches, including FC gradients 2 , co-activation patterns (CAPs) 15 , independent component analysis (ICA) 16 and other latent brain state methods 17 as well as seed-based correlation analyses 6 . We propose that these similar patterns across analysis methods are descriptions of the same underlying spatiotemporal patterns proposed in our first hypothesis. To test the second hypothesis, we compared a systematic survey of zero-lag and time-lag analyses to a set of spatiotemporal patterns derived from CPCA. Our analyses revealed that three spatiotemporal patterns constitute the dominant large-scale spatial structure in spontaneous low-frequency BOLD fluctuations. With these three patterns, we can unify a range of previous findings in resting-state fMRI, including lag projections 7 , the QPP 18 , the topography of the global signal 19 , the task-positive/task-negative pattern 6 , the principal FC gradient 2 and FC network structure. We demonstrate that all of these previous observations are manifestations of three spatiotemporal patterns captured within a unifying framework capable of modeling standing and traveling oscillatory BOLD phenomena. This novel framework allows for a parsimonious description of global functional brain organization that can inspire new hypotheses about the mechanisms underlying coordination of spontaneous activity across the brain. Results Standing and traveling wave simulation We posit that the relative mixture of standing and traveling waves in cortical BOLD signals<|im_end|> <|im_start|>assistant UCLA researchers and colleagues at Emory University and other research centers have combined data simulation and experimental observation to bridge a gap between two major properties of large-scale organization of the human brain—stationary and traveling waves of activity. "Functional magnetic resonance imaging suggests the brain has a globally coherent spatial structure, but there is not yet consensus among scientists on the proper way to catalog this structure. We show that a small number of spatiotemporal patterns can do the job," said Lucina Uddin, professor of psychiatry and biobehavioral sciences and director of the Brain Connectivity and Cognition Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior. Taylor Bolt, the lab's statistician and the study's first author, said, "We showed that a wide range of previously observed empirical phenomena are manifestations of three main spatiotemporal patterns." The study centers on spontaneous low-frequency blood-oxygenation-level dependent (BOLD) fluctuations, a phenomenon discovered in the 1990s. Spontaneous fluctuations have been subjected to increasingly complex analytic techniques, leading to a large landscape of competing descriptions of large-scale functional brain organization. Some researchers have highlighted the simultaneous synchrony of brain regions across the cortex—what the authors refer to as "standing" or "stationary" wave structure. Other researchers have highlighted the time-lag synchrony of brain regions across the cortex—what the authors refer to as "propagatory" or "traveling" wave structure. There has been "little attempt to synthesize findings across different approaches," the researchers said. Uddin likened the lack of consensus to the Indian parable of the blind men and the elephant, where each man encounters one part of the animal and comes up with a description that is different from all the others. "The parable teaches us the perils of missing the 'big picture' due to our own limited observations," she said. Hypothesizing that stationary and traveling wave representations "of intrinsic functional brain organization are capturing different aspects of a small number of spatiotemporal patterns," the authors found that a range of previous observations could be unified in a framework modeling both standing and traveling wave structure. The investigators said their findings provide a "description of global functional brain organization that can inspire new hypotheses about the mechanisms underlying coordination of activity across the brain." The study was published in July 28, 2022 issue of Nature Neuroscience. Uddin and Jason Nomi, an assistant researcher at the UCLA Semel Institute for Neuroscience and Human Behavior, collaborated on the study with an international team including senior author Shella Keilholz, of Emory University in the United States; Dr. Danilo Bzdok, of McGill University in Canada; Jorge Salas and Catie Chang, of Vanderbilt University in the U.S.; and Thomas Yeo, of the National University of Singapore. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Allostery is a pervasive principle to regulate protein function. Growing evidence suggests that also DNA is capable of transmitting allosteric signals. Yet, whether and how DNA-mediated allostery plays a regulatory role in gene expression remained unclear. Here, we show that DNA indeed transmits allosteric signals over long distances to boost the binding cooperativity of transcription factors. Phenotype switching in Bacillus subtilis requires an all-or-none promoter binding of multiple ComK proteins. We use single-molecule FRET to demonstrate that ComK-binding at one promoter site increases affinity at a distant site. Cryo-EM structures of the complex between ComK and its promoter demonstrate that this coupling is due to mechanical forces that alter DNA curvature. Modifications of the spacer between sites tune cooperativity and show how to control allostery, which allows a fine-tuning of the dynamic properties of genetic circuits. Introduction Allostery is the structural coupling between ligand sites in biomolecules. Binding of a ligand to one site facilitates or hampers the binding of a second ligand to a distant site 1 , 2 , 3 , 4 , 5 . The resulting cooperativity regulates the activity of many proteins and molecular machines 6 , 7 , 8 , but it is also key for the behaviour of genetic circuits with binary 9 , oscillatory 10 , excitable 11 , 12 , or pulsing 13 dynamics. The past decades have seen growing evidence that allostery is also an inherent property of DNA 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , which has far reaching consequences for our understanding of promoter sequences. Yet, most insights on DNA-mediated allostery upon transcription factor (TF) binding were either based on artificial promoters 14 , 28 or found to be short-ranged 19 , 20 , 25 . Whether natural promoters evolved to efficiently transmit allosteric signals across many nanometres remained largely unclear. Here, we show that Bacillus subtilis bacteria utilize long-range allostery in a stochastic and reversible phenotype switch (Fig. 1a ). In the competent phenotype, B. subtilis can take up DNA from the medium 11 , 29 . The master regulator of the switch from vegetative to competent cells is the TF ComK 11 , 12 . The model postulates a positive feedback regulation of comK gene expression once ComK levels stochastically surpass a critical threshold (Fig. 1b ) 30 . The critical threshold acts like an analogue-to-digital converter: the ComK target promoter is inactive at low concentrations, but it switches cooperatively to an active state within a narrow ComK concentration range (Fig. 1c ) 11 , 12 . Yet, how the promoter mediates cooperative ComK binding is unknown. Using single-molecule Förster resonance energy transfer (smFRET) and cryo-electron microscopy (cryo-EM) we show how ComK binding at one site enhances binding to a distant site via allosteric changes in DNA. Fig. 1: Schematics describing the model for phenotype switching in B. subtilis . a B. subtilis can reversibly switch to a competent phenotype (red). b Switching is triggered by copy number fluctuations of ComK (grey) that, once stochastically exceeding a threshold (dashed line), cause its auto-amplification to high concentrations (red). Inset: scheme of the auto-amplification of ComK. c The threshold (grey) requires a cooperative DNA binding of ComK, modelled by the Hill equation with cooperativity n , affinity K , and fraction of complexes f . d ComK promoters consist of two boxes separated by a spacer. Here, the comG promoter with an 18 bp spacer and an imperfect A-tract in box 1 is shown. For size comparison, a ComK monomer (Stokes radius: 2.07 ± 0.03 nm, Supplementary Fig. 1 ) is shown as red sphere. Full size image Results Distant binding sites communicate ComK target promoters consist of two elements (box 1 and box 2, hereafter) separated by spacer sequences of variable length (Fig. 1d ) 31 . Three spacers of 8, 18, and 31 base pairs (bp) are known in the ComK response genes addAB , comG , and comK , respectively 31 . Each box in a promoter contains an adenine–thymine (AT)-rich sequence (Fig. 1d). Such A-tracts are ubiquitous throughout all kingdoms of life, presumably due to their potential to curve DNA 32 , 33 . To assess the structural properties of the promoter, we engineered a set of comG promoters (18 bp spacer) that we site-specifically labelled with donor and acceptor fluorophores for confocal smFRET measurements (Supplementary Fig. 2 and Supplementary Table 1 ). When we compared the experimental FRET efficiencies with theoretical values calculated for extended B-type DNA 34 , we noted substantial deviations across one box, suggesting an overall curved topology (Fig. 2a ). Given that DNA curvature scales with DNA stiffness 35 , which is sensitive to the protonation state of the phosphate backbone, we repeated the experiment under more acidic conditions (pH 4.0, Fig. 2b ). Indeed, we obtained reduced FRET values that showed a better apparent agreement with the calculated B-DNA profile. This result indicated that the comG promoter is curved at neutral pH. Importantly, the correlation between donor fluorescence lifetimes and FRET values is close to the expectation from Förster theory (see ‘Methods’), which indicates that the structure of the comG promoter does not fluctuate substantially at the length scale probed by FRET (Fig. 2a,b inset). Yet, small-amplitude motions cannot be ruled out and require a more sophisticated analysis to be identified 36 . Fig. 2: DNA-binding cooperativity of ComK probed with smFRET. a , b Mapping of distances in box 2 with FRET at higher ( a pH 7) and lower ( b pH 4) persistence length. Grey region indicates the expected dependence for B-DNA 34 . Insets: fluorescence lifetimes of the donor as function of the transfer efficiency. Dashed line is the expectation for a single distance and solid line is a fit with a Gaussian distance distribution to account for dye flexibility with widths of 0.76 and 0.66 nm for pH 7 and pH 4,", "role": "user" }, { "content": "Proteins can communicate through DNA, conducting a long-distance dialog that serves as a kind of genetic \"switch,\" according to Weizmann Institute of Science researchers. They found that the binding of proteins to one site of a DNA molecule can physically affect another binding site at a distant location, and that this \"peer effect\" activates certain genes. This effect had previously been observed in artificial systems, but the Weizmann study is the first to show it takes place in the DNA of living organisms. A team headed by Dr. Hagen Hofmann of the Chemical and Structural Biology Department made this discovery while studying a peculiar phenomenon in the soil bacteria Bacillus subtilis. A small minority of these bacteria demonstrate a unique skill: an ability to enrich their genomes by taking up bacterial gene segments scattered in the soil around them. This ability depends on a protein called ComK, a transcription factor, which binds to the DNA to activate the genes that make the scavenging possible. However, it was unknown how exactly this activation works. Staff Scientist Dr. Gabriel Rosenblum led this study, in which the researchers explored the bacterial DNA using advanced biophysical tools—single-molecule FRET and cryogenic electron microscopy. In particular, they focused on the two sites on the DNA molecule to which ComK proteins bind. They found that when two ComK molecules bind to one of the sites, it sets off a signal that facilitates the binding of two additional ComK molecules at the second site. The signal can travel between the sites because physical changes triggered by the original proteins' binding create tension that is transmitted along the DNA, something like twisting a rope from one end. Once all four molecules are bound to the DNA, a threshold is passed, switching on the bacterium's gene scavenging ability. \"We were surprised to discover that DNA, in addition to containing the genetic code, acts like a communication cable, transmitting information over a relatively long distance from one protein binding site to another,\" Rosenblum says. By manipulating the bacterial DNA and monitoring the effects of these manipulations, the scientists clarified the details of the long-distance communication within the DNA. They found that for communication—or cooperation—between two sites to occur, these sites must be located at a particular distance from one another, and they must face the same direction on the DNA helix. Any deviation from these two conditions—for example, increasing the distance—weakened the communication. The sequence of genetic letters running between the two sites was found to have little effect on this communication, whereas a break in the DNA interrupted it completely, providing further evidence that this communication occurs through a physical connection. Knowing these details may help design molecular switches of desired strengths for a variety of applications. The latter may include genetically engineering bacteria to clean up environmental pollution or synthesizing enzymes to be used as drugs. \"Long-distance communication within a DNA molecule is a new type of regulatory mechanism—one that opens up previously unavailable methods for designing the genetic circuits of the future,\" Hofmann says. The study was published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Allostery is a pervasive principle to regulate protein function. Growing evidence suggests that also DNA is capable of transmitting allosteric signals. Yet, whether and how DNA-mediated allostery plays a regulatory role in gene expression remained unclear. Here, we show that DNA indeed transmits allosteric signals over long distances to boost the binding cooperativity of transcription factors. Phenotype switching in Bacillus subtilis requires an all-or-none promoter binding of multiple ComK proteins. We use single-molecule FRET to demonstrate that ComK-binding at one promoter site increases affinity at a distant site. Cryo-EM structures of the complex between ComK and its promoter demonstrate that this coupling is due to mechanical forces that alter DNA curvature. Modifications of the spacer between sites tune cooperativity and show how to control allostery, which allows a fine-tuning of the dynamic properties of genetic circuits. Introduction Allostery is the structural coupling between ligand sites in biomolecules. Binding of a ligand to one site facilitates or hampers the binding of a second ligand to a distant site 1 , 2 , 3 , 4 , 5 . The resulting cooperativity regulates the activity of many proteins and molecular machines 6 , 7 , 8 , but it is also key for the behaviour of genetic circuits with binary 9 , oscillatory 10 , excitable 11 , 12 , or pulsing 13 dynamics. The past decades have seen growing evidence that allostery is also an inherent property of DNA 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , which has far reaching consequences for our understanding of promoter sequences. Yet, most insights on DNA-mediated allostery upon transcription factor (TF) binding were either based on artificial promoters 14 , 28 or found to be short-ranged 19 , 20 , 25 . Whether natural promoters evolved to efficiently transmit allosteric signals across many nanometres remained largely unclear. Here, we show that Bacillus subtilis bacteria utilize long-range allostery in a stochastic and reversible phenotype switch (Fig. 1a ). In the competent phenotype, B. subtilis can take up DNA from the medium 11 , 29 . The master regulator of the switch from vegetative to competent cells is the TF ComK 11 , 12 . The model postulates a positive feedback regulation of comK gene expression once ComK levels stochastically surpass a critical threshold (Fig. 1b ) 30 . The critical threshold acts like an analogue-to-digital converter: the ComK target promoter is inactive at low concentrations, but it switches cooperatively to an active state within a narrow ComK concentration range (Fig. 1c ) 11 , 12 . Yet, how the promoter mediates cooperative ComK binding is unknown. Using single-molecule Förster resonance energy transfer (smFRET) and cryo-electron microscopy (cryo-EM) we show how ComK binding at one site enhances binding to a distant site via allosteric changes in DNA. Fig. 1: Schematics describing the model for phenotype switching in B. subtilis . a B. subtilis can reversibly switch to a competent phenotype (red). b Switching is triggered by copy number fluctuations of ComK (grey) that, once stochastically exceeding a threshold (dashed line), cause its auto-amplification to high concentrations (red). Inset: scheme of the auto-amplification of ComK. c The threshold (grey) requires a cooperative DNA binding of ComK, modelled by the Hill equation with cooperativity n , affinity K , and fraction of complexes f . d ComK promoters consist of two boxes separated by a spacer. Here, the comG promoter with an 18 bp spacer and an imperfect A-tract in box 1 is shown. For size comparison, a ComK monomer (Stokes radius: 2.07 ± 0.03 nm, Supplementary Fig. 1 ) is shown as red sphere. Full size image Results Distant binding sites communicate ComK target promoters consist of two elements (box 1 and box 2, hereafter) separated by spacer sequences of variable length (Fig. 1d ) 31 . Three spacers of 8, 18, and 31 base pairs (bp) are known in the ComK response genes addAB , comG , and comK , respectively 31 . Each box in a promoter contains an adenine–thymine (AT)-rich sequence (Fig. 1d). Such A-tracts are ubiquitous throughout all kingdoms of life, presumably due to their potential to curve DNA 32 , 33 . To assess the structural properties of the promoter, we engineered a set of comG promoters (18 bp spacer) that we site-specifically labelled with donor and acceptor fluorophores for confocal smFRET measurements (Supplementary Fig. 2 and Supplementary Table 1 ). When we compared the experimental FRET efficiencies with theoretical values calculated for extended B-type DNA 34 , we noted substantial deviations across one box, suggesting an overall curved topology (Fig. 2a ). Given that DNA curvature scales with DNA stiffness 35 , which is sensitive to the protonation state of the phosphate backbone, we repeated the experiment under more acidic conditions (pH 4.0, Fig. 2b ). Indeed, we obtained reduced FRET values that showed a better apparent agreement with the calculated B-DNA profile. This result indicated that the comG promoter is curved at neutral pH. Importantly, the correlation between donor fluorescence lifetimes and FRET values is close to the expectation from Förster theory (see ‘Methods’), which indicates that the structure of the comG promoter does not fluctuate substantially at the length scale probed by FRET (Fig. 2a,b inset). Yet, small-amplitude motions cannot be ruled out and require a more sophisticated analysis to be identified 36 . Fig. 2: DNA-binding cooperativity of ComK probed with smFRET. a , b Mapping of distances in box 2 with FRET at higher ( a pH 7) and lower ( b pH 4) persistence length. Grey region indicates the expected dependence for B-DNA 34 . Insets: fluorescence lifetimes of the donor as function of the transfer efficiency. Dashed line is the expectation for a single distance and solid line is a fit with a Gaussian distance distribution to account for dye flexibility with widths of 0.76 and 0.66 nm for pH 7 and pH 4,<|im_end|> <|im_start|>assistant Proteins can communicate through DNA, conducting a long-distance dialog that serves as a kind of genetic "switch," according to Weizmann Institute of Science researchers. They found that the binding of proteins to one site of a DNA molecule can physically affect another binding site at a distant location, and that this "peer effect" activates certain genes. This effect had previously been observed in artificial systems, but the Weizmann study is the first to show it takes place in the DNA of living organisms. A team headed by Dr. Hagen Hofmann of the Chemical and Structural Biology Department made this discovery while studying a peculiar phenomenon in the soil bacteria Bacillus subtilis. A small minority of these bacteria demonstrate a unique skill: an ability to enrich their genomes by taking up bacterial gene segments scattered in the soil around them. This ability depends on a protein called ComK, a transcription factor, which binds to the DNA to activate the genes that make the scavenging possible. However, it was unknown how exactly this activation works. Staff Scientist Dr. Gabriel Rosenblum led this study, in which the researchers explored the bacterial DNA using advanced biophysical tools—single-molecule FRET and cryogenic electron microscopy. In particular, they focused on the two sites on the DNA molecule to which ComK proteins bind. They found that when two ComK molecules bind to one of the sites, it sets off a signal that facilitates the binding of two additional ComK molecules at the second site. The signal can travel between the sites because physical changes triggered by the original proteins' binding create tension that is transmitted along the DNA, something like twisting a rope from one end. Once all four molecules are bound to the DNA, a threshold is passed, switching on the bacterium's gene scavenging ability. "We were surprised to discover that DNA, in addition to containing the genetic code, acts like a communication cable, transmitting information over a relatively long distance from one protein binding site to another," Rosenblum says. By manipulating the bacterial DNA and monitoring the effects of these manipulations, the scientists clarified the details of the long-distance communication within the DNA. They found that for communication—or cooperation—between two sites to occur, these sites must be located at a particular distance from one another, and they must face the same direction on the DNA helix. Any deviation from these two conditions—for example, increasing the distance—weakened the communication. The sequence of genetic letters running between the two sites was found to have little effect on this communication, whereas a break in the DNA interrupted it completely, providing further evidence that this communication occurs through a physical connection. Knowing these details may help design molecular switches of desired strengths for a variety of applications. The latter may include genetically engineering bacteria to clean up environmental pollution or synthesizing enzymes to be used as drugs. "Long-distance communication within a DNA molecule is a new type of regulatory mechanism—one that opens up previously unavailable methods for designing the genetic circuits of the future," Hofmann says. The study was published in Nature Communications. <|im_end|>

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2,039

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding how individual behavior shapes the structure and ecology of populations is key to species conservation and management. Like many elasmobranchs, manta rays are highly mobile and wide-ranging species threatened by anthropogenic impacts. In shallow water environments, these pelagic rays often form groups and perform several apparently socially mediated behaviors. Group structures may result from active choices of individual rays to interact or passive processes. Social behavior is known to affect spatial ecology in other elasmobranchs, but this is the first study providing quantitative evidence for structured social relationships in manta rays. To construct social networks, we collected data from more than 500 groups of reef manta rays ( Mobula alfredi ) over 5 years in the Raja Ampat Regency of West Papua. We used generalized affiliation indices to isolate social preferences from non-social associations, the first study on elasmobranchs to use this method. Longer lasting social preferences were detected mostly between female rays. We detected assortment of social relations by phenotype and variation in social strategies, with the overall social network divided into two main communities. Overall network structure was characteristic of a dynamic fission-fusion society, with differentiated relationships linked to strong fidelity to cleaning station sites. Our results suggest that fine-scale conservation measures will be useful in protecting social groups of M. alfredi in their natural habitats and that a more complete understanding of the social nature of manta rays will help predict population responses to anthropogenic pressures, such as increasing disturbance from dive tourism. Significance statement In social animals, relationships between individuals have important implications for species conservation. Like many other sharks and rays, manta rays are threatened species, and little is known about their natural behavior or how their populations are structured. This study provides evidence of social structure in a wild, free-ranging population of reef manta rays. We show for the first time that individual manta rays have preferred relationships with others that are maintained over time, and structured societies. This study extends our knowledge of elasmobranch ecology and population structuring. Results suggest that understanding social relationships in manta rays will be important in protecting populations from human impacts and developing sustainable, localized conservation and management initiatives. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Knowledge of how individual behavior drives population structure and dynamics is required to predict the response of populations to human impacts (Sutherland 1998 ; Sih 2013 ). In group-living species, social interactions are a fundamental part of population ecology (Hinde 1976 ) important in enabling collective behaviors (Couzin et al. 2002 ; Couzin and Krause 2003 ; Sumpter 2006 ), such as cooperative foraging (Sih et al. 2009 ), predator avoidance (Ward et al. 2011 ), and social learning (Brown et al. 2011 ). Social interactions directly affect key ecological and evolutionary processes such as disease transmission, habitat use, and genetic exchange (Kurvers et al. 2014 ). Social animals are often able to modify their behavior depending on the status of their relationship with various social partners (Krause and Ruxton 2002 ). Social preferences between individuals may have profound effects on movement decisions that lead to the formation of structured social groups (Bode et al. 2011 ). Understanding this structure can aid conservation approaches by explaining individual behavior in the context of a population’s social environment (Berger-Tal et al. 2011 ; Krause et al. 2014 ; Snijders et al. 2017 ). Social heterogeneity tends to produce organization of animal societies into units that respond differently to environmental conditions, such as in their foraging success (Whitehead and Rendell 2004 ). This is likely to cause stratification in survival and reproductive success of group members, so it can be misleading to assess population dynamics without considering the impact of this structure (Lusseau et al. 2006 ). Social network analysis may be used to describe and quantify social structure (Croft et al. 2008 ) that may be particularly useful for populations in which the existence of social relationships between individuals is not immediately evident, such as in fission-fusion societies (Snijders et al. 2017 ). Despite wide literature on social structuring in terrestrial vertebrates and marine mammals (e.g., Baird and Whitehead 2000 ; Gero et al. 2005 ; Lusseau et al. 2006 ; Wolf et al. 2007 ; Foster et al. 2012 ), there are few equivalent studies on marine fish. These are particularly lacking for elasmobranchs, despite their high potential for socially structured populations (Jacoby et al. 2010 ). Sharks and rays are often thought to be solitary creatures, but many species across elasmobranch phylogeny are found in groups or loose aggregations (for review see Jacoby et al. 2012 ). Where individuals vary in their movements and habitat preferences, some are likely to interact more than others by chance. Group formation via passive processes occurs in elasmobranchs during feeding aggregations (e.g., Heyman et al. 2001 ) and seasonal migrations (e.g., Heupel and Simpfendorfer 2005 ; Bass et al. 2017 ). Many elasmobranchs have developmental shifts in habitat and diet (Wetherbee et al. 2004 ) that may drive assortment in size- or sex-segregated groups (Wearmouth and Sims 2008 ). Recently, ex situ studies have shown that some species exhibit complex sociality, including social structure (Jacoby et al. 2010 ; Mourier et al. 2012 ), social learning (Guttridge et al. 2013 ; Thonhauser et al. 2013 ), and individual personalities (Jacoby et al. 2014 ; Byrnes et al. 2016 ). Due to the difficulty in observing multiple interactions between wild elasmobranchs, however, quantitative analysis of the importance of social relations to the structure of their populations is lacking (but see Guttridge et al. 2011 ; Mourier et al. 2012 ). It is usually a considerable challenge to disentangle passive aggregation driven by external forces from active social preferences. Manta rays ( Mobula spp.) are excellent candidates for studies on elasmobranch sociality, including social preferences. Individuals can often be easily observed and accurately identified in the wild. Mobulid rays have the largest brains relative to body size", "role": "user" }, { "content": "Manta rays form social relationships and actively choose their social partners, a new study has revealed. Research published today by scientists from the Marine Megafauna Foundation, Macquarie University and the University of Papua is the first to describe the structure of social relationships in manta rays. Sharks and rays are often thought to be solitary creatures, but reef manta rays typically form groups at shallow-water feeding and cleaning sites. The researchers studied the structure of more than 500 of these groups over five years, in Indonesia's Raja Ampat Marine Park, one of the most biodiverse marine habitats on Earth. They found two distinct but connected communities of rays living together. These social communities were quite differently structured, one being made up of mostly mature female rays, and the other a mix of males, females and juveniles. \"We still understand very little of how mantas live their lives, but we know they are socially interactive, and these interactions seem important to the structure of their populations. Understanding social relationships can help predict manta ray movements, mating patterns and responses to human impacts. That's essential for conservation and ecotourism efforts,\" said lead author Rob Perryman, a researcher for Marine Megafauna Foundation and Ph.D. student at Macquarie University. The study, published in the journal Behavioral Ecology and Sociobiology used social network analysis to show that manta ray communities contain a web of many weak acquaintances, with some stronger, longer-lasting relationships. Though they do not live in tight-knit social groups, the team noticed that female mantas tend to make long-term bonds with other females, while males did not have many strong connections. This could be due to different reproductive strategies or dispersal patterns. Social mantas cyan ocean. Credit: Macquarie University \"Like dolphins, manta rays are intelligent and perform collective behaviors such as foraging and playing. They are curious, often approaching humans, and individuals appear to have different personalities. It turns out that reef manta rays actively choose to group with preferred social partners,\" Perryman added. To identify social structures, the researchers took identification photos of all rays present in each group, and monitored whether individuals were more likely to be seen together (at different times and in different locations) than expected if encounters were random. The locations used by the rays seemed to be important to their social relations. Manta rays form groups at cleaning stations where they are attended to by cleaner wrasse and other small fish. The team observed that certain social groups were regularly seen together at these sites, and so may be using them as social meeting points. Some rays had very strong affinity to certain cleaning stations. The researchers were surprised to find this given the close proximity of all sites and that mantas are generally mobile and wide-ranging animals. They concluded that the rays left and returned to preferred sites where they formed groups through a 'fission-fusion' social process. Like many sharks and rays, manta rays are internationally threatened animals and population declines have been reported in various locations worldwide. They are hunted for their valuable gill plates used in traditional Chinese medicine. Other anthropogenic threats include injuries or entanglement in discarded nets and lines, pollution and habitat destruction. Mantas somersault. Credit: Macquarie University It is important to find the right balance between preserving a species and encouraging sustainable wildlife viewing that brings economic benefits. \"Knowing how mantas interact is important, particularly in areas where they are susceptible to increasing dive tourism,\" said Dr. Andrea Marshall, co-founder and principal scientist at the Marine Megafauna Foundation. \"The increasing number of boats and scuba divers around reef mantas in Raja Ampat, particularly at cleaning stations, could break apart their social structures and have impacts on their reproduction.\" Dr. Ricardo F. Tapilatu, a co-author working at the University of Papua and the main Indonesian counterpart for the project said: \"Pristine marine environments such as the manta ray aggregation sites in Raja Ampat are of increasing interest to tourists. This collaborative research is set in the extremely biodiverse region of the Coral Triangle, located in the Indo-Pacific, where we set up science-based conservation management for such unique natural systems.\" In Indonesia, manta rays have been protected since 2014 but artisanal fishing remains an issue, and there is still little awareness of the threats they face. The team hopes that showing the social nature of manta rays will help broaden support and public enthusiasm for their protection around the world. \"Collecting more information about their social relationships and structures will be needed to develop sustainable ecotourism and conservation initiatives that allow mantas to coexist with humans in their natural habitats,\" concluded Perryman. The study by Rob Perryman et al, titled \"Social preferences and network structure in a population of reef manta rays' is published in the journal Behavioral Ecology and Sociobiology on 22 August 2019. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Understanding how individual behavior shapes the structure and ecology of populations is key to species conservation and management. Like many elasmobranchs, manta rays are highly mobile and wide-ranging species threatened by anthropogenic impacts. In shallow water environments, these pelagic rays often form groups and perform several apparently socially mediated behaviors. Group structures may result from active choices of individual rays to interact or passive processes. Social behavior is known to affect spatial ecology in other elasmobranchs, but this is the first study providing quantitative evidence for structured social relationships in manta rays. To construct social networks, we collected data from more than 500 groups of reef manta rays ( Mobula alfredi ) over 5 years in the Raja Ampat Regency of West Papua. We used generalized affiliation indices to isolate social preferences from non-social associations, the first study on elasmobranchs to use this method. Longer lasting social preferences were detected mostly between female rays. We detected assortment of social relations by phenotype and variation in social strategies, with the overall social network divided into two main communities. Overall network structure was characteristic of a dynamic fission-fusion society, with differentiated relationships linked to strong fidelity to cleaning station sites. Our results suggest that fine-scale conservation measures will be useful in protecting social groups of M. alfredi in their natural habitats and that a more complete understanding of the social nature of manta rays will help predict population responses to anthropogenic pressures, such as increasing disturbance from dive tourism. Significance statement In social animals, relationships between individuals have important implications for species conservation. Like many other sharks and rays, manta rays are threatened species, and little is known about their natural behavior or how their populations are structured. This study provides evidence of social structure in a wild, free-ranging population of reef manta rays. We show for the first time that individual manta rays have preferred relationships with others that are maintained over time, and structured societies. This study extends our knowledge of elasmobranch ecology and population structuring. Results suggest that understanding social relationships in manta rays will be important in protecting populations from human impacts and developing sustainable, localized conservation and management initiatives. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Knowledge of how individual behavior drives population structure and dynamics is required to predict the response of populations to human impacts (Sutherland 1998 ; Sih 2013 ). In group-living species, social interactions are a fundamental part of population ecology (Hinde 1976 ) important in enabling collective behaviors (Couzin et al. 2002 ; Couzin and Krause 2003 ; Sumpter 2006 ), such as cooperative foraging (Sih et al. 2009 ), predator avoidance (Ward et al. 2011 ), and social learning (Brown et al. 2011 ). Social interactions directly affect key ecological and evolutionary processes such as disease transmission, habitat use, and genetic exchange (Kurvers et al. 2014 ). Social animals are often able to modify their behavior depending on the status of their relationship with various social partners (Krause and Ruxton 2002 ). Social preferences between individuals may have profound effects on movement decisions that lead to the formation of structured social groups (Bode et al. 2011 ). Understanding this structure can aid conservation approaches by explaining individual behavior in the context of a population’s social environment (Berger-Tal et al. 2011 ; Krause et al. 2014 ; Snijders et al. 2017 ). Social heterogeneity tends to produce organization of animal societies into units that respond differently to environmental conditions, such as in their foraging success (Whitehead and Rendell 2004 ). This is likely to cause stratification in survival and reproductive success of group members, so it can be misleading to assess population dynamics without considering the impact of this structure (Lusseau et al. 2006 ). Social network analysis may be used to describe and quantify social structure (Croft et al. 2008 ) that may be particularly useful for populations in which the existence of social relationships between individuals is not immediately evident, such as in fission-fusion societies (Snijders et al. 2017 ). Despite wide literature on social structuring in terrestrial vertebrates and marine mammals (e.g., Baird and Whitehead 2000 ; Gero et al. 2005 ; Lusseau et al. 2006 ; Wolf et al. 2007 ; Foster et al. 2012 ), there are few equivalent studies on marine fish. These are particularly lacking for elasmobranchs, despite their high potential for socially structured populations (Jacoby et al. 2010 ). Sharks and rays are often thought to be solitary creatures, but many species across elasmobranch phylogeny are found in groups or loose aggregations (for review see Jacoby et al. 2012 ). Where individuals vary in their movements and habitat preferences, some are likely to interact more than others by chance. Group formation via passive processes occurs in elasmobranchs during feeding aggregations (e.g., Heyman et al. 2001 ) and seasonal migrations (e.g., Heupel and Simpfendorfer 2005 ; Bass et al. 2017 ). Many elasmobranchs have developmental shifts in habitat and diet (Wetherbee et al. 2004 ) that may drive assortment in size- or sex-segregated groups (Wearmouth and Sims 2008 ). Recently, ex situ studies have shown that some species exhibit complex sociality, including social structure (Jacoby et al. 2010 ; Mourier et al. 2012 ), social learning (Guttridge et al. 2013 ; Thonhauser et al. 2013 ), and individual personalities (Jacoby et al. 2014 ; Byrnes et al. 2016 ). Due to the difficulty in observing multiple interactions between wild elasmobranchs, however, quantitative analysis of the importance of social relations to the structure of their populations is lacking (but see Guttridge et al. 2011 ; Mourier et al. 2012 ). It is usually a considerable challenge to disentangle passive aggregation driven by external forces from active social preferences. Manta rays ( Mobula spp.) are excellent candidates for studies on elasmobranch sociality, including social preferences. Individuals can often be easily observed and accurately identified in the wild. Mobulid rays have the largest brains relative to body size<|im_end|> <|im_start|>assistant Manta rays form social relationships and actively choose their social partners, a new study has revealed. Research published today by scientists from the Marine Megafauna Foundation, Macquarie University and the University of Papua is the first to describe the structure of social relationships in manta rays. Sharks and rays are often thought to be solitary creatures, but reef manta rays typically form groups at shallow-water feeding and cleaning sites. The researchers studied the structure of more than 500 of these groups over five years, in Indonesia's Raja Ampat Marine Park, one of the most biodiverse marine habitats on Earth. They found two distinct but connected communities of rays living together. These social communities were quite differently structured, one being made up of mostly mature female rays, and the other a mix of males, females and juveniles. "We still understand very little of how mantas live their lives, but we know they are socially interactive, and these interactions seem important to the structure of their populations. Understanding social relationships can help predict manta ray movements, mating patterns and responses to human impacts. That's essential for conservation and ecotourism efforts," said lead author Rob Perryman, a researcher for Marine Megafauna Foundation and Ph.D. student at Macquarie University. The study, published in the journal Behavioral Ecology and Sociobiology used social network analysis to show that manta ray communities contain a web of many weak acquaintances, with some stronger, longer-lasting relationships. Though they do not live in tight-knit social groups, the team noticed that female mantas tend to make long-term bonds with other females, while males did not have many strong connections. This could be due to different reproductive strategies or dispersal patterns. Social mantas cyan ocean. Credit: Macquarie University "Like dolphins, manta rays are intelligent and perform collective behaviors such as foraging and playing. They are curious, often approaching humans, and individuals appear to have different personalities. It turns out that reef manta rays actively choose to group with preferred social partners," Perryman added. To identify social structures, the researchers took identification photos of all rays present in each group, and monitored whether individuals were more likely to be seen together (at different times and in different locations) than expected if encounters were random. The locations used by the rays seemed to be important to their social relations. Manta rays form groups at cleaning stations where they are attended to by cleaner wrasse and other small fish. The team observed that certain social groups were regularly seen together at these sites, and so may be using them as social meeting points. Some rays had very strong affinity to certain cleaning stations. The researchers were surprised to find this given the close proximity of all sites and that mantas are generally mobile and wide-ranging animals. They concluded that the rays left and returned to preferred sites where they formed groups through a 'fission-fusion' social process. Like many sharks and rays, manta rays are internationally threatened animals and population declines have been reported in various locations worldwide. They are hunted for their valuable gill plates used in traditional Chinese medicine. Other anthropogenic threats include injuries or entanglement in discarded nets and lines, pollution and habitat destruction. Mantas somersault. Credit: Macquarie University It is important to find the right balance between preserving a species and encouraging sustainable wildlife viewing that brings economic benefits. "Knowing how mantas interact is important, particularly in areas where they are susceptible to increasing dive tourism," said Dr. Andrea Marshall, co-founder and principal scientist at the Marine Megafauna Foundation. "The increasing number of boats and scuba divers around reef mantas in Raja Ampat, particularly at cleaning stations, could break apart their social structures and have impacts on their reproduction." Dr. Ricardo F. Tapilatu, a co-author working at the University of Papua and the main Indonesian counterpart for the project said: "Pristine marine environments such as the manta ray aggregation sites in Raja Ampat are of increasing interest to tourists. This collaborative research is set in the extremely biodiverse region of the Coral Triangle, located in the Indo-Pacific, where we set up science-based conservation management for such unique natural systems." In Indonesia, manta rays have been protected since 2014 but artisanal fishing remains an issue, and there is still little awareness of the threats they face. The team hopes that showing the social nature of manta rays will help broaden support and public enthusiasm for their protection around the world. "Collecting more information about their social relationships and structures will be needed to develop sustainable ecotourism and conservation initiatives that allow mantas to coexist with humans in their natural habitats," concluded Perryman. The study by Rob Perryman et al, titled "Social preferences and network structure in a population of reef manta rays' is published in the journal Behavioral Ecology and Sociobiology on 22 August 2019. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Like many other crops, the cultivated peanut ( Arachis hypogaea L.) is of hybrid origin and has a polyploid genome that contains essentially complete sets of chromosomes from two ancestral species. Here we report the genome sequence of peanut and show that after its polyploid origin, the genome has evolved through mobile-element activity, deletions and by the flow of genetic information between corresponding ancestral chromosomes (that is, homeologous recombination). Uniformity of patterns of homeologous recombination at the ends of chromosomes favors a single origin for cultivated peanut and its wild counterpart A. monticola . However, through much of the genome, homeologous recombination has created diversity. Using new polyploid hybrids made from the ancestral species, we show how this can generate phenotypic changes such as spontaneous changes in the color of the flowers. We suggest that diversity generated by these genetic mechanisms helped to favor the domestication of the polyploid A. hypogaea over other diploid Arachis species cultivated by humans. Main The domestication of plants, thousands of years ago, increased food supply and allowed the formation of large, complex human societies. Out of many thousands of wild species, only a few became domesticated crops and they now provide most of the food consumed by humans. It has long been noted that many of these crops are polyploid: their nuclei have more than two sets of chromosomes that are often derived from different species. Although it has been surprisingly difficult to rigorously demonstrate, it has long been thought that domestication may favor polyploids 1 , 2 . Peanut (also called groundnut; Arachis hypogaea L.) is an important food crop (annual production of ~44 million tons based on FAOSTAT data for 2016 ( )). Whereas almost all related species in the genus Arachis are diploid (two sets of ten chromosomes; mostly 2 n = 2× = 20 chromosomes), A. hypogaea is polyploid 3 , 4 . The seeds of all of these species are an attractive food, and several have been cultivated for thousands of years 5 (Supplementary Note 1 ). Indeed, the action of humans was key to the formation of A. hypogaea itself. About 9,400 years ago (estimated by nucleotide divergence 6 ), the human transport of the ‘B’ genome species, A. ipaensis Krapov. & W.C. Greg., into the range of the ‘A’ genome species A. duranensis Krapov. & W.C. Greg. enabled their hybridization and the formation of A. hypogaea 6 . It has two sets of chromosome pairs, one from each of the ancestral species: a type of polyploid termed allotetraploid (AABB-type genome; 2 n = 4× = 40 chromosomes; genome size of ~2.7 Gb). The origin of A. hypogaea was associated with a particularly severe population bottleneck 7 , 8 , 9 . This could, in principle, have reduced the variability on which, over generations, human selection could act. However, A. hypogaea evolved, becoming completely dependent on cultivation and morphologically very diverse 5 . Two subspecies ( hypogaea and fastigiata ) and six botanical varieties ( hypogaea , hirsuta , fastigiata , vulgaris , aequatoriana and peruviana ) are recognized 5 , 10 , 11 . Different grain colors and sizes, pod shapes and growth habits distinguish thousands of landraces and cultivars 5 , 11 (see also United States Department of Agriculture (USDA) Germplasm Resources Information Network ( )). It seems notable that, in spite of the higher genetic diversity of the diploid species 7 , 9 , and their cultivation starting earlier (Supplementary Note 1 ), it was the derived allotetraploid, A. hypogaea , that underwent the transformation to become the crop of worldwide importance. Some time ago, while planning to sequence and assemble the peanut genome, we realized that it would not be possible using the short-read data (~100–200 bp DNA) that were generated by the only technology that was economically feasible at the time; such sequences were too short to reliably resolve the very similar A and B genomes, which frequently have more than 98% DNA identity between corresponding genes 6 , 12 , 13 . This level of similarity is due to the progenitor species that gave rise to the two subgenomes having diverged only around 2.2 million years ago (refs. 6 , 9 , 14 ). Therefore, as a foundation for understanding the genome of cultivated peanut, we first sequenced the genomes of both the diploid ancestral species 6 . These diploid genomes afforded new insights into peanut genetics. Notably, it was possible to infer that some chromosome ends of A. hypogaea had changed from the expected AABB structure to AAAA or BBBB, implying a particular complexity in peanut genetics 6 , 15 , 16 , 17 , 18 . Here, using the much longer-read data obtained with PacBio technology 19 , and scaffolding using Hi-C 20 , 21 , a method used for determining the conformation of DNA in the nucleus, we report the complete chromosome-scale genome sequence of A. hypogaea cv. Tifrunner, a runner-type peanut. We also characterize the genomes of a diverse selection of cultivated peanuts, together with its wild counterpart, A. monticola Krapov. & Rigoni, and induced allotetraploid hybrids derived from the ancestral species. We are able to visualize, in considerable detail, the products of variable deletions from, and genetic recombination between, the A and B subgenomes. It seems likely that these variations in genome structure generated phenotypic variation on which selection could act, and helped to favor A. hypogaea over its diploid relatives during the process of domestication. Results Sequencing and assembly of the peanut genome Arachis hypogaea cv. Tifrunner 22 , a runner-type peanut (registration number CV-93, PI 644011) was sequenced using whole-genome shotgun sequencing. Twenty chromosome sequences were produced (for assembly metrics see Supplementary Tables 1 and 2 ). They were numbered Arahy.01–Arahy.20, where the A subgenome is represented as Arahy.01–Arahy.10 and the B subgenome as Arahy.11–Arahy.20. The chromosome sequences contain 99.3% of the assembled sequence and are 2.54 Gb, 93% of the size estimated by flow cytometry 23 . Chromosome architecture The chromosomes of A.", "role": "user" }, { "content": "Improved pest resistance and drought tolerance are among potential benefits of an international effort in which Agricultural Research Service (ARS) scientists and their collaborators have produced the clearest picture yet of the complex genomic history of the cultivated peanut. Scientists undertook this large project to better understand the molecular and cellular mechanisms that underpin the peanut plant's growth and development, as well as the expression of desirable traits, like high seed yield, improved oil quality and resistance to costly diseases and pests such as root knot nematodes. Cultivated peanut, Arachis hypogaea, is an important grain legume and oilseed crop, with a total global production area of approximately 59 million acres. Besides oil, peanut seed contains protein, vitamins and other nutrients. United States peanut production, valued at $2 billion annually, extends from Virginia south to Florida and westward to New Mexico. The story of the cultivated peanut begins several thousand years ago in South America, where the genomes of two wild ancestors, A. duranensis and A. ipaensis, merged in a rare genetic event. The result, in modern-day peanuts, is a complex genomic blend that's nearly as big as the human genome, which is about 3 billion DNA base pairs. Initially, scientists sequenced the genomes of the two wild ancestors separately, using DNA taken from the two species rather than from cultivated peanut. This made it easier to identify structural features of the genomes and the genes residing on them. The team reported that progress in a 2016 issue of the journal Nature Genetics. Now, using advanced DNA sequencing equipment, the researchers have sequenced the two merged genomes in a single commercially grown peanut, namely 'Tifrunner,' filling in knowledge gaps that the previous effort missed. This latest advance, reported in the May issue of Nature Genetics, has already generated interesting leads, including the geographic origin of A. duranensis, one of the two \"parents\" of cultivated peanut. The team's genomic analysis of populations of plants that make up the wild peanut species pointed to a region in northern Argentina known as Rio Seco. Researchers surmise that ancient farmers migrating there from Bolivia exposed A. duranensis plants to another species they had brought with them—A. ipaensis, considered the other parent of cultivated peanut. The researchers also recreated this genomic merger by crossing the two ancient peanuts species and analyzing the results in seven generations of offspring plants. This revealed an interesting pattern of DNA swapping and deletions (eliminations) taking place in the offspring plants that likely explains the diverse seed size, shape, color and other traits seen in commercial peanuts today. The DNA swapping is unusual in that it occurs between the two \"subgenomes\" of the two contributing wild species—something that's possible due to their high similarity. Led by University of Georgia researcher David Bertioli, the effort is a continuation of the \"International Peanut Genome Initiative\" and involves scientists from four ARS laboratories and other partner organizations in the United States, Argentina, Brazil, China and India. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Like many other crops, the cultivated peanut ( Arachis hypogaea L.) is of hybrid origin and has a polyploid genome that contains essentially complete sets of chromosomes from two ancestral species. Here we report the genome sequence of peanut and show that after its polyploid origin, the genome has evolved through mobile-element activity, deletions and by the flow of genetic information between corresponding ancestral chromosomes (that is, homeologous recombination). Uniformity of patterns of homeologous recombination at the ends of chromosomes favors a single origin for cultivated peanut and its wild counterpart A. monticola . However, through much of the genome, homeologous recombination has created diversity. Using new polyploid hybrids made from the ancestral species, we show how this can generate phenotypic changes such as spontaneous changes in the color of the flowers. We suggest that diversity generated by these genetic mechanisms helped to favor the domestication of the polyploid A. hypogaea over other diploid Arachis species cultivated by humans. Main The domestication of plants, thousands of years ago, increased food supply and allowed the formation of large, complex human societies. Out of many thousands of wild species, only a few became domesticated crops and they now provide most of the food consumed by humans. It has long been noted that many of these crops are polyploid: their nuclei have more than two sets of chromosomes that are often derived from different species. Although it has been surprisingly difficult to rigorously demonstrate, it has long been thought that domestication may favor polyploids 1 , 2 . Peanut (also called groundnut; Arachis hypogaea L.) is an important food crop (annual production of ~44 million tons based on FAOSTAT data for 2016 ( )). Whereas almost all related species in the genus Arachis are diploid (two sets of ten chromosomes; mostly 2 n = 2× = 20 chromosomes), A. hypogaea is polyploid 3 , 4 . The seeds of all of these species are an attractive food, and several have been cultivated for thousands of years 5 (Supplementary Note 1 ). Indeed, the action of humans was key to the formation of A. hypogaea itself. About 9,400 years ago (estimated by nucleotide divergence 6 ), the human transport of the ‘B’ genome species, A. ipaensis Krapov. & W.C. Greg., into the range of the ‘A’ genome species A. duranensis Krapov. & W.C. Greg. enabled their hybridization and the formation of A. hypogaea 6 . It has two sets of chromosome pairs, one from each of the ancestral species: a type of polyploid termed allotetraploid (AABB-type genome; 2 n = 4× = 40 chromosomes; genome size of ~2.7 Gb). The origin of A. hypogaea was associated with a particularly severe population bottleneck 7 , 8 , 9 . This could, in principle, have reduced the variability on which, over generations, human selection could act. However, A. hypogaea evolved, becoming completely dependent on cultivation and morphologically very diverse 5 . Two subspecies ( hypogaea and fastigiata ) and six botanical varieties ( hypogaea , hirsuta , fastigiata , vulgaris , aequatoriana and peruviana ) are recognized 5 , 10 , 11 . Different grain colors and sizes, pod shapes and growth habits distinguish thousands of landraces and cultivars 5 , 11 (see also United States Department of Agriculture (USDA) Germplasm Resources Information Network ( )). It seems notable that, in spite of the higher genetic diversity of the diploid species 7 , 9 , and their cultivation starting earlier (Supplementary Note 1 ), it was the derived allotetraploid, A. hypogaea , that underwent the transformation to become the crop of worldwide importance. Some time ago, while planning to sequence and assemble the peanut genome, we realized that it would not be possible using the short-read data (~100–200 bp DNA) that were generated by the only technology that was economically feasible at the time; such sequences were too short to reliably resolve the very similar A and B genomes, which frequently have more than 98% DNA identity between corresponding genes 6 , 12 , 13 . This level of similarity is due to the progenitor species that gave rise to the two subgenomes having diverged only around 2.2 million years ago (refs. 6 , 9 , 14 ). Therefore, as a foundation for understanding the genome of cultivated peanut, we first sequenced the genomes of both the diploid ancestral species 6 . These diploid genomes afforded new insights into peanut genetics. Notably, it was possible to infer that some chromosome ends of A. hypogaea had changed from the expected AABB structure to AAAA or BBBB, implying a particular complexity in peanut genetics 6 , 15 , 16 , 17 , 18 . Here, using the much longer-read data obtained with PacBio technology 19 , and scaffolding using Hi-C 20 , 21 , a method used for determining the conformation of DNA in the nucleus, we report the complete chromosome-scale genome sequence of A. hypogaea cv. Tifrunner, a runner-type peanut. We also characterize the genomes of a diverse selection of cultivated peanuts, together with its wild counterpart, A. monticola Krapov. & Rigoni, and induced allotetraploid hybrids derived from the ancestral species. We are able to visualize, in considerable detail, the products of variable deletions from, and genetic recombination between, the A and B subgenomes. It seems likely that these variations in genome structure generated phenotypic variation on which selection could act, and helped to favor A. hypogaea over its diploid relatives during the process of domestication. Results Sequencing and assembly of the peanut genome Arachis hypogaea cv. Tifrunner 22 , a runner-type peanut (registration number CV-93, PI 644011) was sequenced using whole-genome shotgun sequencing. Twenty chromosome sequences were produced (for assembly metrics see Supplementary Tables 1 and 2 ). They were numbered Arahy.01–Arahy.20, where the A subgenome is represented as Arahy.01–Arahy.10 and the B subgenome as Arahy.11–Arahy.20. The chromosome sequences contain 99.3% of the assembled sequence and are 2.54 Gb, 93% of the size estimated by flow cytometry 23 . Chromosome architecture The chromosomes of A.<|im_end|> <|im_start|>assistant Improved pest resistance and drought tolerance are among potential benefits of an international effort in which Agricultural Research Service (ARS) scientists and their collaborators have produced the clearest picture yet of the complex genomic history of the cultivated peanut. Scientists undertook this large project to better understand the molecular and cellular mechanisms that underpin the peanut plant's growth and development, as well as the expression of desirable traits, like high seed yield, improved oil quality and resistance to costly diseases and pests such as root knot nematodes. Cultivated peanut, Arachis hypogaea, is an important grain legume and oilseed crop, with a total global production area of approximately 59 million acres. Besides oil, peanut seed contains protein, vitamins and other nutrients. United States peanut production, valued at $2 billion annually, extends from Virginia south to Florida and westward to New Mexico. The story of the cultivated peanut begins several thousand years ago in South America, where the genomes of two wild ancestors, A. duranensis and A. ipaensis, merged in a rare genetic event. The result, in modern-day peanuts, is a complex genomic blend that's nearly as big as the human genome, which is about 3 billion DNA base pairs. Initially, scientists sequenced the genomes of the two wild ancestors separately, using DNA taken from the two species rather than from cultivated peanut. This made it easier to identify structural features of the genomes and the genes residing on them. The team reported that progress in a 2016 issue of the journal Nature Genetics. Now, using advanced DNA sequencing equipment, the researchers have sequenced the two merged genomes in a single commercially grown peanut, namely 'Tifrunner,' filling in knowledge gaps that the previous effort missed. This latest advance, reported in the May issue of Nature Genetics, has already generated interesting leads, including the geographic origin of A. duranensis, one of the two "parents" of cultivated peanut. The team's genomic analysis of populations of plants that make up the wild peanut species pointed to a region in northern Argentina known as Rio Seco. Researchers surmise that ancient farmers migrating there from Bolivia exposed A. duranensis plants to another species they had brought with them—A. ipaensis, considered the other parent of cultivated peanut. The researchers also recreated this genomic merger by crossing the two ancient peanuts species and analyzing the results in seven generations of offspring plants. This revealed an interesting pattern of DNA swapping and deletions (eliminations) taking place in the offspring plants that likely explains the diverse seed size, shape, color and other traits seen in commercial peanuts today. The DNA swapping is unusual in that it occurs between the two "subgenomes" of the two contributing wild species—something that's possible due to their high similarity. Led by University of Georgia researcher David Bertioli, the effort is a continuation of the "International Peanut Genome Initiative" and involves scientists from four ARS laboratories and other partner organizations in the United States, Argentina, Brazil, China and India. <|im_end|>

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2,051

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine. Main Phosphoinositide 3-kinases (PI3Ks) are a family of lipid-modifying enzymes that phosphorylate the 3′-OH group of inositol phospholipids and play key roles in physiology ranging from cell growth and metabolism to organismal development. Dysfunction of PI3K signaling is implicated in human diseases including cancer, immunodeficiency, diabetes and neurological disorders 1 , 2 , 3 . Mammalian PI3Ks are grouped into three classes based on their structural organization. Class I PI3Ks are receptor-activated heterodimeric enzymes with pivotal roles in cell signaling (for example, cell growth) via synthesis of phosphatidylinositol (PI) 3,4,5-trisphosphate (PI(3,4,5)P 3 ) at the plasma membrane 2 , 4 , 5 , 6 . Isoform-specific pharmacological inhibitors of class I PI3K activity have undergone clinical development as anticancer therapeutics and for the treatment of human disorders caused by PI3K pathway hyperactivation. Complexes of Vps34, the sole class III PI3K member, produce PI 3-phosphate (PI(3)P) in the endolysosomal system and during autophagy to regulate vesicle-mediated sorting en route to lysosomes 1 . Recent structural studies 7 , 8 have enabled the development of selective Vps34 inhibitors that have been instrumental for the analysis and manipulation of class III PI3K function in autophagy and in the regulation of nutrient signaling. The class II PI3K isoforms PI3KC2α, PI3KC2β and PI3KC2γ are unique in directly synthesizing PI 3,4-bisphosphate (PI(3,4)P 2 ) from PI 4-phosphate (PI(4)P) at the plasma membrane and within the endolysosomal system 9 , 10 , in addition to synthesis of PI 3-phosphate (PI(3)P) 11 , 12 , 13 , 14 . The mechanistic basis for the ability of class II PI3Ks to recognize PI(4)P as a substrate to directly produce local pools of PI(3,4)P 2 at defined endocytic membrane nanodomains is unknown. PI3KC2α is essential in mice 13 . Loss of its catalytic activity is associated with cellular defects in endocytosis 15 , 16 , angiogenesis and endothelial cell function 17 , 18 , 19 , regulation of blood pressure 20 , viral replication 21 , 22 , platelet formation 23 , 24 and primary cilia signaling 13 . Abrogation of PI3KC2α activity in animal models and in humans leads to kidney cyst formation, skeletal abnormalities, neurological symptoms and cataract formation 25 . In addition to these catalytic roles, PI3KC2α is also required for genome stability by acting as a scaffold at the mitotic spindle during cell division 26 . In contrast to class I 4 , 6 and class III PI3Ks (refs. 4 , 7 , 8 , 27 ) that are understood in structural detail, little is known about the structural and functional architecture, and mechanism of activation of class II PI3Ks including PI3KC2α. Unlike their class I and class III relatives that are targeted to their site of action via associated subunits, class II enzymes such as PI3KC2α lack stable association with other subunits 4 , 14 and, thus, must be activated via a distinct regulatory mechanism that so far has remained elusive. The lack of structural information on PI3KC2α and related class II PI3Ks has also greatly hampered the development of isoform-selective pharmacological inhibitors for clinical applications. Moreover, the molecular basis of the scaffolding function of PI3KC2α at the mitotic spindle via its association with the microtubule-binding protein TACC3 at kinetochore fibers to prevent aneuploidy 26 is unknown. To address these important unresolved issues, we have determined high-resolution crystal structures as well as a 4.4-Å cryogenic- electron microscopic (cryo-EM) structure of PI3KC2α in different conformational states and in the presence of nonselective small molecule inhibitors. Our results identify a hitherto unknown coincident mechanism of lipid-induced activation of PI3KC2α that is distinct from that of all other PI3Ks and can serve as a model for the entire class II PI3K family. Moreover, our structural and functional biochemical data will greatly facilitate the future development of isoform-selective PI3KC2α inhibitors with biomedical applications that range from the treatment of thrombosis 28 to viral infections 21 , 22 , diabetes 29 and cancer 1 , 14 . Results Overall architecture of PI3KC2α Like other members of the PI3K family 1 , 4 , PI3KC2α contains a PI3K core that consists of a Ras-binding domain (RBD) and an N-terminal C2 domain, as well as helical and kinase domains (KDs). In addition, PI3KC2α harbors the C-terminal Phox-homology (PX) and C2 domains that are unique to class II enzymes (Fig. 1a ). To determine the X-ray crystal structure of PI3KC2α, we embarked on an iterative process of construct screening and optimization of various forms of PI3KC2α from different species assisted by hydrogen/deuterium exchange–mass spectrometry (HDX–MS) to identify disordered regions. A purified mouse PI3KC2α construct containing a re-engineered internal loop sequence and lacking the intrinsically disordered N-terminal region and the C-terminal C2 domain (C-C2) (Extended Data Figs. 1a,b and 2 ) was used to obtain the 3.3 Å crystal structure of PI3KC2α ΔN+ΔC−C2 (Table 1 ). Fig. 1: Overall structure of PI3KC2α. a , Domain organization of PI3Ks. ABD, adapter binding domain, C2, C2 domain, HD, helical domain, N-KD, C-KD, N- and C-terminal lobes of the kinase core domain. Amino acids 1–377 of PI3KC2α are predicted to be disordered. HBD specific to", "role": "user" }, { "content": "Phosphatidylinositol 3-kinase, or PI3K for short, is a family of lipid kinases that plays a key role in the human body, performing functions such as cell division, metabolism, and cell growth. While class I PI3Kα is well-researched and an important target for cancer drugs, little is known about class II of this lipid kinase family. Now, researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have been able to shed light on its structure and function. The results pave the way for the development of new types of antithrombotic drugs. Moreover, it is likely that the inhibition of class II PI3KC2α is able to arrest tumor angiogenesis. The study has now been published in Nature Structural & Molecular Biology. A second paper published in Science provides another important lead. Lipid kinases are among the promising targets of new classes of drugs, due mainly to class I PI3Kα, which plays a crucial role in carcinogenesis and metastasis. This enzyme is hyperactive in 30-40% of all tumors, leading to uncontrolled cell growth. For this reason, this well-researched lipid kinase has become a prime target for the development of anticancer drugs for the past two decades. In contrast, little is known about its sister enzyme, class II PI3Kα. It is thought that this lipid kinase is likewise associated with numerous biomedical processes such as platelet aggregation or the formation of new blood vessels, referred to as angiogenesis. However, before its dysfunction can be better understood and targeted by drugs, it is essential to know exactly what this kinase looks like and how it functions. This is precisely what researchers from FMP have now managed to achieve. Using a combination of X-ray protein crystallography and cryo-electron microscopy (cryo-EM), Professor Volker Haucke's research group has succeeded in resolving the structure of class II PI3Kα (PI3KC2α) and in describing the activation mechanism of the enzyme for the first time. These findings pave the way for entirely novel therapeutic approaches. Inhibition of kinase activity could help numerous patients \"Inhibition of kinase activity is thought to play a role in many applications in biomedicine, such as tumor growth and angiogenesis,\" explained Volker Haucke. \"It is also likely to be important for the inhibition of platelet aggregation.\" It is known, for example, that the kinase is required for platelets to form a thrombus. It is interesting to note that the function of kinase PI3KC2α is flow-dependent, i.e. it depends on blood pressure. If a drug were now used to inhibit the kinase, platelet aggregation would be arrested, especially in the case of an increase in blood pressure. However, most anticoagulants currently prescribed to patients to prevent thromboembolic events such as heart attack or stroke are also effective at normal blood pressure levels, which can have fatal side effects such as brain hemorrhage. The FMP researchers conjecture that PI3KC2α kinase inhibitors would have a significantly better pharmacological and biomedical profile than existing antiplatelet drugs. Initial experiments with potential drug candidates have already demonstrated that inhibition of the kinase is possible in principle. Unraveling the structure and activation mechanism was key to this. Conditions created for new drugs The researchers have in fact discovered the structure of the binding pocket of the kinase that binds the lipid and adenosine triphosphate (ATP) as the \"cellular currency,\" enabling the transfer of a phosphate group to the lipid. The scientists now also know what kind of \"molecular gymnastics\" the kinase must undergo in order to be activated at exactly the right place in the cell. \"This information is crucial for developing a specific inhibitor that blocks only PI3KC2a, but no other related enzyme,\" stated Wen-Ting Lo, the first author of the study. The team around Volker Haucke and Wen-Ting Lo is already collaborating with other scientists at the institute to find specific inhibitors that occupy the ATP-binding pocket of the enzyme, preventing the enzymatic reaction. Kinase involved in the final step of cell division But this is not all that FMP researchers have found out about PI3KC2a. Together with Emilio Hirsch's research group at the University of Torino, the researchers have been able to demonstrate that the kinase is also involved in the final step of cell division, referred to as cytokinesis. Patients lacking the kinase due to mutations were the starting point of the study published in Science. Besides having various organ defects, these individuals suffer from a clouding of the lens, known as a cataract. Using experiments in mice and zebrafish, the research team was able to show how the loss of function of the enzyme leads to cataracts. The genetic material is duplicated and subsequently distributed to the two daughter cells during cell division. Membrane abscission eventually separates the daughter cells. In the absence of the kinase, however, this final cut fails to occur because a crucial lipid that can only be produced by PI3KC2a is missing. As a result, the lens epithelial cells suffer from impaired cytokinesis, which explains why these patients develop cataracts. The finding also has further implications: With the realization that the kinase is an essential component of cytokinesis, i.e. the separation of daughter cells—this mechanism could also be of great importance for tumors that rely on continuous cell division. Consequently, PI3KC2a inhibitors would potentially also open up new perspectives in cancer therapy. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine. Main Phosphoinositide 3-kinases (PI3Ks) are a family of lipid-modifying enzymes that phosphorylate the 3′-OH group of inositol phospholipids and play key roles in physiology ranging from cell growth and metabolism to organismal development. Dysfunction of PI3K signaling is implicated in human diseases including cancer, immunodeficiency, diabetes and neurological disorders 1 , 2 , 3 . Mammalian PI3Ks are grouped into three classes based on their structural organization. Class I PI3Ks are receptor-activated heterodimeric enzymes with pivotal roles in cell signaling (for example, cell growth) via synthesis of phosphatidylinositol (PI) 3,4,5-trisphosphate (PI(3,4,5)P 3 ) at the plasma membrane 2 , 4 , 5 , 6 . Isoform-specific pharmacological inhibitors of class I PI3K activity have undergone clinical development as anticancer therapeutics and for the treatment of human disorders caused by PI3K pathway hyperactivation. Complexes of Vps34, the sole class III PI3K member, produce PI 3-phosphate (PI(3)P) in the endolysosomal system and during autophagy to regulate vesicle-mediated sorting en route to lysosomes 1 . Recent structural studies 7 , 8 have enabled the development of selective Vps34 inhibitors that have been instrumental for the analysis and manipulation of class III PI3K function in autophagy and in the regulation of nutrient signaling. The class II PI3K isoforms PI3KC2α, PI3KC2β and PI3KC2γ are unique in directly synthesizing PI 3,4-bisphosphate (PI(3,4)P 2 ) from PI 4-phosphate (PI(4)P) at the plasma membrane and within the endolysosomal system 9 , 10 , in addition to synthesis of PI 3-phosphate (PI(3)P) 11 , 12 , 13 , 14 . The mechanistic basis for the ability of class II PI3Ks to recognize PI(4)P as a substrate to directly produce local pools of PI(3,4)P 2 at defined endocytic membrane nanodomains is unknown. PI3KC2α is essential in mice 13 . Loss of its catalytic activity is associated with cellular defects in endocytosis 15 , 16 , angiogenesis and endothelial cell function 17 , 18 , 19 , regulation of blood pressure 20 , viral replication 21 , 22 , platelet formation 23 , 24 and primary cilia signaling 13 . Abrogation of PI3KC2α activity in animal models and in humans leads to kidney cyst formation, skeletal abnormalities, neurological symptoms and cataract formation 25 . In addition to these catalytic roles, PI3KC2α is also required for genome stability by acting as a scaffold at the mitotic spindle during cell division 26 . In contrast to class I 4 , 6 and class III PI3Ks (refs. 4 , 7 , 8 , 27 ) that are understood in structural detail, little is known about the structural and functional architecture, and mechanism of activation of class II PI3Ks including PI3KC2α. Unlike their class I and class III relatives that are targeted to their site of action via associated subunits, class II enzymes such as PI3KC2α lack stable association with other subunits 4 , 14 and, thus, must be activated via a distinct regulatory mechanism that so far has remained elusive. The lack of structural information on PI3KC2α and related class II PI3Ks has also greatly hampered the development of isoform-selective pharmacological inhibitors for clinical applications. Moreover, the molecular basis of the scaffolding function of PI3KC2α at the mitotic spindle via its association with the microtubule-binding protein TACC3 at kinetochore fibers to prevent aneuploidy 26 is unknown. To address these important unresolved issues, we have determined high-resolution crystal structures as well as a 4.4-Å cryogenic- electron microscopic (cryo-EM) structure of PI3KC2α in different conformational states and in the presence of nonselective small molecule inhibitors. Our results identify a hitherto unknown coincident mechanism of lipid-induced activation of PI3KC2α that is distinct from that of all other PI3Ks and can serve as a model for the entire class II PI3K family. Moreover, our structural and functional biochemical data will greatly facilitate the future development of isoform-selective PI3KC2α inhibitors with biomedical applications that range from the treatment of thrombosis 28 to viral infections 21 , 22 , diabetes 29 and cancer 1 , 14 . Results Overall architecture of PI3KC2α Like other members of the PI3K family 1 , 4 , PI3KC2α contains a PI3K core that consists of a Ras-binding domain (RBD) and an N-terminal C2 domain, as well as helical and kinase domains (KDs). In addition, PI3KC2α harbors the C-terminal Phox-homology (PX) and C2 domains that are unique to class II enzymes (Fig. 1a ). To determine the X-ray crystal structure of PI3KC2α, we embarked on an iterative process of construct screening and optimization of various forms of PI3KC2α from different species assisted by hydrogen/deuterium exchange–mass spectrometry (HDX–MS) to identify disordered regions. A purified mouse PI3KC2α construct containing a re-engineered internal loop sequence and lacking the intrinsically disordered N-terminal region and the C-terminal C2 domain (C-C2) (Extended Data Figs. 1a,b and 2 ) was used to obtain the 3.3 Å crystal structure of PI3KC2α ΔN+ΔC−C2 (Table 1 ). Fig. 1: Overall structure of PI3KC2α. a , Domain organization of PI3Ks. ABD, adapter binding domain, C2, C2 domain, HD, helical domain, N-KD, C-KD, N- and C-terminal lobes of the kinase core domain. Amino acids 1–377 of PI3KC2α are predicted to be disordered. HBD specific to<|im_end|> <|im_start|>assistant Phosphatidylinositol 3-kinase, or PI3K for short, is a family of lipid kinases that plays a key role in the human body, performing functions such as cell division, metabolism, and cell growth. While class I PI3Kα is well-researched and an important target for cancer drugs, little is known about class II of this lipid kinase family. Now, researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have been able to shed light on its structure and function. The results pave the way for the development of new types of antithrombotic drugs. Moreover, it is likely that the inhibition of class II PI3KC2α is able to arrest tumor angiogenesis. The study has now been published in Nature Structural & Molecular Biology. A second paper published in Science provides another important lead. Lipid kinases are among the promising targets of new classes of drugs, due mainly to class I PI3Kα, which plays a crucial role in carcinogenesis and metastasis. This enzyme is hyperactive in 30-40% of all tumors, leading to uncontrolled cell growth. For this reason, this well-researched lipid kinase has become a prime target for the development of anticancer drugs for the past two decades. In contrast, little is known about its sister enzyme, class II PI3Kα. It is thought that this lipid kinase is likewise associated with numerous biomedical processes such as platelet aggregation or the formation of new blood vessels, referred to as angiogenesis. However, before its dysfunction can be better understood and targeted by drugs, it is essential to know exactly what this kinase looks like and how it functions. This is precisely what researchers from FMP have now managed to achieve. Using a combination of X-ray protein crystallography and cryo-electron microscopy (cryo-EM), Professor Volker Haucke's research group has succeeded in resolving the structure of class II PI3Kα (PI3KC2α) and in describing the activation mechanism of the enzyme for the first time. These findings pave the way for entirely novel therapeutic approaches. Inhibition of kinase activity could help numerous patients "Inhibition of kinase activity is thought to play a role in many applications in biomedicine, such as tumor growth and angiogenesis," explained Volker Haucke. "It is also likely to be important for the inhibition of platelet aggregation." It is known, for example, that the kinase is required for platelets to form a thrombus. It is interesting to note that the function of kinase PI3KC2α is flow-dependent, i.e. it depends on blood pressure. If a drug were now used to inhibit the kinase, platelet aggregation would be arrested, especially in the case of an increase in blood pressure. However, most anticoagulants currently prescribed to patients to prevent thromboembolic events such as heart attack or stroke are also effective at normal blood pressure levels, which can have fatal side effects such as brain hemorrhage. The FMP researchers conjecture that PI3KC2α kinase inhibitors would have a significantly better pharmacological and biomedical profile than existing antiplatelet drugs. Initial experiments with potential drug candidates have already demonstrated that inhibition of the kinase is possible in principle. Unraveling the structure and activation mechanism was key to this. Conditions created for new drugs The researchers have in fact discovered the structure of the binding pocket of the kinase that binds the lipid and adenosine triphosphate (ATP) as the "cellular currency," enabling the transfer of a phosphate group to the lipid. The scientists now also know what kind of "molecular gymnastics" the kinase must undergo in order to be activated at exactly the right place in the cell. "This information is crucial for developing a specific inhibitor that blocks only PI3KC2a, but no other related enzyme," stated Wen-Ting Lo, the first author of the study. The team around Volker Haucke and Wen-Ting Lo is already collaborating with other scientists at the institute to find specific inhibitors that occupy the ATP-binding pocket of the enzyme, preventing the enzymatic reaction. Kinase involved in the final step of cell division But this is not all that FMP researchers have found out about PI3KC2a. Together with Emilio Hirsch's research group at the University of Torino, the researchers have been able to demonstrate that the kinase is also involved in the final step of cell division, referred to as cytokinesis. Patients lacking the kinase due to mutations were the starting point of the study published in Science. Besides having various organ defects, these individuals suffer from a clouding of the lens, known as a cataract. Using experiments in mice and zebrafish, the research team was able to show how the loss of function of the enzyme leads to cataracts. The genetic material is duplicated and subsequently distributed to the two daughter cells during cell division. Membrane abscission eventually separates the daughter cells. In the absence of the kinase, however, this final cut fails to occur because a crucial lipid that can only be produced by PI3KC2a is missing. As a result, the lens epithelial cells suffer from impaired cytokinesis, which explains why these patients develop cataracts. The finding also has further implications: With the realization that the kinase is an essential component of cytokinesis, i.e. the separation of daughter cells—this mechanism could also be of great importance for tumors that rely on continuous cell division. Consequently, PI3KC2a inhibitors would potentially also open up new perspectives in cancer therapy. <|im_end|>

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23674, 11, 1057, 24693, 323, 16003, 93532, 828, 690, 19407, 28696, 279, 3938, 4500, 315, 34556, 630, 21090, 535, 23396, 18, 65738, 17, 19481, 68642, 449, 94612, 8522, 430, 2134, 505, 279, 6514, 315, 84664, 65, 10934, 220, 1591, 311, 29962, 30020, 220, 1691, 1174, 220, 1313, 1174, 20335, 220, 1682, 323, 9572, 220, 16, 1174, 220, 975, 662, 18591, 28993, 18112, 315, 23396, 18, 65738, 17, 19481, 9086, 1023, 3697, 315, 279, 23396, 18, 42, 3070, 220, 16, 1174, 220, 19, 1174, 23396, 18, 65738, 17, 19481, 5727, 264, 23396, 18, 42, 6332, 430, 17610, 315, 264, 59130, 65500, 8106, 320, 49, 9740, 8, 323, 459, 452, 91723, 356, 17, 8106, 11, 439, 1664, 439, 11591, 950, 323, 82160, 31576, 320, 42, 68050, 570, 763, 5369, 11, 23396, 18, 65738, 17, 19481, 69566, 1105, 279, 356, 91723, 2405, 5241, 2902, 316, 2508, 320, 74912, 8, 323, 356, 17, 31576, 430, 527, 5016, 311, 538, 8105, 56067, 320, 30035, 13, 220, 16, 64, 7609, 2057, 8417, 279, 1630, 30630, 26110, 6070, 315, 23396, 18, 65738, 17, 19481, 11, 584, 79120, 389, 459, 87975, 1920, 315, 9429, 23061, 323, 26329, 315, 5370, 7739, 315, 23396, 18, 65738, 17, 19481, 505, 2204, 9606, 39061, 555, 35784, 23365, 29051, 2411, 9473, 4235, 27428, 9618, 442, 15501, 320, 39, 17001, 4235, 4931, 8, 311, 10765, 834, 10767, 13918, 13, 362, 92600, 8814, 23396, 18, 65738, 17, 19481, 9429, 8649, 264, 312, 50725, 12616, 5419, 6471, 8668, 323, 32161, 279, 10805, 1354, 2740, 834, 10767, 452, 91723, 5654, 323, 279, 356, 91723, 356, 17, 8106, 320, 34, 7813, 17, 8, 320, 54290, 2956, 435, 14801, 13, 220, 16, 64, 8568, 323, 220, 17, 883, 574, 1511, 311, 6994, 279, 220, 18, 13, 18, 80352, 26110, 6070, 315, 23396, 18, 65738, 17, 19481, 82263, 45, 10, 101561, 34, 34363, 34, 17, 320, 2620, 220, 16, 7609, 23966, 13, 220, 16, 25, 28993, 6070, 315, 23396, 18, 65738, 17, 19481, 13, 264, 1174, 21749, 7471, 315, 23396, 18, 42, 82, 13, 107905, 11, 13253, 11212, 8106, 11, 356, 17, 11, 356, 17, 8106, 11, 12445, 11, 11591, 950, 8106, 11, 452, 16222, 35, 11, 356, 16222, 35, 11, 452, 12, 323, 356, 91723, 41253, 288, 315, 279, 82160, 6332, 8106, 13, 362, 32924, 33969, 220, 16, 4235, 10898, 315, 23396, 18, 65738, 17, 19481, 527, 19698, 311, 387, 834, 10767, 13, 473, 9740, 3230, 311, 128257, 198, 128256, 78191, 198, 3438, 24527, 266, 43686, 3817, 437, 27094, 220, 18, 12, 8148, 521, 11, 477, 23396, 18, 42, 369, 2875, 11, 374, 264, 3070, 315, 68700, 24890, 2315, 430, 11335, 264, 1401, 3560, 304, 279, 3823, 2547, 11, 16785, 5865, 1778, 439, 2849, 13096, 11, 39097, 11, 323, 2849, 6650, 13, 6104, 538, 358, 23396, 18, 42, 19481, 374, 1664, 5621, 1874, 291, 323, 459, 3062, 2218, 369, 9572, 11217, 11, 2697, 374, 3967, 922, 538, 8105, 315, 420, 68700, 82160, 3070, 13, 4800, 11, 12074, 505, 279, 2009, 581, 77, 450, 7424, 81085, 2234, 16319, 3781, 332, 7328, 386, 1286, 91295, 548, 25603, 587, 38469, 320, 37, 5901, 8, 617, 1027, 3025, 311, 25351, 3177, 389, 1202, 6070, 323, 734, 13, 578, 3135, 94123, 279, 1648, 369, 279, 4500, 315, 502, 4595, 315, 3276, 411, 442, 6465, 292, 11217, 13, 23674, 11, 433, 374, 4461, 430, 279, 61478, 315, 538, 8105, 23396, 18, 65738, 17, 19481, 374, 3025, 311, 8163, 36254, 92962, 52379, 13, 578, 4007, 706, 1457, 1027, 4756, 304, 22037, 73800, 612, 60825, 40023, 13, 362, 2132, 5684, 4756, 304, 10170, 5825, 2500, 3062, 3063, 13, 42239, 307, 24890, 2315, 527, 4315, 279, 26455, 11811, 315, 502, 6989, 315, 11217, 11, 4245, 14918, 311, 538, 358, 23396, 18, 42, 19481, 11, 902, 11335, 264, 16996, 3560, 304, 52788, 52379, 323, 68370, 10949, 13, 1115, 49242, 374, 17508, 3104, 304, 220, 966, 12, 1272, 4, 315, 682, 56071, 11, 6522, 311, 653, 59707, 2849, 6650, 13, 1789, 420, 2944, 11, 420, 1664, 5621, 1874, 291, 68700, 82160, 706, 3719, 264, 10461, 2218, 369, 279, 4500, 315, 88143, 11967, 11217, 369, 279, 3347, 1403, 11026, 13, 763, 13168, 11, 2697, 374, 3967, 922, 1202, 13219, 49242, 11, 538, 8105, 23396, 18, 42, 19481, 13, 1102, 374, 3463, 430, 420, 68700, 82160, 374, 39022, 5938, 449, 12387, 94612, 11618, 1778, 439, 12235, 1169, 52729, 477, 279, 18488, 315, 502, 6680, 31080, 11, 14183, 311, 439, 92962, 52379, 13, 4452, 11, 1603, 1202, 32403, 649, 387, 2731, 16365, 323, 17550, 555, 11217, 11, 433, 374, 7718, 311, 1440, 7041, 1148, 420, 82160, 5992, 1093, 323, 1268, 433, 5865, 13, 1115, 374, 24559, 1148, 12074, 505, 435, 5901, 617, 1457, 9152, 311, 11322, 13, 12362, 264, 10824, 315, 1630, 30630, 13128, 26110, 848, 1976, 88, 323, 16106, 78, 37081, 2298, 92914, 320, 62238, 78, 12, 2783, 705, 17054, 11119, 7197, 14433, 1983, 68, 596, 3495, 1912, 706, 26399, 304, 53583, 279, 6070, 315, 538, 8105, 23396, 18, 42, 19481, 320, 1932, 18, 65738, 17, 19481, 8, 323, 304, 23524, 279, 15449, 17383, 315, 279, 49242, 369, 279, 1176, 892, 13, 4314, 14955, 94123, 279, 1648, 369, 11622, 11775, 37471, 20414, 13, 763, 60073, 315, 82160, 5820, 1436, 1520, 12387, 6978, 330, 644, 60073, 315, 82160, 5820, 374, 3463, 311, 1514, 264, 3560, 304, 1690, 8522, 304, 6160, 25111, 55103, 11, 1778, 439, 36254, 6650, 323, 92962, 52379, 1359, 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1169, 11217, 13, 4220, 21896, 449, 4754, 5623, 11426, 617, 2736, 21091, 430, 61478, 315, 279, 82160, 374, 3284, 304, 17966, 13, 1252, 114348, 287, 279, 6070, 323, 15449, 17383, 574, 1401, 311, 420, 13, 32934, 3549, 369, 502, 11217, 578, 12074, 617, 304, 2144, 11352, 279, 6070, 315, 279, 11212, 18301, 315, 279, 82160, 430, 58585, 279, 68700, 323, 1008, 71970, 483, 2463, 764, 93473, 320, 835, 47, 8, 439, 279, 330, 5997, 1299, 11667, 1359, 28462, 279, 8481, 315, 264, 79106, 1912, 311, 279, 68700, 13, 578, 14248, 1457, 1101, 1440, 1148, 3169, 315, 330, 76, 43943, 70221, 39171, 1, 279, 82160, 2011, 37771, 304, 2015, 311, 387, 22756, 520, 7041, 279, 1314, 2035, 304, 279, 2849, 13, 330, 2028, 2038, 374, 16996, 369, 11469, 264, 3230, 70785, 430, 10215, 1193, 23396, 18, 65738, 17, 64, 11, 719, 912, 1023, 5552, 49242, 1359, 11224, 62323, 9469, 287, 6621, 11, 279, 1176, 3229, 315, 279, 4007, 13, 578, 2128, 2212, 11119, 7197, 14433, 1983, 68, 323, 62323, 9469, 287, 6621, 374, 2736, 73301, 449, 1023, 14248, 520, 279, 44798, 311, 1505, 3230, 68642, 430, 48678, 279, 67656, 65500, 18301, 315, 279, 49242, 11, 27252, 279, 32011, 780, 13010, 13, 31991, 521, 6532, 304, 279, 1620, 3094, 315, 2849, 13096, 2030, 420, 374, 539, 682, 430, 435, 5901, 12074, 617, 1766, 704, 922, 23396, 18, 65738, 17, 64, 13, 32255, 449, 5867, 34429, 473, 82965, 596, 3495, 1912, 520, 279, 3907, 315, 8611, 3394, 11, 279, 12074, 617, 1027, 3025, 311, 20461, 430, 279, 82160, 374, 1101, 6532, 304, 279, 1620, 3094, 315, 2849, 13096, 11, 14183, 311, 439, 83185, 83889, 13, 44430, 32161, 279, 82160, 4245, 311, 34684, 1051, 279, 6041, 1486, 315, 279, 4007, 4756, 304, 10170, 13, 31909, 3515, 5370, 2942, 42655, 11, 1521, 7931, 7831, 505, 264, 9624, 287, 315, 279, 18848, 11, 3967, 439, 264, 272, 6526, 533, 13, 12362, 21896, 304, 24548, 323, 1167, 3141, 15817, 819, 11, 279, 3495, 2128, 574, 3025, 311, 1501, 1268, 279, 4814, 315, 734, 315, 279, 49242, 11767, 311, 272, 6526, 11613, 13, 578, 19465, 3769, 374, 56003, 323, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract One of the notable features of penguin evolution is the occurrence of very large species in the early Cenozoic, whose body size greatly exceeded that of the largest extant penguins. Here we describe a new giant species from the late Paleocene of New Zealand that documents the very early evolution of large body size in penguins. Kumimanu biceae , n. gen. et sp. is larger than all other fossil penguins that have substantial skeletal portions preserved. Several plesiomorphic features place the new species outside a clade including all post-Paleocene giant penguins. It is phylogenetically separated from giant Eocene and Oligocene penguin species by various smaller taxa, which indicates multiple origins of giant size in penguin evolution. That a penguin rivaling the largest previously known species existed in the Paleocene suggests that gigantism in penguins arose shortly after these birds became flightless divers. Our study therefore strengthens previous suggestions that the absence of very large penguins today is likely due to the Oligo-Miocene radiation of marine mammals. Introduction New Zealand has yielded several fossils of Paleocene Sphenisciformes, which shed considerable light on the early evolution of penguins. All of the described specimens come from exposures of the Waipara Greensand in the Canterbury region and the two named species, Waimanu manneringi and W. tuatahi , are the oldest and phylogenetically most basal Sphenisciformes reported so far 1 , 2 , 3 . Recently, remains of a very large penguin have also been found in the Waipara Greensand 4 . These fossils, an incomplete tarsometatarsus and associated pedal phalanges, belong to an unnamed species that is phylogenetically closer to the crown group (the clade including the extant species) than Waimanu . A definitive taxonomic assignment of the fragmentary fossils is, however, not possible and this is also true for Crossvallia unienwillia , an equally large stem group penguin from the late Paleocene of Antarctica 5 , 6 . Gigantism, that is, the evolution of a size exceeding that of the extant Emperor Penguin ( Aptenodytes forsteri ), is much better documented in post-Paleocene penguins, and the Eocene Anthropornis nordenskjoeldi and Pachydyptes ponderosus were for a long time considered to be the largest known penguin species 7 , 8 . Pachydyptes ponderosus , from the late Eocene of New Zealand, is known only from a few wing and pectoral girdle bones 7 ; however, numerous isolated skeletal elements as well as a few partial skeletons have been reported for A. nordenskjoeldi , from the late Eocene and early Oligocene of Antarctica 9 , 10 . Recently, it was hypothesised that the well-preserved Kairuku grebneffi from the late Oligocene of New Zealand may have been taller, although less massive than P. ponderosus ; for the largest individual of K. grebneffi , a total body length of about 1.5 m was estimated 8 . Based on isolated limb bones, lengths of 1.6 and 1.5 m were also calculated for Anthropornis nordenskjoeldi and the very large Palaeeudyptes klekowskii from the Eocene and Oligocene of Antarctica 11 . While partial skeletons of P. klekowskii indicate a somewhat shorter body length of about 1.4 m 12 , 13 , a recently described humerus fragment and a tarsometatarsus may come from individuals with an estimated length of about 2.0 m 14 . A large size is reached by other Palaeeudyptes species from the Eocene and Oligocene of Antarctica and New Zealand 2 , 15 , 16 , and further, very large Sphenisciformes occurred in the late Eocene of Australia 17 and the late Eocene of Peru 18 , 19 . Some authors assumed that penguins achieved a giant size multiple times 6 , but the giant taxa Anthropornis , Palaeeudyptes , Kairuku , Icadyptes , and Inkayacu were recovered as parts of subsequently branching clades and it was therefore considered more likely that extremely large size evolved only once 18 . Definitive conclusions about size evolution in fossil Sphenisciformes are, however, impeded by the fact that even in more recent analyses the exact interrelationships between giant sphenisciform taxa are poorly resolved 8 , 19 , 20 . Here we report a partial skeleton of a giant stem penguin from the Paleocene Moeraki Formation at Hampden Beach in the Otago region of New Zealand, some 300 km southwest of the exposures of the Waipara Greensand in the Canterbury region. A few fragmentary bird remains from the Moeraki Formation were previously mentioned 21 and the age of the Moeraki Formation has been constrained to the late Paleocene based on foraminiferal biostratigraphy 22 , 23 . The new fossil is one of the oldest giant penguins found so far and is clearly outside a clade including the giant Eocene and Oligocene Sphenisciformes, substantiating multiple origins of gigantism in fossil penguins. Results Systematic paleontology. Aves Linnaeus, 1758 Sphenisciformes Sharpe, 1891 Kumimanu biceae , n. gen. et sp. Holotype . NMNZ S.45877: partial skeleton of a single individual including cranial end of left scapula, incomplete right coracoid, cranialmost portion of sternum, partial left humerus, incomplete proximal end of left ulna, right femur, right tibiotarsus lacking proximal end, partial synsacrum, three vertebrae, and various bone fragments. Etymology . From kumi (Maori), a large mythological monster, and manu (Maori), bird. The species epithet honors Beatrice (“Bice”) A. Tennyson, the mother of AJDT, who fostered his interest in natural history (pronounced “bee-chee-ae”). Type locality and horizon . Hampden Beach, Otago, New Zealand (NZ Fossil Record Number J42/f0956; precise locality information is recorded at NMNZ); Moeraki Formation, late Paleocene (late Teurian, local stratigraphic level NZP5 22 , which has an absolute age of 55.5.-59.5 million years 23 ; a matrix sample taken from the fossil (GNS Science sample L29126) contained a specimen of the dinoflagellate Palaeocystodinium australinum and an unnamed dinoflagellate taxon that support a Teurian age for this sample; C. Clowes, pers. comm.). Diagnosis . A very large-sized sphenisciform species, which is characterized by proximodistally low and widely spaced condyles of the tibiotarsus. Distinguished from the late Paleocene Crossvallia and all post-Paleocene Sphenisciformes of which humeri are", "role": "user" }, { "content": "Fossils from New Zealand have revealed a giant penguin that was as big as a grown man, roughly the size of the captain of the Pittsburgh Penguins. The creature was slightly shorter in length and about 20 pounds (9 kilograms) heavier than the official stats for hockey star Sidney Crosby. It measured nearly 5 feet, 10 inches (1.77 meters) long when swimming and weighed in at 223 pounds (101 kilograms). If the penguin and the Penguin faced off on the ice, however, things would look different. When standing, the ancient bird was maybe only 5-foot-3 (1.6 meters). The newly found bird is about 7 inches (18 centimeters) longer than any other ancient penguin that has left a substantial portion of a skeleton, said Gerald Mayr of the Senckenberg Research Institute and Natural History Museum in Frankfurt, Germany. A potentially bigger rival is known only from a fragment of leg bone, making a size estimate difficult. The biggest penguin today, the emperor in Antarctica, stands less than 4 feet (1.2 meters) tall. Mayr and others describe the giant creature in a paper released Tuesday by the journal Nature Communications. They named it Kumimanu biceae, which refers to Maori words for a large mythological monster and a bird, and the mother of one of the study's authors. The fossils are 56 million to 60 million years old. This illustration provided by Gerald Mayr shows the sizes of an ancient giant penguin Kumimanu biceae and a human being. On Tuesday, Dec. 12, 2017, researchers announced their find of fossils from approximately 60-55 million years ago, discovered in New Zealand, that put the creature at about 5 feet, 10 inches (1.77 meters) long when swimming, and 223 pounds (101 kilograms). (Gerald Mayr/Senckenberg Research Institute via AP) That's nearly as old as the very earliest known penguin fossils, which were much smaller, said Daniel Ksepka, curator at the Bruce Museum of Greenwich, Connecticut. He has studied New Zealand fossil penguins but didn't participate in the new study. The new discovery shows penguins \"got big very rapidly\" after the mass extinction of 66 million years ago that's best known for killing off the dinosaurs, he wrote in an email. That event played a big role in penguin history. Beforehand, a non-flying seabird would be threatened by big marine reptile predators, which also would compete with the birds for food. But once the extinction wiped out those reptiles, the ability to fly was not so crucial, opening the door for penguins to appear. The partly prepared skeleton of the Paleocene giant penguin Kumimanu biceae. The rectangles emphasize the humerus and a bone from the shoulder girdle (coracoid), which are shown separated from the original bone cluster Credit: G. Mayr/Senckenberg Research Institute Birds often evolve toward larger sizes after they lose the ability to fly, Mayr said. In fact, the new paper concludes that big size appeared more than once within the penguin family tree. What happened to the giants? Mayr said researchers believe they died out when large marine mammals like toothed whales and seals showed up and provided competition for safe breeding places and food. The newcomers may also have hunted the big penguins, he said. The humerus (top) and a bone from the shoulder girdle (coracoid, bottom) of the Paleocene giant penguin Kumimanu biceae, compared to the corresponding bones of one of the largest fossil penguins known to date (Pachydyptes ponderosus from the Eocene in New Zealand) and those of an Emperor Penguin (Aptendodytes forsteri). Credit: G. Mayr/Senckenberg Research Institute ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract One of the notable features of penguin evolution is the occurrence of very large species in the early Cenozoic, whose body size greatly exceeded that of the largest extant penguins. Here we describe a new giant species from the late Paleocene of New Zealand that documents the very early evolution of large body size in penguins. Kumimanu biceae , n. gen. et sp. is larger than all other fossil penguins that have substantial skeletal portions preserved. Several plesiomorphic features place the new species outside a clade including all post-Paleocene giant penguins. It is phylogenetically separated from giant Eocene and Oligocene penguin species by various smaller taxa, which indicates multiple origins of giant size in penguin evolution. That a penguin rivaling the largest previously known species existed in the Paleocene suggests that gigantism in penguins arose shortly after these birds became flightless divers. Our study therefore strengthens previous suggestions that the absence of very large penguins today is likely due to the Oligo-Miocene radiation of marine mammals. Introduction New Zealand has yielded several fossils of Paleocene Sphenisciformes, which shed considerable light on the early evolution of penguins. All of the described specimens come from exposures of the Waipara Greensand in the Canterbury region and the two named species, Waimanu manneringi and W. tuatahi , are the oldest and phylogenetically most basal Sphenisciformes reported so far 1 , 2 , 3 . Recently, remains of a very large penguin have also been found in the Waipara Greensand 4 . These fossils, an incomplete tarsometatarsus and associated pedal phalanges, belong to an unnamed species that is phylogenetically closer to the crown group (the clade including the extant species) than Waimanu . A definitive taxonomic assignment of the fragmentary fossils is, however, not possible and this is also true for Crossvallia unienwillia , an equally large stem group penguin from the late Paleocene of Antarctica 5 , 6 . Gigantism, that is, the evolution of a size exceeding that of the extant Emperor Penguin ( Aptenodytes forsteri ), is much better documented in post-Paleocene penguins, and the Eocene Anthropornis nordenskjoeldi and Pachydyptes ponderosus were for a long time considered to be the largest known penguin species 7 , 8 . Pachydyptes ponderosus , from the late Eocene of New Zealand, is known only from a few wing and pectoral girdle bones 7 ; however, numerous isolated skeletal elements as well as a few partial skeletons have been reported for A. nordenskjoeldi , from the late Eocene and early Oligocene of Antarctica 9 , 10 . Recently, it was hypothesised that the well-preserved Kairuku grebneffi from the late Oligocene of New Zealand may have been taller, although less massive than P. ponderosus ; for the largest individual of K. grebneffi , a total body length of about 1.5 m was estimated 8 . Based on isolated limb bones, lengths of 1.6 and 1.5 m were also calculated for Anthropornis nordenskjoeldi and the very large Palaeeudyptes klekowskii from the Eocene and Oligocene of Antarctica 11 . While partial skeletons of P. klekowskii indicate a somewhat shorter body length of about 1.4 m 12 , 13 , a recently described humerus fragment and a tarsometatarsus may come from individuals with an estimated length of about 2.0 m 14 . A large size is reached by other Palaeeudyptes species from the Eocene and Oligocene of Antarctica and New Zealand 2 , 15 , 16 , and further, very large Sphenisciformes occurred in the late Eocene of Australia 17 and the late Eocene of Peru 18 , 19 . Some authors assumed that penguins achieved a giant size multiple times 6 , but the giant taxa Anthropornis , Palaeeudyptes , Kairuku , Icadyptes , and Inkayacu were recovered as parts of subsequently branching clades and it was therefore considered more likely that extremely large size evolved only once 18 . Definitive conclusions about size evolution in fossil Sphenisciformes are, however, impeded by the fact that even in more recent analyses the exact interrelationships between giant sphenisciform taxa are poorly resolved 8 , 19 , 20 . Here we report a partial skeleton of a giant stem penguin from the Paleocene Moeraki Formation at Hampden Beach in the Otago region of New Zealand, some 300 km southwest of the exposures of the Waipara Greensand in the Canterbury region. A few fragmentary bird remains from the Moeraki Formation were previously mentioned 21 and the age of the Moeraki Formation has been constrained to the late Paleocene based on foraminiferal biostratigraphy 22 , 23 . The new fossil is one of the oldest giant penguins found so far and is clearly outside a clade including the giant Eocene and Oligocene Sphenisciformes, substantiating multiple origins of gigantism in fossil penguins. Results Systematic paleontology. Aves Linnaeus, 1758 Sphenisciformes Sharpe, 1891 Kumimanu biceae , n. gen. et sp. Holotype . NMNZ S.45877: partial skeleton of a single individual including cranial end of left scapula, incomplete right coracoid, cranialmost portion of sternum, partial left humerus, incomplete proximal end of left ulna, right femur, right tibiotarsus lacking proximal end, partial synsacrum, three vertebrae, and various bone fragments. Etymology . From kumi (Maori), a large mythological monster, and manu (Maori), bird. The species epithet honors Beatrice (“Bice”) A. Tennyson, the mother of AJDT, who fostered his interest in natural history (pronounced “bee-chee-ae”). Type locality and horizon . Hampden Beach, Otago, New Zealand (NZ Fossil Record Number J42/f0956; precise locality information is recorded at NMNZ); Moeraki Formation, late Paleocene (late Teurian, local stratigraphic level NZP5 22 , which has an absolute age of 55.5.-59.5 million years 23 ; a matrix sample taken from the fossil (GNS Science sample L29126) contained a specimen of the dinoflagellate Palaeocystodinium australinum and an unnamed dinoflagellate taxon that support a Teurian age for this sample; C. Clowes, pers. comm.). Diagnosis . A very large-sized sphenisciform species, which is characterized by proximodistally low and widely spaced condyles of the tibiotarsus. Distinguished from the late Paleocene Crossvallia and all post-Paleocene Sphenisciformes of which humeri are<|im_end|> <|im_start|>assistant Fossils from New Zealand have revealed a giant penguin that was as big as a grown man, roughly the size of the captain of the Pittsburgh Penguins. The creature was slightly shorter in length and about 20 pounds (9 kilograms) heavier than the official stats for hockey star Sidney Crosby. It measured nearly 5 feet, 10 inches (1.77 meters) long when swimming and weighed in at 223 pounds (101 kilograms). If the penguin and the Penguin faced off on the ice, however, things would look different. When standing, the ancient bird was maybe only 5-foot-3 (1.6 meters). The newly found bird is about 7 inches (18 centimeters) longer than any other ancient penguin that has left a substantial portion of a skeleton, said Gerald Mayr of the Senckenberg Research Institute and Natural History Museum in Frankfurt, Germany. A potentially bigger rival is known only from a fragment of leg bone, making a size estimate difficult. The biggest penguin today, the emperor in Antarctica, stands less than 4 feet (1.2 meters) tall. Mayr and others describe the giant creature in a paper released Tuesday by the journal Nature Communications. They named it Kumimanu biceae, which refers to Maori words for a large mythological monster and a bird, and the mother of one of the study's authors. The fossils are 56 million to 60 million years old. This illustration provided by Gerald Mayr shows the sizes of an ancient giant penguin Kumimanu biceae and a human being. On Tuesday, Dec. 12, 2017, researchers announced their find of fossils from approximately 60-55 million years ago, discovered in New Zealand, that put the creature at about 5 feet, 10 inches (1.77 meters) long when swimming, and 223 pounds (101 kilograms). (Gerald Mayr/Senckenberg Research Institute via AP) That's nearly as old as the very earliest known penguin fossils, which were much smaller, said Daniel Ksepka, curator at the Bruce Museum of Greenwich, Connecticut. He has studied New Zealand fossil penguins but didn't participate in the new study. The new discovery shows penguins "got big very rapidly" after the mass extinction of 66 million years ago that's best known for killing off the dinosaurs, he wrote in an email. That event played a big role in penguin history. Beforehand, a non-flying seabird would be threatened by big marine reptile predators, which also would compete with the birds for food. But once the extinction wiped out those reptiles, the ability to fly was not so crucial, opening the door for penguins to appear. The partly prepared skeleton of the Paleocene giant penguin Kumimanu biceae. The rectangles emphasize the humerus and a bone from the shoulder girdle (coracoid), which are shown separated from the original bone cluster Credit: G. Mayr/Senckenberg Research Institute Birds often evolve toward larger sizes after they lose the ability to fly, Mayr said. In fact, the new paper concludes that big size appeared more than once within the penguin family tree. What happened to the giants? Mayr said researchers believe they died out when large marine mammals like toothed whales and seals showed up and provided competition for safe breeding places and food. The newcomers may also have hunted the big penguins, he said. The humerus (top) and a bone from the shoulder girdle (coracoid, bottom) of the Paleocene giant penguin Kumimanu biceae, compared to the corresponding bones of one of the largest fossil penguins known to date (Pachydyptes ponderosus from the Eocene in New Zealand) and those of an Emperor Penguin (Aptendodytes forsteri). Credit: G. Mayr/Senckenberg Research Institute <|im_end|>

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2,380

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Taking risks is part of everyday life. Some people actively pursue risky activities (e.g., jumping out of a plane), while others avoid any risk (e.g., people with anxiety disorders). Paradoxically, risk-taking is a primitive behaviour that may lead to a happier life by offering a sense of excitement through self-actualization. Here, we demonstrate for the first time that sour - amongst the five basic tastes (sweet, bitter, sour, salty, and umami) - promotes risk-taking. Based on a series of three experiments, we show that sour has the potential to modulate risk-taking behaviour across two countries (UK and Vietnam), across individual differences in risk-taking personality and styles of thinking (analytic versus intuitive). Modulating risk-taking can improve everyday life for a wide range of people. Introduction From the earliest days of human history, people have made risky decisions to ensure survival 1 . We know that some humans are more likely to take risks than others 2 , 3 , 4 and standardized measures accounting for individual differences in sensation seeking 5 and risk-taking 6 have been established. In a similar vein, taste is a dedicated warning system that helps people to make important decisions under risk (ingesting or rejecting a given food) 7 , 8 , 9 , 10 . Given the parallel between human decision making under risk and the unique properties of the gustatory system 11 , an interaction between risk-taking and the sense of taste can be expected. Recent studies, indeed, demonstrated and validated a correlation between risk-taking personalities and spicy food 12 , 13 . However, there is no prior knowledge of the relations between the basic tastes and humans risk-taking behaviour. Here we establish for the first time the sour taste as the unique taste quality promoting risk-taking. Related works 14 , 15 , 16 , 17 , 18 , 19 suggest that taste has an effect on cognitive processes and decision-making. In particular, Obrist et al . 14 identified different temporal characteristics for the five basic tastes and discussed those differences based on the dual-process theory 20 , 21 , 22 that accounts for two styles of thinking. The first is the intuition-based System 1 with its associative reasoning that is fast and automatic with strong emotional bonds. The second is the reasoning-based System 2 which is slower and more volatile, being influenced by conscious judgements and attitudes. This prior work suggests that, for instance, based on the explosive but short-lived sensation of a sour taste, people would be left wondering, hence become more rational in their decision-making and act slower. In contrast, the residual characteristic of sweetness coupled with its typically perceived pleasantness (affordance of ingestion) was suggested to stimulate a more intuitive decision-making behaviour and faster actions. Similar to sweet, this prior work suggested that bitter had a tendency to facilitate faster decision-making due to its clear signal of an unpleasant taste (affordance of rejection). However, there were no clear findings suggested for the salty and umami tastes. In this work, we aim not only to investigate the relationship between the five basics tastes (sweet, sour, bitter, salty, and umami) and human risk-taking behaviour, but also to analyse the temporal differences in their behaviour depending on the taste administered, which has never been reported before, but is motivated by the above cited work 14 . We conducted three between-participants experiments comparing the five taste groups (plus a neutral stimulus) across two countries, UK and Vietnam, accounting for cultural differences in taste perception, in particular of the consumption of MSG, a food additive to create the umami taste 9 , 23 , 24 . We used the standardized Balloon Analogue Risk-Taking (BART) task 25 , a computerized gambling task, in our investigation. Each participant ingested only one basic taste and a neutral (water) stimulus in a randomized order across the two blocks of the BART task. Then, participants were asked to pump-up a balloon on a computer screen by clicking the mouse button with the potential either for an accumulated monetary reward or for losing it. After each pump-up action (left mouse click), the balloon increases its size or explodes depending on a randomized algorithm. To win the monetary reward, participants must decide when to stop pumping up the balloon and click ‘cash out’ before the balloon explodes. If the balloon explodes, participants lose all the accumulated money in that trial. (see details in Materials and Methods). Based on the previously established analytic approach for the BART task 25 , risk-taking behaviour is best measured via the average value of the number of pumps for unexploded balloons (referred to as the ‘adjusted number of pumps’) which has been shown to provide the highest correlation for assessing the risk-taking behaviour. A higher adjusted number of pumps is indicative of greater risk-taking propensity 25 . In addition, we excluded trials with ‘contaminated’ balloons, i.e., balloons used in the neutral stimuli group of the second block of the BART task (see analysis in SI). Thus, we used the total amount of unexploded and uncontaminated balloons as main indicator to determine participants’ risk-taking behaviour. Furthermore, to investigate the specific temporal patterns underlying the decision-making under risk, we analysed the clicking behaviour in the BART task (the time elapsed between pump actions, i.e. the ‘inter-click time’). We used this information as an indication of the participant’s hesitation level when pumping up the balloons (i.e., decide quickly or slowly). We extended this temporal analysis by accounting for both the exploded and unexploded balloons separately, motivated by prior work showing that neural activations when performing the BART task differ between pump-up actions before cashing out or deciding to pump-up more, suggesting that analysing both exploded and unexploded balloons could predict safe or risky choices 26 . In all three experiments carried out in the UK and Vietnam, we controlled for the distribution of high and low risk-taker personalities in the taste groups by using two standardized questionnaires (Sensation Seeking Scale - SSS 27 and Barratt Impulsiveness Scale - BIS 6", "role": "user" }, { "content": "Anyone needing a little excitement in their lives could do worse than suck a lemon, surprising new research at the University of Sussex suggests. Scientists at the Sussex Computer Human Interaction (SCHI) Lab say they have found for the first time empirical evidence that sour tastes lead to more risk-taking behaviour in a paper published in Scientific Reports today (7 June). The researchers recommend that risk-averse people, such as those suffering from anxiety disorders or depression, could benefit from sour-enriched diets to boost risk-taking behaviour such as leaving the house or talking to a stranger. They also recommend that people in professions where risk-taking could have serious repercussions, such as airline pilots, may benefit from reducing the amount of sour they have in their daily diet. Dr Chi Thanh Vi, Research Fellow in Multisensory Experiences at the University of Sussex's Department of Informatics, said: \"Risk-taking can mean different things for different people; for some that is jumping out of a plane at 30,000 feet but for others it can be simply leaving the house. But while it may have negative connotations for some, risk taking is actually one of the primary behaviours that leads to a happier life.\" Dr Marianna Obrist, Reader in Interaction Design at the University of Sussex's Department of Informatics, added: \"Our research indicates that sour does not provoke people to indulge in reckless risky habits, but does have unique attributes to modulate risk-taking and may encourage risk-averse people to take new opportunities. \"This is supported by previous work which indicated that people suffering psychiatric disorders such as depression, anxiety, or stress-related disorders could benefit from the use of lemon oils which also had stress-reducing qualities.\" The study involved 168 participants from the UK and Vietnam who were given a 20ml solution representing one of the five main taste groups (bitter, salty, sour sweet and umami) and a neutral control of mineral water. PhD Student Giada Brianza and designer Tu-Anh Nguyen of the SCHI Lab at the University of Sussex. Credit: University of Sussex They were then asked to take part in the standardized Balloon Analogue Risk-Taking (BART) - a measure of risk taking behaviour where participants take part in a computer simulation to fill up a balloon with air. The more air in the balloon the more money the participants win until the balloon pops and they lose everything. Participants have the option to cash out at any time as each click sees the balloon increase in size along with the prize or it explodes, dependent on a randomized algorithm. On average, participants who drank citric acid pumped the balloons at a significantly higher frequency than with any other taste; more than 39% more than sweet (sucrose), 20.50% more than bitter (caffeine), 16.03% more than salty (sodium chloride), and 40.29% more than umami (monosodium glutamate or MSG). The study also found that sour promotes risk-taking behaviour regardless of an individual's own level of risk-taking and style of thinking with the sour effect effective for both intuitive and analytical thinkers. The researchers say their experiments indicate the risk-taking influence can last for at least 20 minutes but believe that it could last considerably longer depending on the amount of concentration of sour consumed. Dr Vi said: \"We don't know exactly what happens within the brain that controls this type of behaviour and it is something we would now like to pursue further. \"We know what happens in the brain when people have a certain taste and we know what happens when someone decides a certain course of action but what is missing is tracking the neural pathway to show how taste can affect that decision-making process. \"It could be that by taking that first bite of something sour we are already exhibiting some risk-taking behaviour to eat fruit which might not be quite right.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Taking risks is part of everyday life. Some people actively pursue risky activities (e.g., jumping out of a plane), while others avoid any risk (e.g., people with anxiety disorders). Paradoxically, risk-taking is a primitive behaviour that may lead to a happier life by offering a sense of excitement through self-actualization. Here, we demonstrate for the first time that sour - amongst the five basic tastes (sweet, bitter, sour, salty, and umami) - promotes risk-taking. Based on a series of three experiments, we show that sour has the potential to modulate risk-taking behaviour across two countries (UK and Vietnam), across individual differences in risk-taking personality and styles of thinking (analytic versus intuitive). Modulating risk-taking can improve everyday life for a wide range of people. Introduction From the earliest days of human history, people have made risky decisions to ensure survival 1 . We know that some humans are more likely to take risks than others 2 , 3 , 4 and standardized measures accounting for individual differences in sensation seeking 5 and risk-taking 6 have been established. In a similar vein, taste is a dedicated warning system that helps people to make important decisions under risk (ingesting or rejecting a given food) 7 , 8 , 9 , 10 . Given the parallel between human decision making under risk and the unique properties of the gustatory system 11 , an interaction between risk-taking and the sense of taste can be expected. Recent studies, indeed, demonstrated and validated a correlation between risk-taking personalities and spicy food 12 , 13 . However, there is no prior knowledge of the relations between the basic tastes and humans risk-taking behaviour. Here we establish for the first time the sour taste as the unique taste quality promoting risk-taking. Related works 14 , 15 , 16 , 17 , 18 , 19 suggest that taste has an effect on cognitive processes and decision-making. In particular, Obrist et al . 14 identified different temporal characteristics for the five basic tastes and discussed those differences based on the dual-process theory 20 , 21 , 22 that accounts for two styles of thinking. The first is the intuition-based System 1 with its associative reasoning that is fast and automatic with strong emotional bonds. The second is the reasoning-based System 2 which is slower and more volatile, being influenced by conscious judgements and attitudes. This prior work suggests that, for instance, based on the explosive but short-lived sensation of a sour taste, people would be left wondering, hence become more rational in their decision-making and act slower. In contrast, the residual characteristic of sweetness coupled with its typically perceived pleasantness (affordance of ingestion) was suggested to stimulate a more intuitive decision-making behaviour and faster actions. Similar to sweet, this prior work suggested that bitter had a tendency to facilitate faster decision-making due to its clear signal of an unpleasant taste (affordance of rejection). However, there were no clear findings suggested for the salty and umami tastes. In this work, we aim not only to investigate the relationship between the five basics tastes (sweet, sour, bitter, salty, and umami) and human risk-taking behaviour, but also to analyse the temporal differences in their behaviour depending on the taste administered, which has never been reported before, but is motivated by the above cited work 14 . We conducted three between-participants experiments comparing the five taste groups (plus a neutral stimulus) across two countries, UK and Vietnam, accounting for cultural differences in taste perception, in particular of the consumption of MSG, a food additive to create the umami taste 9 , 23 , 24 . We used the standardized Balloon Analogue Risk-Taking (BART) task 25 , a computerized gambling task, in our investigation. Each participant ingested only one basic taste and a neutral (water) stimulus in a randomized order across the two blocks of the BART task. Then, participants were asked to pump-up a balloon on a computer screen by clicking the mouse button with the potential either for an accumulated monetary reward or for losing it. After each pump-up action (left mouse click), the balloon increases its size or explodes depending on a randomized algorithm. To win the monetary reward, participants must decide when to stop pumping up the balloon and click ‘cash out’ before the balloon explodes. If the balloon explodes, participants lose all the accumulated money in that trial. (see details in Materials and Methods). Based on the previously established analytic approach for the BART task 25 , risk-taking behaviour is best measured via the average value of the number of pumps for unexploded balloons (referred to as the ‘adjusted number of pumps’) which has been shown to provide the highest correlation for assessing the risk-taking behaviour. A higher adjusted number of pumps is indicative of greater risk-taking propensity 25 . In addition, we excluded trials with ‘contaminated’ balloons, i.e., balloons used in the neutral stimuli group of the second block of the BART task (see analysis in SI). Thus, we used the total amount of unexploded and uncontaminated balloons as main indicator to determine participants’ risk-taking behaviour. Furthermore, to investigate the specific temporal patterns underlying the decision-making under risk, we analysed the clicking behaviour in the BART task (the time elapsed between pump actions, i.e. the ‘inter-click time’). We used this information as an indication of the participant’s hesitation level when pumping up the balloons (i.e., decide quickly or slowly). We extended this temporal analysis by accounting for both the exploded and unexploded balloons separately, motivated by prior work showing that neural activations when performing the BART task differ between pump-up actions before cashing out or deciding to pump-up more, suggesting that analysing both exploded and unexploded balloons could predict safe or risky choices 26 . In all three experiments carried out in the UK and Vietnam, we controlled for the distribution of high and low risk-taker personalities in the taste groups by using two standardized questionnaires (Sensation Seeking Scale - SSS 27 and Barratt Impulsiveness Scale - BIS 6<|im_end|> <|im_start|>assistant Anyone needing a little excitement in their lives could do worse than suck a lemon, surprising new research at the University of Sussex suggests. Scientists at the Sussex Computer Human Interaction (SCHI) Lab say they have found for the first time empirical evidence that sour tastes lead to more risk-taking behaviour in a paper published in Scientific Reports today (7 June). The researchers recommend that risk-averse people, such as those suffering from anxiety disorders or depression, could benefit from sour-enriched diets to boost risk-taking behaviour such as leaving the house or talking to a stranger. They also recommend that people in professions where risk-taking could have serious repercussions, such as airline pilots, may benefit from reducing the amount of sour they have in their daily diet. Dr Chi Thanh Vi, Research Fellow in Multisensory Experiences at the University of Sussex's Department of Informatics, said: "Risk-taking can mean different things for different people; for some that is jumping out of a plane at 30,000 feet but for others it can be simply leaving the house. But while it may have negative connotations for some, risk taking is actually one of the primary behaviours that leads to a happier life." Dr Marianna Obrist, Reader in Interaction Design at the University of Sussex's Department of Informatics, added: "Our research indicates that sour does not provoke people to indulge in reckless risky habits, but does have unique attributes to modulate risk-taking and may encourage risk-averse people to take new opportunities. "This is supported by previous work which indicated that people suffering psychiatric disorders such as depression, anxiety, or stress-related disorders could benefit from the use of lemon oils which also had stress-reducing qualities." The study involved 168 participants from the UK and Vietnam who were given a 20ml solution representing one of the five main taste groups (bitter, salty, sour sweet and umami) and a neutral control of mineral water. PhD Student Giada Brianza and designer Tu-Anh Nguyen of the SCHI Lab at the University of Sussex. Credit: University of Sussex They were then asked to take part in the standardized Balloon Analogue Risk-Taking (BART) - a measure of risk taking behaviour where participants take part in a computer simulation to fill up a balloon with air. The more air in the balloon the more money the participants win until the balloon pops and they lose everything. Participants have the option to cash out at any time as each click sees the balloon increase in size along with the prize or it explodes, dependent on a randomized algorithm. On average, participants who drank citric acid pumped the balloons at a significantly higher frequency than with any other taste; more than 39% more than sweet (sucrose), 20.50% more than bitter (caffeine), 16.03% more than salty (sodium chloride), and 40.29% more than umami (monosodium glutamate or MSG). The study also found that sour promotes risk-taking behaviour regardless of an individual's own level of risk-taking and style of thinking with the sour effect effective for both intuitive and analytical thinkers. The researchers say their experiments indicate the risk-taking influence can last for at least 20 minutes but believe that it could last considerably longer depending on the amount of concentration of sour consumed. Dr Vi said: "We don't know exactly what happens within the brain that controls this type of behaviour and it is something we would now like to pursue further. "We know what happens in the brain when people have a certain taste and we know what happens when someone decides a certain course of action but what is missing is tracking the neural pathway to show how taste can affect that decision-making process. "It could be that by taking that first bite of something sour we are already exhibiting some risk-taking behaviour to eat fruit which might not be quite right." <|im_end|>

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5352, 1957, 320, 2414, 8814, 4299, 705, 279, 47856, 12992, 1202, 1404, 477, 95013, 11911, 389, 264, 47341, 12384, 13, 2057, 3243, 279, 33384, 11565, 11, 13324, 2011, 10491, 994, 311, 3009, 53226, 709, 279, 47856, 323, 4299, 3451, 42371, 704, 529, 1603, 279, 47856, 95013, 13, 1442, 279, 47856, 95013, 11, 13324, 9229, 682, 279, 41165, 3300, 304, 430, 9269, 13, 320, 4151, 3649, 304, 32009, 323, 19331, 570, 20817, 389, 279, 8767, 9749, 79136, 5603, 369, 279, 426, 3065, 3465, 220, 914, 1174, 5326, 80671, 17432, 374, 1888, 17303, 4669, 279, 5578, 907, 315, 279, 1396, 315, 43875, 369, 653, 30992, 6879, 70580, 320, 265, 5671, 311, 439, 279, 3451, 88897, 1396, 315, 43875, 96206, 902, 706, 1027, 6982, 311, 3493, 279, 8592, 26670, 369, 47614, 279, 5326, 80671, 17432, 13, 362, 5190, 24257, 1396, 315, 43875, 374, 64005, 315, 7191, 5326, 80671, 95323, 220, 914, 662, 763, 5369, 11, 584, 28544, 19622, 449, 3451, 778, 8778, 660, 529, 70580, 11, 602, 1770, 2637, 70580, 1511, 304, 279, 21277, 56688, 1912, 315, 279, 2132, 2565, 315, 279, 426, 3065, 3465, 320, 4151, 6492, 304, 31648, 570, 14636, 11, 584, 1511, 279, 2860, 3392, 315, 653, 30992, 6879, 323, 71093, 8778, 660, 70580, 439, 1925, 21070, 311, 8417, 13324, 529, 5326, 80671, 17432, 13, 24296, 11, 311, 19874, 279, 3230, 37015, 12912, 16940, 279, 5597, 28846, 1234, 5326, 11, 584, 67458, 279, 18965, 17432, 304, 279, 426, 3065, 3465, 320, 1820, 892, 26401, 1990, 14155, 6299, 11, 602, 1770, 13, 279, 3451, 2295, 29218, 892, 529, 570, 1226, 1511, 420, 2038, 439, 459, 28137, 315, 279, 25923, 753, 65437, 2237, 994, 53226, 709, 279, 70580, 320, 72, 1770, 2637, 10491, 6288, 477, 14297, 570, 1226, 11838, 420, 37015, 6492, 555, 24043, 369, 2225, 279, 44913, 323, 653, 30992, 6879, 70580, 26214, 11, 27762, 555, 4972, 990, 9204, 430, 30828, 93595, 994, 16785, 279, 426, 3065, 3465, 1782, 1990, 14155, 5352, 6299, 1603, 8515, 287, 704, 477, 30230, 311, 14155, 5352, 810, 11, 23377, 430, 22209, 287, 2225, 44913, 323, 653, 30992, 6879, 70580, 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80671, 17432, 1778, 439, 9564, 279, 3838, 477, 7556, 311, 264, 35058, 13, 2435, 1101, 7079, 430, 1274, 304, 69792, 1405, 5326, 80671, 1436, 617, 6129, 81909, 11, 1778, 439, 33575, 36377, 11, 1253, 8935, 505, 18189, 279, 3392, 315, 20897, 814, 617, 304, 872, 7446, 10173, 13, 2999, 34382, 109259, 11655, 11, 8483, 37946, 304, 22950, 285, 729, 683, 1398, 69597, 520, 279, 3907, 315, 70608, 596, 6011, 315, 31701, 29470, 11, 1071, 25, 330, 86407, 80671, 649, 3152, 2204, 2574, 369, 2204, 1274, 26, 369, 1063, 430, 374, 30102, 704, 315, 264, 11277, 520, 220, 966, 11, 931, 7693, 719, 369, 3885, 433, 649, 387, 5042, 9564, 279, 3838, 13, 2030, 1418, 433, 1253, 617, 8389, 390, 14632, 369, 1063, 11, 5326, 4737, 374, 3604, 832, 315, 279, 6156, 71177, 430, 11767, 311, 264, 44467, 2324, 1210, 2999, 29829, 12930, 113098, 380, 11, 26226, 304, 43807, 7127, 520, 279, 3907, 315, 70608, 596, 6011, 315, 31701, 29470, 11, 3779, 25, 330, 8140, 3495, 15151, 430, 20897, 1587, 539, 73093, 1274, 311, 68190, 304, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Avoidance of noxious ambient heat is crucial for survival. A well-known phenomenon is that animals are sensitive to the rate of temperature change. However, the cellular and molecular underpinnings through which animals sense and respond much more vigorously to fast temperature changes are unknown. Using Drosophila larvae, we found that nociceptive rolling behavior was triggered at lower temperatures and at higher frequencies when the temperature increased rapidly. We identified neurons in the brain that were sensitive to the speed of the temperature increase rather than just to the absolute temperature. These cellular and behavioral responses depended on the TRPA1 channel, whose activity responded to the rate of temperature increase. We propose that larvae use low-threshold sensors in the brain to monitor rapid temperature increases as a protective alert signal to trigger rolling behaviors, allowing fast escape before the temperature of the brain rises to dangerous levels. Main An important class of molecules that contributes to thermosensation is transient receptor potential channels (thermoTRPs) 1 , 2 , 3 . ThermoTRPs 2 are activated directly or indirectly by changes in temperature and enable animals to respond behaviorally to temperature fluctuations in the environment 1 , 4 . The founding thermoTRP, mouse TRPV1, is activated by temperatures higher than 42 °C and is required for avoidance of noxious heat 5 , 6 . Other mammalian thermoTRPs are activated with different thresholds, such as mouse TRPM8 and TRPA1, which are activated directly by low temperatures below ∼ 23 °C and ∼ 17 °C, respectively 7 , 8 , 9 , 10 . The contribution of TRPs to thermosensation is evolutionarily conserved and is well-documented in the invertebrate model organisms Caenorhabditis elegans and Drosophila melanogaster 4 , 11 . In Drosophila larvae, noxious heat is detected through direct activation of three TRPA (transient receptor potential A) channels: Painless, Pyrexia and TRPA1 (refs. 12 , 13 , 14 , 15 ). The TRPA1 channel also enables larvae to sense exquisitely small deviations above the preferred temperature 16 . In the comfortable range, this fine thermal detection occurs through indirect activation of TRPA1 via a rhodopsin-dependent thermosensory signaling cascade 17 . This signaling cascade may serve to lower the threshold for direct activation of TRPA1. The extensive studies on thermoTRPs in model organisms have contributed greatly to the theory that warm or hot temperatures of different thresholds are sensed by direct activation of TRP channels. However, a long-known but poorly understood aspect of thermosensation is that the rate of temperature change, rather than just the temperature threshold, can affect the nociceptive response. Classic experiments on frogs performed more than 130 years ago demonstrate their highly sensitive escape response to fast rises in heat and indifference to slow increases in temperature 18 . Stronger nociceptive reactions to fast temperature rises have been documented throughout the animal kingdom, in organisms as diverse as worms and humans 19 , 20 . However, the mechanism underlying temperature rate detection is not clear. To explore the mechanism through which an animal responds differentially to slow and fast elevations in temperature, we developed Drosophila larvae as an animal model. We found that if we subjected larvae to a rapid temperature rise, a very high proportion of the animals exhibited nociceptive rolling behavior. However, if the temperature increase was gradual, the percentage of larvae that rolled was much lower, even after we exceeded temperatures that induced robust nociceptive avoidance after a fast temperature increase. We found that one of the TRPA1 isoforms was the key rate-sensor and that it was required in neurons in the brain that responded to the rate of temperature increase rather than just the temperature threshold. Our results indicate that larvae use a TRPA1-dependent rate-sensing mechanism to safeguard the brain from exposure to noxious heat. Results Dependence of the nociceptive rolling response on the rate of temperature increase To characterize the behavior of larvae in response to different rates of temperature change, we built an apparatus that allowed us to accurately control the heating speed while monitoring larval movement. The temperature control system was comprised of a Peltier pad and a programmable integrated circuit responsible for voltage regulation. We used this apparatus to heat and cool an agarose surface for larval navigation. A video camera recorded the larvae's behavior, and a computer program, MAGAT Analyzer 21 , recognized the larvae in each frame. To automatically and objectively analyze the large volume of data, we wrote an algorithm that employed several parameters to discern rolling from nonrolling larvae. These included the speed of the larvae, their direction of movement perpendicular to the body, acceleration and acceleration perpendicular to the body. We used a machine-learning 22 , 23 approach to successively improve the ability of the computer to accurately identify rolling larvae with minimal noise. We exposed wild-type second-instar larvae to temperature ramps with different slopes and determined how rolling was dependent on the rate of temperature change (d T /d t ). In each experiment, we initially maintained the temperature at ∼ 23.5 °C for 30 s and then increased the temperature to 40 °C. Larvae rolled when the temperature increased quickly (0.3 °C per s; Supplementary Video 1 ). As the temperature approached 40 °C, the larvae stopped moving and the rolling behavior ceased ( Fig. 1a ). However, the animals still responded to a mechanical stimulus ( Supplementary Video 2 ). Figure 1: Rolling responses of wild-type larvae exposed to different rates of temperature increase. ( a – i ) The fraction of control ( w 1118 ) second-instar larvae that rolled ( F rolling ) as a function of d T /d t (indicated above each plot). Scale bars indicate the time (in s) required for the temperature to rise by 5 °C. F rolling was defined as N rolling / N total , where N rolling was the number of larvae rolling and N total was the total number of larvae. The curves (thicker lines) were fit using a sigmoid function. Total number of larvae per", "role": "user" }, { "content": "In classic experiments on frogs, scientists found that the amphibians' urge to escape from dangerously hot water decreased significantly when the water temperature rose very gradually. In fact, sensitivity of many animals to temperature—including humans—is similarly affected by the rate of increase. Exactly why, however, has not been understood. Hoping to shed light on this phenomenon, UC Santa Barbara professor Craig Montell and graduate students Junjie Luo and Wei Shen developed fruit fly larvae as a model to reveal a mechanism through which the animal shows different behavioral responses to fast and slow rises in temperature. The researchers discovered that a rapid 25-degree Fahrenheit temperature change caused a writhing response in fruit fly larvae. However, when the temperature was raised gradually, far fewer animals reacted, and for those that did, the average threshold temperature was significantly higher. The team's findings appear in the journal Nature Neuroscience. \"We know a lot about how animals sense large and sudden increases in temperature,\" said Montell, the Patricia and Robert Duggan Professor of Neuroscience in UCSB's Department of Molecular, Cellular, and Developmental Biology. \"They respond to noxious heat by initiating an escape response. But how is it that animals are so much less sensitive to the same hot temperature when the change is really slow?\" The answer to that question turned out to have two parts. First, Montell and his team identified the thermosensory neurons in the brain responsible for sensing the rate of temperature change, which helped to define the underlying molecular mechanism. Craig Montell and Junjie Luo. Credit: Sonia Fernandez \"When there is a really rapid change in temperature, you want to protect the brain, particularly in fly larvae because they're cold-blooded and their body temperature equilibrates to the outside,\" explained Montell. \"If their brains feel a rapid increase in temperature, that stimulates the writhing response.\" Second, the researchers discovered that the fast response to rapidly increasing heat depended on a transient receptor potential (TRP) channel. The activation of the cellular temperature sensor, a protein called TRPA1, was not simply a function of the absolute temperature but rather depended on the rate of temperature change. If the temperature increase was rapid, TRPA1 turned on quickly and excited those thermosensory brain neurons. When the temperature increased slowly, TRPA1 was less active. \"There's a feedback mechanism that turns off this protein as quickly as it's turned on,\" Montell said. \"When it's turned on quickly, it stimulates the pathway to cause the writhing response. But when the process occurs slowly, the on and off mechanisms cancel each other out.\" The scientists posit that the ability to sense the rate of temperature change is a critical survival mechanism that allows an animal to quickly respond to and escape from a noxious thermal landscape before it is too late. \"We think similar mechanisms occur in other animals—for example, the frog,\" Montell said. \"It could be that related mechanisms affect temperature-sensitive TRP channels in humans as well. Ultimately, if a common mechanism is conserved across species, our findings may provide insight into how different animals adapt to the rate of temperature change.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Avoidance of noxious ambient heat is crucial for survival. A well-known phenomenon is that animals are sensitive to the rate of temperature change. However, the cellular and molecular underpinnings through which animals sense and respond much more vigorously to fast temperature changes are unknown. Using Drosophila larvae, we found that nociceptive rolling behavior was triggered at lower temperatures and at higher frequencies when the temperature increased rapidly. We identified neurons in the brain that were sensitive to the speed of the temperature increase rather than just to the absolute temperature. These cellular and behavioral responses depended on the TRPA1 channel, whose activity responded to the rate of temperature increase. We propose that larvae use low-threshold sensors in the brain to monitor rapid temperature increases as a protective alert signal to trigger rolling behaviors, allowing fast escape before the temperature of the brain rises to dangerous levels. Main An important class of molecules that contributes to thermosensation is transient receptor potential channels (thermoTRPs) 1 , 2 , 3 . ThermoTRPs 2 are activated directly or indirectly by changes in temperature and enable animals to respond behaviorally to temperature fluctuations in the environment 1 , 4 . The founding thermoTRP, mouse TRPV1, is activated by temperatures higher than 42 °C and is required for avoidance of noxious heat 5 , 6 . Other mammalian thermoTRPs are activated with different thresholds, such as mouse TRPM8 and TRPA1, which are activated directly by low temperatures below ∼ 23 °C and ∼ 17 °C, respectively 7 , 8 , 9 , 10 . The contribution of TRPs to thermosensation is evolutionarily conserved and is well-documented in the invertebrate model organisms Caenorhabditis elegans and Drosophila melanogaster 4 , 11 . In Drosophila larvae, noxious heat is detected through direct activation of three TRPA (transient receptor potential A) channels: Painless, Pyrexia and TRPA1 (refs. 12 , 13 , 14 , 15 ). The TRPA1 channel also enables larvae to sense exquisitely small deviations above the preferred temperature 16 . In the comfortable range, this fine thermal detection occurs through indirect activation of TRPA1 via a rhodopsin-dependent thermosensory signaling cascade 17 . This signaling cascade may serve to lower the threshold for direct activation of TRPA1. The extensive studies on thermoTRPs in model organisms have contributed greatly to the theory that warm or hot temperatures of different thresholds are sensed by direct activation of TRP channels. However, a long-known but poorly understood aspect of thermosensation is that the rate of temperature change, rather than just the temperature threshold, can affect the nociceptive response. Classic experiments on frogs performed more than 130 years ago demonstrate their highly sensitive escape response to fast rises in heat and indifference to slow increases in temperature 18 . Stronger nociceptive reactions to fast temperature rises have been documented throughout the animal kingdom, in organisms as diverse as worms and humans 19 , 20 . However, the mechanism underlying temperature rate detection is not clear. To explore the mechanism through which an animal responds differentially to slow and fast elevations in temperature, we developed Drosophila larvae as an animal model. We found that if we subjected larvae to a rapid temperature rise, a very high proportion of the animals exhibited nociceptive rolling behavior. However, if the temperature increase was gradual, the percentage of larvae that rolled was much lower, even after we exceeded temperatures that induced robust nociceptive avoidance after a fast temperature increase. We found that one of the TRPA1 isoforms was the key rate-sensor and that it was required in neurons in the brain that responded to the rate of temperature increase rather than just the temperature threshold. Our results indicate that larvae use a TRPA1-dependent rate-sensing mechanism to safeguard the brain from exposure to noxious heat. Results Dependence of the nociceptive rolling response on the rate of temperature increase To characterize the behavior of larvae in response to different rates of temperature change, we built an apparatus that allowed us to accurately control the heating speed while monitoring larval movement. The temperature control system was comprised of a Peltier pad and a programmable integrated circuit responsible for voltage regulation. We used this apparatus to heat and cool an agarose surface for larval navigation. A video camera recorded the larvae's behavior, and a computer program, MAGAT Analyzer 21 , recognized the larvae in each frame. To automatically and objectively analyze the large volume of data, we wrote an algorithm that employed several parameters to discern rolling from nonrolling larvae. These included the speed of the larvae, their direction of movement perpendicular to the body, acceleration and acceleration perpendicular to the body. We used a machine-learning 22 , 23 approach to successively improve the ability of the computer to accurately identify rolling larvae with minimal noise. We exposed wild-type second-instar larvae to temperature ramps with different slopes and determined how rolling was dependent on the rate of temperature change (d T /d t ). In each experiment, we initially maintained the temperature at ∼ 23.5 °C for 30 s and then increased the temperature to 40 °C. Larvae rolled when the temperature increased quickly (0.3 °C per s; Supplementary Video 1 ). As the temperature approached 40 °C, the larvae stopped moving and the rolling behavior ceased ( Fig. 1a ). However, the animals still responded to a mechanical stimulus ( Supplementary Video 2 ). Figure 1: Rolling responses of wild-type larvae exposed to different rates of temperature increase. ( a – i ) The fraction of control ( w 1118 ) second-instar larvae that rolled ( F rolling ) as a function of d T /d t (indicated above each plot). Scale bars indicate the time (in s) required for the temperature to rise by 5 °C. F rolling was defined as N rolling / N total , where N rolling was the number of larvae rolling and N total was the total number of larvae. The curves (thicker lines) were fit using a sigmoid function. Total number of larvae per<|im_end|> <|im_start|>assistant In classic experiments on frogs, scientists found that the amphibians' urge to escape from dangerously hot water decreased significantly when the water temperature rose very gradually. In fact, sensitivity of many animals to temperature—including humans—is similarly affected by the rate of increase. Exactly why, however, has not been understood. Hoping to shed light on this phenomenon, UC Santa Barbara professor Craig Montell and graduate students Junjie Luo and Wei Shen developed fruit fly larvae as a model to reveal a mechanism through which the animal shows different behavioral responses to fast and slow rises in temperature. The researchers discovered that a rapid 25-degree Fahrenheit temperature change caused a writhing response in fruit fly larvae. However, when the temperature was raised gradually, far fewer animals reacted, and for those that did, the average threshold temperature was significantly higher. The team's findings appear in the journal Nature Neuroscience. "We know a lot about how animals sense large and sudden increases in temperature," said Montell, the Patricia and Robert Duggan Professor of Neuroscience in UCSB's Department of Molecular, Cellular, and Developmental Biology. "They respond to noxious heat by initiating an escape response. But how is it that animals are so much less sensitive to the same hot temperature when the change is really slow?" The answer to that question turned out to have two parts. First, Montell and his team identified the thermosensory neurons in the brain responsible for sensing the rate of temperature change, which helped to define the underlying molecular mechanism. Craig Montell and Junjie Luo. Credit: Sonia Fernandez "When there is a really rapid change in temperature, you want to protect the brain, particularly in fly larvae because they're cold-blooded and their body temperature equilibrates to the outside," explained Montell. "If their brains feel a rapid increase in temperature, that stimulates the writhing response." Second, the researchers discovered that the fast response to rapidly increasing heat depended on a transient receptor potential (TRP) channel. The activation of the cellular temperature sensor, a protein called TRPA1, was not simply a function of the absolute temperature but rather depended on the rate of temperature change. If the temperature increase was rapid, TRPA1 turned on quickly and excited those thermosensory brain neurons. When the temperature increased slowly, TRPA1 was less active. "There's a feedback mechanism that turns off this protein as quickly as it's turned on," Montell said. "When it's turned on quickly, it stimulates the pathway to cause the writhing response. But when the process occurs slowly, the on and off mechanisms cancel each other out." The scientists posit that the ability to sense the rate of temperature change is a critical survival mechanism that allows an animal to quickly respond to and escape from a noxious thermal landscape before it is too late. "We think similar mechanisms occur in other animals—for example, the frog," Montell said. "It could be that related mechanisms affect temperature-sensitive TRP channels in humans as well. Ultimately, if a common mechanism is conserved across species, our findings may provide insight into how different animals adapt to the rate of temperature change." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo . Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623. Introduction Lysyl oxidase (LOX) is a copper and quinone-cofactor containing amine oxidase that is secreted as an inactive pro-enzyme, and is then cleaved to a mature active form by extracellular metalloproteases such as BMP-1 (ref. 1 ). LOX catalyses the formation of covalent bonds in collagens and elastin and thereby increases the stiffness of the extracellular matrix (ECM), increasing the tensile strength of extracellular fibres 2 , 3 . Importantly, LOX is also implicated in cancer, because high LOX expression correlates to poor outcome in colon, breast, pancreas, prostate and lung cancers 4 , 5 , 6 , 7 , 8 . Secreted LOX is reported to cross-link the ECM at distal sites to create pre-metastatic niches to which bone marrow-derived and tumour cells are recruited, facilitating the metastatic spread of cancer 9 . Moreover, within the tumour LOX-mediated ECM stiffening is reported to drive integrin activation and tumour initiation in a mouse model of breast cancer 10 , and also to drive the growth of the primary tumours in colorectal cancer 11 . Thus, by modulating tissue stiffness, LOX promotes tumour progression, but intriguingly, when myofibroblasts are depleted in a mouse pancreatic cancer model, collagen content and tissue stiffness are reduced, but disease progression is accelerated 12 . Notably, LOX expression remains strong in this model suggesting that LOX functions beyond regulating matrix stiffness, and a recent study demonstrates that secreted LOX induces bone pre-metastatic lesion formation by regulating NFATc1 driven osteoclastogenesis 13 . Extracellular LOX is also reported to regulate signalling by the platelet-derived growth factor receptor (PDGFR) 14 and transforming growth factor β1 (TGFβ1) 15 , 16 . PDGFR regulation by LOX is implicated in angiogenesis 17 , but how LOX controls intracellular signalling to drive tumour progression is still poorly understood. In this study, we examined how LOX regulates intracellular signalling. Using an unbiased approach, we show that LOX regulates the EGF receptor (EGFR). We also show that LOX inhibits TGFβ1 through the serine protease HTRA1, and that this increases expression of the secreted protein MATN2. MATN2 traps EGFR at the cell surface for enhanced activation by EGF, driving tumour progression. Moreover in vivo inhibition of LOX by our inhibitor CCT365623 disrupts this signalling axis and reduces tumour progression. Results LOX regulates the EGFR To discover unidentified functions of LOX, we examined how its depletion by short-hairpin RNA (shRNA) affects cell signalling using an antibody array to measure receptor tyrosine kinase (RTK) phosphorylation in MDA-MB-231 cells. We found that when LOX was depleted in MDA-MB-231 breast cancer cells grown in standard plastic (2D) culture conditions, phosphorylation of several RTKs including the EGFR was reduced ( Fig. 1a ). LOX cross-links collagen and drives cell invasion and metastasis, so we performed this assay on cells grown within collagen gels (3D) and observed that the strongest effects of LOX depletion are on EGFR and SRC phosphorylation ( Fig. 1b ). Although LOX has previously been linked to SRC 8 , its role in EGFR signalling has not been reported, but like LOX, EGFR is implicated in both tumour cell growth and metastasis. For example, in breast cancer paracrine EGF signalling by tumour-associated macrophages promoted breast cancer cell invasion 18 and the EGFR ligand heparin-binding EGF-like growth factor (HBEGF) was implicated in brain metastasis 19 . Since our results show the link from LOX to EGFR, we focused on their interaction. Figure 1: LOX regulates EGFR activation and cell surface retention. ( a ) Protein phosphorylation changes in LOX-depleted MDA-MB-231 cells on 2D plastic and ( b ) in 3D collagen gels as shown by a RTK antibody array (±20% arbitrary cut-off). ( c ) Western blots of LOX, pY1068 EGFR, surface EGFR, total EGFR and GAPDH in control (shCtl) or LOX-depleted (shLOX A,B) MDA-MB-231 and U87 cells. ( d ) Quantification of LOX protein expression, ( e ) EGFR activation and ( f ) surface EGFR level in MDA-MB-231 and U87 cells from experiments in c . All data are represented as mean±s.d. from three independent experiments. ** P <0.01, Student’s t -test. ( g , h ) Levels of EGFR activation and ( i , j ) surface EGFR in MDA-MB-231 or U87 control (shCtl) or LOX-depleted (shLOX A) cells following EGF stimulation for indicated time. ( k , l ) AKT activation in MDA-MB-231 or U87 control (shCtl) or LOX-depleted (shLOX A,B) cells following EGF stimulation for indicated time. All data in g – l are represented as mean±s.d. from three independent experiments at each indicated time point. ** P <0.01, Student’s t -test. Full size image By western blot, we confirm that in standard 2D tissue culture conditions LOX depletion by shRNA causes reduced phosphorylation of EGFR in MDA-MB-231 and U87 cells ( Fig. 1c–e ). Critically, this occurs without impacting the levels of total EGFR in the cells ( Fig. 1c ), so we examined whether LOX depletion affects surface retention of EGFR by biotinylating the intact cells and capturing the biotinylated surface proteins on streptavidin beads for western blot analysis. Notably, LOX depletion caused a substantial reduction in the levels of EGFR at the cell surface in MDA-MB-231 and U87 cells ( Fig. 1c,f ). Next, we examined EGFR activation", "role": "user" }, { "content": "Scientists have discovered a brand new way of attacking breast cancer that could lead to a new generation of drugs. Researchers have revealed a new driver for the growth and spread of breast cancer cells and have designed a novel type of drug to block it. The next step will be to select the most effective drug from this new class of inhibitors and take it into clinical trials of patients. A team at The Institute of Cancer Research, London working with a team at the Cancer Research UK Manchester Institute at The University of Manchester discovered that a protein called lysyl oxidase, or LOX, plays an important role in driving breast cancer growth and cancer spread (metastasis). The researchers found, in mice, that LOX seemed to help breast cancer cells 'trap' growth receptors on their surface as a means of growing more quickly. Crucially, the team also designed and validated a prototype drug, called CCT365623, which blocks this function, and is able to slow tumour growth and metastases in mice. The study is published in Nature Communications today (Tuesday) and was funded by Wellcome, Cancer Research UK, and The Institute of Cancer Research (ICR). Previously, LOX had been known for its ability to help control formation of the extracellular matrix that holds tissues together, and its use by cancer cells to travel more easily around the body. But this major new study reveals for the first time how LOX is able to control tumour growth. The team discovered that the strongest effect of LOX depletion in breast cancer cells was a reduction in the surface levels of epidermal growth factor receptor (EGFR), a receptor which is often responsible for promoting cancer growth. Scientists worked with mice that spontaneously develop breast cancer and demonstrated that they could reduce both the tumour volume and the size and number of metastases when they genetically removed the LOX gene. All the mice that had the LOX gene genetically removed from their cancer cells survived more than 50 days. The teams also created CCT365623, a new inhibitor of LOX. In mice that had developed breast cancer, the drug slowed tumour growth and reduced cancer spread with no side-effects. LOX has also been shown to be involved in bowel, prostate, pancreatic and lung cancer, so treatments targeting it could potentially benefit a wide range of patients. Professor Caroline Springer, joint senior author and Team Leader of Gene and Oncogene Targeting at The Institute of Cancer Research, London, said: \"We knew that LOX had a role in cancer's spread round the body, but to discover how it also appears to drive the growth of breast cancer cells is a real game changer. It means that drugs that disrupt LOX's ability to promote growth signals might be able to slow or block cancer progression in patients – as we saw in mice.\" Professor Richard Marais, joint senior author and Director of the Cancer Research UK Manchester Institute at The University of Manchester, said: \"In this study we show how improving our knowledge of cancer biology can spearhead the development of new drugs. By understanding better how LOX works, we will make new precision drugs that could improve the survival of patients with many different types of cancer.\" Dr Justine Alford, senior science information officer at Cancer Research UK, said: \"This research in mice is exciting because it not only reveals new details of how breast cancer grows and spreads, but it could lead to a completely new way to stop these processes in patients if proven in people. This could help improve outcomes for patients, since cancer that has spread is harder to treat. LOX is also thought to play a role in a number of other cancers, so this research could also have applications beyond breast cancer.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo . Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623. Introduction Lysyl oxidase (LOX) is a copper and quinone-cofactor containing amine oxidase that is secreted as an inactive pro-enzyme, and is then cleaved to a mature active form by extracellular metalloproteases such as BMP-1 (ref. 1 ). LOX catalyses the formation of covalent bonds in collagens and elastin and thereby increases the stiffness of the extracellular matrix (ECM), increasing the tensile strength of extracellular fibres 2 , 3 . Importantly, LOX is also implicated in cancer, because high LOX expression correlates to poor outcome in colon, breast, pancreas, prostate and lung cancers 4 , 5 , 6 , 7 , 8 . Secreted LOX is reported to cross-link the ECM at distal sites to create pre-metastatic niches to which bone marrow-derived and tumour cells are recruited, facilitating the metastatic spread of cancer 9 . Moreover, within the tumour LOX-mediated ECM stiffening is reported to drive integrin activation and tumour initiation in a mouse model of breast cancer 10 , and also to drive the growth of the primary tumours in colorectal cancer 11 . Thus, by modulating tissue stiffness, LOX promotes tumour progression, but intriguingly, when myofibroblasts are depleted in a mouse pancreatic cancer model, collagen content and tissue stiffness are reduced, but disease progression is accelerated 12 . Notably, LOX expression remains strong in this model suggesting that LOX functions beyond regulating matrix stiffness, and a recent study demonstrates that secreted LOX induces bone pre-metastatic lesion formation by regulating NFATc1 driven osteoclastogenesis 13 . Extracellular LOX is also reported to regulate signalling by the platelet-derived growth factor receptor (PDGFR) 14 and transforming growth factor β1 (TGFβ1) 15 , 16 . PDGFR regulation by LOX is implicated in angiogenesis 17 , but how LOX controls intracellular signalling to drive tumour progression is still poorly understood. In this study, we examined how LOX regulates intracellular signalling. Using an unbiased approach, we show that LOX regulates the EGF receptor (EGFR). We also show that LOX inhibits TGFβ1 through the serine protease HTRA1, and that this increases expression of the secreted protein MATN2. MATN2 traps EGFR at the cell surface for enhanced activation by EGF, driving tumour progression. Moreover in vivo inhibition of LOX by our inhibitor CCT365623 disrupts this signalling axis and reduces tumour progression. Results LOX regulates the EGFR To discover unidentified functions of LOX, we examined how its depletion by short-hairpin RNA (shRNA) affects cell signalling using an antibody array to measure receptor tyrosine kinase (RTK) phosphorylation in MDA-MB-231 cells. We found that when LOX was depleted in MDA-MB-231 breast cancer cells grown in standard plastic (2D) culture conditions, phosphorylation of several RTKs including the EGFR was reduced ( Fig. 1a ). LOX cross-links collagen and drives cell invasion and metastasis, so we performed this assay on cells grown within collagen gels (3D) and observed that the strongest effects of LOX depletion are on EGFR and SRC phosphorylation ( Fig. 1b ). Although LOX has previously been linked to SRC 8 , its role in EGFR signalling has not been reported, but like LOX, EGFR is implicated in both tumour cell growth and metastasis. For example, in breast cancer paracrine EGF signalling by tumour-associated macrophages promoted breast cancer cell invasion 18 and the EGFR ligand heparin-binding EGF-like growth factor (HBEGF) was implicated in brain metastasis 19 . Since our results show the link from LOX to EGFR, we focused on their interaction. Figure 1: LOX regulates EGFR activation and cell surface retention. ( a ) Protein phosphorylation changes in LOX-depleted MDA-MB-231 cells on 2D plastic and ( b ) in 3D collagen gels as shown by a RTK antibody array (±20% arbitrary cut-off). ( c ) Western blots of LOX, pY1068 EGFR, surface EGFR, total EGFR and GAPDH in control (shCtl) or LOX-depleted (shLOX A,B) MDA-MB-231 and U87 cells. ( d ) Quantification of LOX protein expression, ( e ) EGFR activation and ( f ) surface EGFR level in MDA-MB-231 and U87 cells from experiments in c . All data are represented as mean±s.d. from three independent experiments. ** P <0.01, Student’s t -test. ( g , h ) Levels of EGFR activation and ( i , j ) surface EGFR in MDA-MB-231 or U87 control (shCtl) or LOX-depleted (shLOX A) cells following EGF stimulation for indicated time. ( k , l ) AKT activation in MDA-MB-231 or U87 control (shCtl) or LOX-depleted (shLOX A,B) cells following EGF stimulation for indicated time. All data in g – l are represented as mean±s.d. from three independent experiments at each indicated time point. ** P <0.01, Student’s t -test. Full size image By western blot, we confirm that in standard 2D tissue culture conditions LOX depletion by shRNA causes reduced phosphorylation of EGFR in MDA-MB-231 and U87 cells ( Fig. 1c–e ). Critically, this occurs without impacting the levels of total EGFR in the cells ( Fig. 1c ), so we examined whether LOX depletion affects surface retention of EGFR by biotinylating the intact cells and capturing the biotinylated surface proteins on streptavidin beads for western blot analysis. Notably, LOX depletion caused a substantial reduction in the levels of EGFR at the cell surface in MDA-MB-231 and U87 cells ( Fig. 1c,f ). Next, we examined EGFR activation<|im_end|> <|im_start|>assistant Scientists have discovered a brand new way of attacking breast cancer that could lead to a new generation of drugs. Researchers have revealed a new driver for the growth and spread of breast cancer cells and have designed a novel type of drug to block it. The next step will be to select the most effective drug from this new class of inhibitors and take it into clinical trials of patients. A team at The Institute of Cancer Research, London working with a team at the Cancer Research UK Manchester Institute at The University of Manchester discovered that a protein called lysyl oxidase, or LOX, plays an important role in driving breast cancer growth and cancer spread (metastasis). The researchers found, in mice, that LOX seemed to help breast cancer cells 'trap' growth receptors on their surface as a means of growing more quickly. Crucially, the team also designed and validated a prototype drug, called CCT365623, which blocks this function, and is able to slow tumour growth and metastases in mice. The study is published in Nature Communications today (Tuesday) and was funded by Wellcome, Cancer Research UK, and The Institute of Cancer Research (ICR). Previously, LOX had been known for its ability to help control formation of the extracellular matrix that holds tissues together, and its use by cancer cells to travel more easily around the body. But this major new study reveals for the first time how LOX is able to control tumour growth. The team discovered that the strongest effect of LOX depletion in breast cancer cells was a reduction in the surface levels of epidermal growth factor receptor (EGFR), a receptor which is often responsible for promoting cancer growth. Scientists worked with mice that spontaneously develop breast cancer and demonstrated that they could reduce both the tumour volume and the size and number of metastases when they genetically removed the LOX gene. All the mice that had the LOX gene genetically removed from their cancer cells survived more than 50 days. The teams also created CCT365623, a new inhibitor of LOX. In mice that had developed breast cancer, the drug slowed tumour growth and reduced cancer spread with no side-effects. LOX has also been shown to be involved in bowel, prostate, pancreatic and lung cancer, so treatments targeting it could potentially benefit a wide range of patients. Professor Caroline Springer, joint senior author and Team Leader of Gene and Oncogene Targeting at The Institute of Cancer Research, London, said: "We knew that LOX had a role in cancer's spread round the body, but to discover how it also appears to drive the growth of breast cancer cells is a real game changer. It means that drugs that disrupt LOX's ability to promote growth signals might be able to slow or block cancer progression in patients – as we saw in mice." Professor Richard Marais, joint senior author and Director of the Cancer Research UK Manchester Institute at The University of Manchester, said: "In this study we show how improving our knowledge of cancer biology can spearhead the development of new drugs. By understanding better how LOX works, we will make new precision drugs that could improve the survival of patients with many different types of cancer." Dr Justine Alford, senior science information officer at Cancer Research UK, said: "This research in mice is exciting because it not only reveals new details of how breast cancer grows and spreads, but it could lead to a completely new way to stop these processes in patients if proven in people. This could help improve outcomes for patients, since cancer that has spread is harder to treat. LOX is also thought to play a role in a number of other cancers, so this research could also have applications beyond breast cancer." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Organic solvents are widely used in polymer synthesis, despite their use lengthening purification steps and generating chemical waste. All-dry synthesis techniques, such as initiated chemical vapour deposition polymerization, eliminate the use of solvents; however, only a narrow palette of material properties are accessible. Inspired by the principles of solvent engineering in solution synthesis, we report a strategy to broaden this palette by vapour phase complexing (namely, vapour phase solvation) mediated by hydrogen bonding. Broad ranges of polymer chain length, as well as the mechanical strength and variety of film surface morphology, are demonstrated using this strategy. We further achieve an unprecedented solvation modality; more specifically, interfacial solvation. The molecular interactions, locations of solvation and kinetics of the coupled solvation–adsorption–polymerization process are investigated using molecular dynamics simulations and experimental validation of a theoretical kinetics model. The strategy can be applied to various methacrylate and vinyl monomers. Solvation in all-dry polymerization offers a concept in polymer design and synthesis with improved environmental benignness, pointing to accelerated discovery of polymer thin films by simply introducing active solvents in the vapour phase. Main Organic solvents are often considered a necessity in polymerization as they can improve molecular mobility and stabilize reaction intermediates 1 , 2 . Beyond serving the basic function of a liquid medium, new light has been shed on solvents in the past decade, with recent research pointing to their influence on polymer properties, such as molecular weight and stereoregularity 3 , hence enabling new control modalities via solvent engineering. Nevertheless, the profuse use of organic solvents in polymer synthesis made lengthy purification steps unavoidable, generating large amounts of toxic waste while rendering the production of plastics unsustainable 4 . Furthermore, the usage of organic solvents itself could pose constraints on materials design. For example, a cosolvent may not exist for monomers with contrasting solubility 5 , which has hindered the development of amphiphilic copolymers that present desirable antifouling properties 6 . To address the drawbacks of conventional solution-based polymerization, all-dry polymerization techniques have been developed, such as initiated chemical vapour deposition (iCVD), plasma-enhanced chemical vapour deposition 7 and parylene deposition 8 . These all-dry processes enable one-step synthesis, processing and application of polymers as a high-purity coating without the need for solvent removal or other purification steps, hence reducing the environmental impact of polymer synthesis. Furthermore, all-dry synthesis has enabled novel materials properties, such as superhydrophobicity and statistical amphiphilicity, which could revolutionize a broad cross-section of existing and future technologies, ranging from advanced fouling-resistant membranes and efficient energy storage devices to soft microrobots with novel mechanisms for sensing and actuation 9 , 10 , 11 , 12 , 13 , 14 . All-dry polymerization techniques afford powerful in situ and real-time monitoring of the synthesis process, such as continuous control of the reactant feed with picomole precision, and film thickness control on the nanoscale 7 . However, the material properties of the resultant polymer are largely determined by the choice of monomer(s). For example, mechanical strength is improved by increasing crosslinker content, which inevitably modifies the nature of the resultant polymer thin film 15 , 16 . Although there have been examples of controlling polymer properties via deposition conditions 17 , the success of such control methods is highly variable. For example, increasing the surface monomer concentration in iCVD could lead to a higher molecular weight for butylacrylate 18 , but not for 4-vinylpyridine (4VP), as shown below. To address the critical need for novel mechanisms to enable facile control of polymer properties in all-dry polymerization, we drew inspiration from the principles of solvent engineering. As a demonstration of this strategy, we focused on the effect of hydrogen bonding between a solvent and a monomer and demonstrated the generalizability of this approach using a variety of solvent–monomer combinations. This focus is motivated by the recent discovery that the hydrogen bonding between hexafluoroisopropanol (HFIP) and 4VP can affect the molecular weight of poly(4VP) (p4VP) during the Cu(0)-catalysed controlled radical polymerization in solution 3 . While liquid solvents have been used in past iCVD studies (for example, to anneal a polymer thin film 19 or to serve as porogens 20 or liquid substrate 21 ), monomer–solvent interactions have not been explored in the context of manipulating polymer properties or polymerization kinetics. We showed that solvation of 4VP by HFIP occurred in the vapour phase, which greatly accelerated the deposition rate, increased the upper bound of p4VP’s molecular weight and enabled facile film morphology control. We then extended the concept of solvation to acetic acid (AcOH), whose effects are not well understood, and revealed an unprecedented interfacial solvation mechanism. We demonstrated the generalizability of this approach using a variety of monomers, including methyl methacrylate (MMA), cyclohexyl methacrylate (CHMA), hydroxyethyl methacrylate (HEMA), dimethylaminoethyl acrylate (DMAEMA) and acrylic acid. Therefore, the solvation approach represents a concept in materials design and synthesis for all-dry polymerization, enabling unprecedented control modalities over polymer properties. It points to the exciting discovery of CVD polymers, in which polymer thin-film properties that were previously inaccessible can be achieved by simply introducing vapourized solvents 7 . Results and discussion Broadened polymer film properties by vapour phase solvation We chose 4VP as the monomer and HFIP as the vapour phase solvent (Fig. 1a ) for investigating all-dry solvation based on their reported strong interactions in solution polymerization 22 , 23 . This selection also simplifies the stoichiometry of complexing in our subsequent modelling of the solvation–adsorption–polymerization process, as 4VP and HFIP each presents a single site for hydrogen bonding 24 , 25 , 26 . Fig. 1: The strategy of vapour phase solvation to control polymer deposition kinetics, molecular weight and film mechanical properties. a , Schematic of the mechanism of solvation-enhanced polymerization in iCVD. b , Enhanced rate of polymerization of 4VP by replacing Ar (inert gas) with HFIP (vapourized solvent) while keeping the deposition conditions unchanged otherwise. c , Molecular weight of p4VP deposited using iCVD, which was tunable in a much broader range, by replacing Ar with HFIP. d ,", "role": "user" }, { "content": "A new all-dry polymerization technique uses reactive vapors to create thin films with enhanced properties, such as mechanical strength, kinetics and morphology. The synthesis process is gentler on the environment than traditional high-temperature or solution-based manufacturing and could lead to improved polymer coatings for microelectronics, advanced batteries and therapeutics. \"This scalable technique of initiated chemical vapor deposition polymerization allows us to make new materials, without redesigning or revamping the whole chemistry. We just simply add an 'active' solvent,\" said Rong Yang, assistant professor in the Smith School of Chemical and Biomolecular Engineering in Cornell Engineering. \"It's a little bit like a Lego. You team up with a new connecting piece. There's a ton you can build now that you couldn't do before.\" Yang collaborated on the project with Jingjie Yeo, assistant professor in the Sibley School of Mechanical and Aerospace Engineering, and Shefford Baker, associate professor of materials science and engineering. The group's paper, \"Engineering Solvation in Initiated Chemical Vapour Deposition for Control over Polymerization Kinetics and Material Properties,\" published Feb. 9 in Nature Synthesis. The lead author is doctoral student Pengyu Chen. Yang and Yeo are co-senior authors. Chemical vapor deposition (CVD) is a common process used to make defect-free inorganic nanolayer materials in semiconductor manufacturing and in the production of computer microchips. Because the process requires materials to be heated at thousands of degrees, organic polymers do not fare well. CVD polymerization techniques such as initiated CVD (iCVD) are low-temperature counterparts developed for polymer synthesis. However, it is also limiting, Yang said, because \"over the years, people have grown to the boundary of the chemistry you can make with this method.\" Yang's lab studies how vapor-deposited polymers interact with bacterial pathogens and how bacteria, in turn, colonize polymeric coatings, from the paint used in ship hulls to the coating for biomedical devices. She and Chen sought to develop a different approach to diversify CVD polymers by borrowing a concept from conventional solutions synthesis: the use of a \"magic\" solvent, i.e., an inert vapor molecule, that isn't incorporated into the final material, but instead interacts with a precursor in a way that produces new material properties at room temperature. \"It's an old chemistry but with new features,\" Yang said. The solvent in this case interacted with a common CVD monomer via hydrogen-bonding. \"It is a novel mechanism, although the concept is simple and elegant,\" Chen said. \"Building on this interesting strategy, we are developing a robust and generalizable science of solvation engineering.\" Yang and Chen then turned to Yeo, whose lab simulated the molecular dynamics behind the solvent and monomer interaction, and how their stoichiometry, or chemical balance, could be tuned. \"We distinguished the effects of different solvents at the molecular scale and we clearly observed which solvent molecules were more inclined to bind with the monomer,\" Yeo said. \"Thus, we can eventually screen which Lego pieces will be able to fit best with each other.\" The researchers brought the resulting thin film to Baker's lab, which used nanoindentation testing to study it and found that the solvation mechanism had strengthened the material. The solvent also caused the polymer coating to grow faster and change its morphology. This method can now be applied to various methacrylate and vinyl monomers—for essentially anything with a polymer coating, such as the dielectric materials in microelectronics, the anti-fouling coating in ship hulls, and the separation membranes that enable purification in wastewater treatment. The technique could also allow researchers to manipulate the permeability of pharmaceutical products for controlled drug release. \"This adds a new dimension to materials design. You can imagine all kinds of solvents that could form hydrogen-bonding with the monomer and manipulate the reaction kinetics differently. Or you can have solvent molecules incorporated into your material permanently, if you design the molecular interaction correctly,\" Yang said. \"There's so much to explore with this added degree of freedom going forward.\" Co-authors include Baker, Zheyuan Zhang, and Zach Rouse. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Organic solvents are widely used in polymer synthesis, despite their use lengthening purification steps and generating chemical waste. All-dry synthesis techniques, such as initiated chemical vapour deposition polymerization, eliminate the use of solvents; however, only a narrow palette of material properties are accessible. Inspired by the principles of solvent engineering in solution synthesis, we report a strategy to broaden this palette by vapour phase complexing (namely, vapour phase solvation) mediated by hydrogen bonding. Broad ranges of polymer chain length, as well as the mechanical strength and variety of film surface morphology, are demonstrated using this strategy. We further achieve an unprecedented solvation modality; more specifically, interfacial solvation. The molecular interactions, locations of solvation and kinetics of the coupled solvation–adsorption–polymerization process are investigated using molecular dynamics simulations and experimental validation of a theoretical kinetics model. The strategy can be applied to various methacrylate and vinyl monomers. Solvation in all-dry polymerization offers a concept in polymer design and synthesis with improved environmental benignness, pointing to accelerated discovery of polymer thin films by simply introducing active solvents in the vapour phase. Main Organic solvents are often considered a necessity in polymerization as they can improve molecular mobility and stabilize reaction intermediates 1 , 2 . Beyond serving the basic function of a liquid medium, new light has been shed on solvents in the past decade, with recent research pointing to their influence on polymer properties, such as molecular weight and stereoregularity 3 , hence enabling new control modalities via solvent engineering. Nevertheless, the profuse use of organic solvents in polymer synthesis made lengthy purification steps unavoidable, generating large amounts of toxic waste while rendering the production of plastics unsustainable 4 . Furthermore, the usage of organic solvents itself could pose constraints on materials design. For example, a cosolvent may not exist for monomers with contrasting solubility 5 , which has hindered the development of amphiphilic copolymers that present desirable antifouling properties 6 . To address the drawbacks of conventional solution-based polymerization, all-dry polymerization techniques have been developed, such as initiated chemical vapour deposition (iCVD), plasma-enhanced chemical vapour deposition 7 and parylene deposition 8 . These all-dry processes enable one-step synthesis, processing and application of polymers as a high-purity coating without the need for solvent removal or other purification steps, hence reducing the environmental impact of polymer synthesis. Furthermore, all-dry synthesis has enabled novel materials properties, such as superhydrophobicity and statistical amphiphilicity, which could revolutionize a broad cross-section of existing and future technologies, ranging from advanced fouling-resistant membranes and efficient energy storage devices to soft microrobots with novel mechanisms for sensing and actuation 9 , 10 , 11 , 12 , 13 , 14 . All-dry polymerization techniques afford powerful in situ and real-time monitoring of the synthesis process, such as continuous control of the reactant feed with picomole precision, and film thickness control on the nanoscale 7 . However, the material properties of the resultant polymer are largely determined by the choice of monomer(s). For example, mechanical strength is improved by increasing crosslinker content, which inevitably modifies the nature of the resultant polymer thin film 15 , 16 . Although there have been examples of controlling polymer properties via deposition conditions 17 , the success of such control methods is highly variable. For example, increasing the surface monomer concentration in iCVD could lead to a higher molecular weight for butylacrylate 18 , but not for 4-vinylpyridine (4VP), as shown below. To address the critical need for novel mechanisms to enable facile control of polymer properties in all-dry polymerization, we drew inspiration from the principles of solvent engineering. As a demonstration of this strategy, we focused on the effect of hydrogen bonding between a solvent and a monomer and demonstrated the generalizability of this approach using a variety of solvent–monomer combinations. This focus is motivated by the recent discovery that the hydrogen bonding between hexafluoroisopropanol (HFIP) and 4VP can affect the molecular weight of poly(4VP) (p4VP) during the Cu(0)-catalysed controlled radical polymerization in solution 3 . While liquid solvents have been used in past iCVD studies (for example, to anneal a polymer thin film 19 or to serve as porogens 20 or liquid substrate 21 ), monomer–solvent interactions have not been explored in the context of manipulating polymer properties or polymerization kinetics. We showed that solvation of 4VP by HFIP occurred in the vapour phase, which greatly accelerated the deposition rate, increased the upper bound of p4VP’s molecular weight and enabled facile film morphology control. We then extended the concept of solvation to acetic acid (AcOH), whose effects are not well understood, and revealed an unprecedented interfacial solvation mechanism. We demonstrated the generalizability of this approach using a variety of monomers, including methyl methacrylate (MMA), cyclohexyl methacrylate (CHMA), hydroxyethyl methacrylate (HEMA), dimethylaminoethyl acrylate (DMAEMA) and acrylic acid. Therefore, the solvation approach represents a concept in materials design and synthesis for all-dry polymerization, enabling unprecedented control modalities over polymer properties. It points to the exciting discovery of CVD polymers, in which polymer thin-film properties that were previously inaccessible can be achieved by simply introducing vapourized solvents 7 . Results and discussion Broadened polymer film properties by vapour phase solvation We chose 4VP as the monomer and HFIP as the vapour phase solvent (Fig. 1a ) for investigating all-dry solvation based on their reported strong interactions in solution polymerization 22 , 23 . This selection also simplifies the stoichiometry of complexing in our subsequent modelling of the solvation–adsorption–polymerization process, as 4VP and HFIP each presents a single site for hydrogen bonding 24 , 25 , 26 . Fig. 1: The strategy of vapour phase solvation to control polymer deposition kinetics, molecular weight and film mechanical properties. a , Schematic of the mechanism of solvation-enhanced polymerization in iCVD. b , Enhanced rate of polymerization of 4VP by replacing Ar (inert gas) with HFIP (vapourized solvent) while keeping the deposition conditions unchanged otherwise. c , Molecular weight of p4VP deposited using iCVD, which was tunable in a much broader range, by replacing Ar with HFIP. d ,<|im_end|> <|im_start|>assistant A new all-dry polymerization technique uses reactive vapors to create thin films with enhanced properties, such as mechanical strength, kinetics and morphology. The synthesis process is gentler on the environment than traditional high-temperature or solution-based manufacturing and could lead to improved polymer coatings for microelectronics, advanced batteries and therapeutics. "This scalable technique of initiated chemical vapor deposition polymerization allows us to make new materials, without redesigning or revamping the whole chemistry. We just simply add an 'active' solvent," said Rong Yang, assistant professor in the Smith School of Chemical and Biomolecular Engineering in Cornell Engineering. "It's a little bit like a Lego. You team up with a new connecting piece. There's a ton you can build now that you couldn't do before." Yang collaborated on the project with Jingjie Yeo, assistant professor in the Sibley School of Mechanical and Aerospace Engineering, and Shefford Baker, associate professor of materials science and engineering. The group's paper, "Engineering Solvation in Initiated Chemical Vapour Deposition for Control over Polymerization Kinetics and Material Properties," published Feb. 9 in Nature Synthesis. The lead author is doctoral student Pengyu Chen. Yang and Yeo are co-senior authors. Chemical vapor deposition (CVD) is a common process used to make defect-free inorganic nanolayer materials in semiconductor manufacturing and in the production of computer microchips. Because the process requires materials to be heated at thousands of degrees, organic polymers do not fare well. CVD polymerization techniques such as initiated CVD (iCVD) are low-temperature counterparts developed for polymer synthesis. However, it is also limiting, Yang said, because "over the years, people have grown to the boundary of the chemistry you can make with this method." Yang's lab studies how vapor-deposited polymers interact with bacterial pathogens and how bacteria, in turn, colonize polymeric coatings, from the paint used in ship hulls to the coating for biomedical devices. She and Chen sought to develop a different approach to diversify CVD polymers by borrowing a concept from conventional solutions synthesis: the use of a "magic" solvent, i.e., an inert vapor molecule, that isn't incorporated into the final material, but instead interacts with a precursor in a way that produces new material properties at room temperature. "It's an old chemistry but with new features," Yang said. The solvent in this case interacted with a common CVD monomer via hydrogen-bonding. "It is a novel mechanism, although the concept is simple and elegant," Chen said. "Building on this interesting strategy, we are developing a robust and generalizable science of solvation engineering." Yang and Chen then turned to Yeo, whose lab simulated the molecular dynamics behind the solvent and monomer interaction, and how their stoichiometry, or chemical balance, could be tuned. "We distinguished the effects of different solvents at the molecular scale and we clearly observed which solvent molecules were more inclined to bind with the monomer," Yeo said. "Thus, we can eventually screen which Lego pieces will be able to fit best with each other." The researchers brought the resulting thin film to Baker's lab, which used nanoindentation testing to study it and found that the solvation mechanism had strengthened the material. The solvent also caused the polymer coating to grow faster and change its morphology. This method can now be applied to various methacrylate and vinyl monomers—for essentially anything with a polymer coating, such as the dielectric materials in microelectronics, the anti-fouling coating in ship hulls, and the separation membranes that enable purification in wastewater treatment. The technique could also allow researchers to manipulate the permeability of pharmaceutical products for controlled drug release. "This adds a new dimension to materials design. You can imagine all kinds of solvents that could form hydrogen-bonding with the monomer and manipulate the reaction kinetics differently. Or you can have solvent molecules incorporated into your material permanently, if you design the molecular interaction correctly," Yang said. "There's so much to explore with this added degree of freedom going forward." Co-authors include Baker, Zheyuan Zhang, and Zach Rouse. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chemical differences between mid-ocean ridge basalts (MORBs) and ocean island basalts (OIBs) provide critical evidence that the Earth’s mantle is compositionally heterogeneous. MORBs generally exhibit a relatively low and narrow range of 3 He/ 4 He ratios on a global scale, whereas OIBs display larger variability in both time and space. The primordial origin of 3 He in OIBs has motivated hypotheses that high 3 He/ 4 He ratios are the product of mantle plumes sampling chemically distinct material, but do not account for lower MORB-like 3 He/ 4 He ratios in OIBs, nor their observed spatial and temporal variability. Here we perform thermochemical convection calculations which show the variable 3 He/ 4 He signature of OIBs can be reproduced by deep isolated mantle reservoirs of primordial material that are viscously entrained by thermal plumes. Entrainment is highly time-dependent, producing a wide range of 3 He/ 4 He ratios similar to that observed in OIBs worldwide and indicate MORB-like 3 He/ 4 He ratios in OIBs cannot be used to preclude deep mantle-sourced hotspots. Introduction With respect to the atmospheric ratio of 3 He/ 4 He (denoted by R A ), mid-ocean ridge basalts (MORBs) sampled at spreading centres not influenced by hotspot activity are globally characterized by a narrow range of values (ca. 6–11 R A ), whereas ocean island basalts (OIBs) display a much wider spectrum (ca. 5–50 R A ) 1 . Furthermore, the variability in OIB 3 He/ 4 He values is not only observed spatially between different hotspots, but temporally within the different-aged lavas of a single hotspot track 2 , 3 , 4 ( Fig. 1 ). The difference in MORB and OIB 3 He/ 4 He ratios provides evidence that they are derived from different source regions in the mantle. The relative uniformity of MORB values combined with the more variable 3 He/ 4 He ratios observed in OIB has motivated conceptual models of Earth’s mantle that involve a relatively degassed, homogenous background mantle source for MORBs and a deeper, primordial (less degassed) reservoir that is tapped by mantle plumes to produce OIBs at the surface 2 , 3 . Earlier conceptual mantle models hypothesized the primordial reservoir to be a more-dense continuous layer within Earth’s lowermost mantle that completely envelops the core–mantle boundary 5 , 6 . Samuel and Farnetani 6 investigated the longevity and chemical evolution of such a basal layer and found that the mixture of materials entrained in mantle plumes can explain the wide variability of 3 He/ 4 He ratios observed in OIBs as well as the relatively uniform distribution of 3 He/ 4 He ratios observed in MORB. Figure 1: Global distribution of 3 He/ 4 He ratios in volcanic systems. Blue circles represent MORB sample locations with 3 He/ 4 He ratios ca. 8 R A . Red circles are centred at OIB sample locations and display 3 He/ 4 He ratios from MORB-like values to more elevated values. Compilation from the GEOROC ( ), PetDB ( ) and USGS noble gas ( ) databases. Full size image In contrast to a globally continuous dense layer surrounding the entire core–mantle boundary, seismic tomography has revealed the presence of geographically discrete large low shear-wave velocity provinces in the lowermost mantle beneath Africa and the Pacific 7 , 8 , 9 that underlie a majority of surface hotspots 10 , 11 , 12 , 13 . A principal hypothesis for the formation of the large low shear-wave velocity provinces posits that these objects represent intrinsically more dense, primordial material that has been ‘swept’ into discrete thermochemical piles by convective forces of the ambient mantle 3 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . These geodynamical studies reveal the presence of mantle plumes interacting with thermochemical piles, resulting in the entrainment of pile material into the plume conduits. For example, Deschamps et al. 21 performed thermochemical convection calculations where plumes interacted with chemically distinct piles and, when integrated throughout Earth’s history and throughout the entire upper mantle, found that the entrainment of pile material into plumes does not exceed ∼ 9% of the plume mass flux. Here, we investigate whether a simple conceptual model of mantle plumes that originate in the lower mantle and interact with dense, chemically distinct primordial piles can explain the complex spatial and temporal variability of 3 He/ 4 He ratios observed in OIBs. This simplification focuses only on a primordial reservoir and neglects the possible contribution due to recycled oceanic crust 23 . In particular, this model tests the hypothesis that time-dependent entrainment of primordial material into the hottest portions of mantle plumes (that will ultimately melt near the surface) will result in changes in the 3 He/ 4 He ratio as individual hotspot tracks develop as well as differences in the 3 He/ 4 He ratio between geographically distinct hotspot tracks. Furthermore, this study investigates the dynamics of entrainment associated with both long-lived, stable mantle plumes and shorter-lived, more mobile mantle plumes, and whether these two types of plumes are expected to produce characteristically different 3 He/ 4 He signals as a function of time and space. Results Dynamic entrainment of isolated lower mantle material This study solves the conservation equations of mass, momentum and energy in the Boussinesq approximation using an updated version of the two-dimensional Cartesian mantle convection code Citcom 24 , modified for thermochemical convection 25 . The reference case employs a Rayleigh number of 5 × 10 7 , and a viscosity that is both temperature and depth dependent. There is a 10,000 × viscosity variation between the hottest and coldest temperatures, and a 50 × viscosity step increase from upper mantle into lower mantle. The compositional field is advected using circa eight million tracers with the ratio tracer method 26 . The model domain represents the entire mantle thickness with a mesh that has 257 elements in the vertical direction and an aspect ratio of four.", "role": "user" }, { "content": "The journey for volcanic rocks found on many volcanic islands began deep within the Earth. Brought to the Earth's surface in eruptions of deep volcanic material, these rocks hold clues as to what is going on deep beneath Earth's surface. Studies of rocks found on certain volcanic islands, known as ocean island basalts, revealed that although these erupted rocks originate from Earth's interior, they are not the same chemically. According to a group of current and former researchers at Arizona State University, the key to unlocking this complex, geochemical puzzle rests in a model of mantle dynamics consisting of plumes - upwelling's of abnormally hot rock within the Earth's mantle - that originate in the lower mantle and physically interact with chemically distinct piles of material. The team revealed that this theoretical model of material transport can easily produce the chemical variability observed at hotspot volcanoes (such as Hawaii) around the world. \"This model provides a platform for understanding links between the physics and chemistry that formed our modern world as well as habitable planets elsewhere,\" says Curtis Williams, lead author of the study whose results are published in the Nov. 24 issue of the journal Nature Communications. Basalts collected from ocean islands such as Hawaii and those collected from mid-ocean ridges (that erupt at spreading centers deep below oceans) may look similar to the naked eye; however, in detail their trace elements and isotopic compositions can be quite distinct. These differences provide valuable insight into the chemical structure and temporal evolution of Earth's interior. \"In particular, it means that the Earth's mantle - the hot rock below Earth's crust but above the planet's iron core - is compositionally heterogeneous. Understanding when and where these heterogeneities are formed and how they are transported through the mantle directly relates to the initial composition of the Earth and how it has evolved to its current, habitable state,\" said Williams, a postdoc at UC Davis. While a graduate student in ASU's School of Earth and Space Exploration, Williams and faculty members Allen McNamara and Ed Garnero conceived a study to further understand how chemical complexities that exist deep inside the Earth are transported to the surface and erupt as intraplate volcanism (such as that which formed the Hawaiian islands). Along with fellow graduate student Mingming Li and Professional Research Associate Matthijs van Soest, the researchers depict a model Earth, where in its interior resides distinct reservoirs of mantle material that may have formed during the earliest stages of Earth's evolution. Employing such reservoirs into their models is supported by geophysical observations of two, continent-sized regions - one below the Pacific Ocean and one below parts of the Atlantic Ocean and Africa - sitting atop the core-mantle boundary. \"In the last several years, we have witnessed a sharpening of the focus knob on seismic imaging of Earth's deep interior. We have learned that the two large anomalous structures at the base of the mantle behave as if they are compositionally distinct. That is, we are talking about different stuff compared to the surrounding mantle. These represent the largest internal anomalies in Earth of unknown chemistry and origin,\" said Garnero. These chemically distinct regions also underlie a majority of hotspot volcanism, via hot mantle plumes from the top of the piles to Earth's surface, suggesting a potential link between these ancient, chemically distinct regions and the chemistry of hotspot volcanism. To test the validity of their model, Williams and coauthors compare their predictions of the variability of the ratios of helium isotopes (helium-3 and helium-4) in plumes to that observed in ocean island basalts. 3He is a so-called primordial isotope found in the Earth's mantle. It was created before the Earth was formed and is thought to have become entrapped within the Earth during planetary formation. Today, it is not being added to Earth's inventory at a significant rate, unlike 4He, which accumulates over time. Williams explained: \"The ratio of helium-3 to helium-4 in mid-ocean ridge basalts are globally characterized by a narrow range of small values and are thought to sample a relatively homogenous upper mantle. On the other hand, ocean island basalts display a much wider range, from small to very large, providing evidence that they are derived from different source regions and are thought to sample the lower mantle either partially or in its entirety.\" The variability of 3He to 4He in ocean island basalts is not only observed between different hotspots, but temporally within the different-aged lavas of a single hotspot track. \"The reservoirs and dynamics associated with this variability had remained unclear and was the primary motivation behind the study presented here,\" said Williams. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chemical differences between mid-ocean ridge basalts (MORBs) and ocean island basalts (OIBs) provide critical evidence that the Earth’s mantle is compositionally heterogeneous. MORBs generally exhibit a relatively low and narrow range of 3 He/ 4 He ratios on a global scale, whereas OIBs display larger variability in both time and space. The primordial origin of 3 He in OIBs has motivated hypotheses that high 3 He/ 4 He ratios are the product of mantle plumes sampling chemically distinct material, but do not account for lower MORB-like 3 He/ 4 He ratios in OIBs, nor their observed spatial and temporal variability. Here we perform thermochemical convection calculations which show the variable 3 He/ 4 He signature of OIBs can be reproduced by deep isolated mantle reservoirs of primordial material that are viscously entrained by thermal plumes. Entrainment is highly time-dependent, producing a wide range of 3 He/ 4 He ratios similar to that observed in OIBs worldwide and indicate MORB-like 3 He/ 4 He ratios in OIBs cannot be used to preclude deep mantle-sourced hotspots. Introduction With respect to the atmospheric ratio of 3 He/ 4 He (denoted by R A ), mid-ocean ridge basalts (MORBs) sampled at spreading centres not influenced by hotspot activity are globally characterized by a narrow range of values (ca. 6–11 R A ), whereas ocean island basalts (OIBs) display a much wider spectrum (ca. 5–50 R A ) 1 . Furthermore, the variability in OIB 3 He/ 4 He values is not only observed spatially between different hotspots, but temporally within the different-aged lavas of a single hotspot track 2 , 3 , 4 ( Fig. 1 ). The difference in MORB and OIB 3 He/ 4 He ratios provides evidence that they are derived from different source regions in the mantle. The relative uniformity of MORB values combined with the more variable 3 He/ 4 He ratios observed in OIB has motivated conceptual models of Earth’s mantle that involve a relatively degassed, homogenous background mantle source for MORBs and a deeper, primordial (less degassed) reservoir that is tapped by mantle plumes to produce OIBs at the surface 2 , 3 . Earlier conceptual mantle models hypothesized the primordial reservoir to be a more-dense continuous layer within Earth’s lowermost mantle that completely envelops the core–mantle boundary 5 , 6 . Samuel and Farnetani 6 investigated the longevity and chemical evolution of such a basal layer and found that the mixture of materials entrained in mantle plumes can explain the wide variability of 3 He/ 4 He ratios observed in OIBs as well as the relatively uniform distribution of 3 He/ 4 He ratios observed in MORB. Figure 1: Global distribution of 3 He/ 4 He ratios in volcanic systems. Blue circles represent MORB sample locations with 3 He/ 4 He ratios ca. 8 R A . Red circles are centred at OIB sample locations and display 3 He/ 4 He ratios from MORB-like values to more elevated values. Compilation from the GEOROC ( ), PetDB ( ) and USGS noble gas ( ) databases. Full size image In contrast to a globally continuous dense layer surrounding the entire core–mantle boundary, seismic tomography has revealed the presence of geographically discrete large low shear-wave velocity provinces in the lowermost mantle beneath Africa and the Pacific 7 , 8 , 9 that underlie a majority of surface hotspots 10 , 11 , 12 , 13 . A principal hypothesis for the formation of the large low shear-wave velocity provinces posits that these objects represent intrinsically more dense, primordial material that has been ‘swept’ into discrete thermochemical piles by convective forces of the ambient mantle 3 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . These geodynamical studies reveal the presence of mantle plumes interacting with thermochemical piles, resulting in the entrainment of pile material into the plume conduits. For example, Deschamps et al. 21 performed thermochemical convection calculations where plumes interacted with chemically distinct piles and, when integrated throughout Earth’s history and throughout the entire upper mantle, found that the entrainment of pile material into plumes does not exceed ∼ 9% of the plume mass flux. Here, we investigate whether a simple conceptual model of mantle plumes that originate in the lower mantle and interact with dense, chemically distinct primordial piles can explain the complex spatial and temporal variability of 3 He/ 4 He ratios observed in OIBs. This simplification focuses only on a primordial reservoir and neglects the possible contribution due to recycled oceanic crust 23 . In particular, this model tests the hypothesis that time-dependent entrainment of primordial material into the hottest portions of mantle plumes (that will ultimately melt near the surface) will result in changes in the 3 He/ 4 He ratio as individual hotspot tracks develop as well as differences in the 3 He/ 4 He ratio between geographically distinct hotspot tracks. Furthermore, this study investigates the dynamics of entrainment associated with both long-lived, stable mantle plumes and shorter-lived, more mobile mantle plumes, and whether these two types of plumes are expected to produce characteristically different 3 He/ 4 He signals as a function of time and space. Results Dynamic entrainment of isolated lower mantle material This study solves the conservation equations of mass, momentum and energy in the Boussinesq approximation using an updated version of the two-dimensional Cartesian mantle convection code Citcom 24 , modified for thermochemical convection 25 . The reference case employs a Rayleigh number of 5 × 10 7 , and a viscosity that is both temperature and depth dependent. There is a 10,000 × viscosity variation between the hottest and coldest temperatures, and a 50 × viscosity step increase from upper mantle into lower mantle. The compositional field is advected using circa eight million tracers with the ratio tracer method 26 . The model domain represents the entire mantle thickness with a mesh that has 257 elements in the vertical direction and an aspect ratio of four.<|im_end|> <|im_start|>assistant The journey for volcanic rocks found on many volcanic islands began deep within the Earth. Brought to the Earth's surface in eruptions of deep volcanic material, these rocks hold clues as to what is going on deep beneath Earth's surface. Studies of rocks found on certain volcanic islands, known as ocean island basalts, revealed that although these erupted rocks originate from Earth's interior, they are not the same chemically. According to a group of current and former researchers at Arizona State University, the key to unlocking this complex, geochemical puzzle rests in a model of mantle dynamics consisting of plumes - upwelling's of abnormally hot rock within the Earth's mantle - that originate in the lower mantle and physically interact with chemically distinct piles of material. The team revealed that this theoretical model of material transport can easily produce the chemical variability observed at hotspot volcanoes (such as Hawaii) around the world. "This model provides a platform for understanding links between the physics and chemistry that formed our modern world as well as habitable planets elsewhere," says Curtis Williams, lead author of the study whose results are published in the Nov. 24 issue of the journal Nature Communications. Basalts collected from ocean islands such as Hawaii and those collected from mid-ocean ridges (that erupt at spreading centers deep below oceans) may look similar to the naked eye; however, in detail their trace elements and isotopic compositions can be quite distinct. These differences provide valuable insight into the chemical structure and temporal evolution of Earth's interior. "In particular, it means that the Earth's mantle - the hot rock below Earth's crust but above the planet's iron core - is compositionally heterogeneous. Understanding when and where these heterogeneities are formed and how they are transported through the mantle directly relates to the initial composition of the Earth and how it has evolved to its current, habitable state," said Williams, a postdoc at UC Davis. While a graduate student in ASU's School of Earth and Space Exploration, Williams and faculty members Allen McNamara and Ed Garnero conceived a study to further understand how chemical complexities that exist deep inside the Earth are transported to the surface and erupt as intraplate volcanism (such as that which formed the Hawaiian islands). Along with fellow graduate student Mingming Li and Professional Research Associate Matthijs van Soest, the researchers depict a model Earth, where in its interior resides distinct reservoirs of mantle material that may have formed during the earliest stages of Earth's evolution. Employing such reservoirs into their models is supported by geophysical observations of two, continent-sized regions - one below the Pacific Ocean and one below parts of the Atlantic Ocean and Africa - sitting atop the core-mantle boundary. "In the last several years, we have witnessed a sharpening of the focus knob on seismic imaging of Earth's deep interior. We have learned that the two large anomalous structures at the base of the mantle behave as if they are compositionally distinct. That is, we are talking about different stuff compared to the surrounding mantle. These represent the largest internal anomalies in Earth of unknown chemistry and origin," said Garnero. These chemically distinct regions also underlie a majority of hotspot volcanism, via hot mantle plumes from the top of the piles to Earth's surface, suggesting a potential link between these ancient, chemically distinct regions and the chemistry of hotspot volcanism. To test the validity of their model, Williams and coauthors compare their predictions of the variability of the ratios of helium isotopes (helium-3 and helium-4) in plumes to that observed in ocean island basalts. 3He is a so-called primordial isotope found in the Earth's mantle. It was created before the Earth was formed and is thought to have become entrapped within the Earth during planetary formation. Today, it is not being added to Earth's inventory at a significant rate, unlike 4He, which accumulates over time. Williams explained: "The ratio of helium-3 to helium-4 in mid-ocean ridge basalts are globally characterized by a narrow range of small values and are thought to sample a relatively homogenous upper mantle. On the other hand, ocean island basalts display a much wider range, from small to very large, providing evidence that they are derived from different source regions and are thought to sample the lower mantle either partially or in its entirety." The variability of 3He to 4He in ocean island basalts is not only observed between different hotspots, but temporally within the different-aged lavas of a single hotspot track. "The reservoirs and dynamics associated with this variability had remained unclear and was the primary motivation behind the study presented here," said Williams. <|im_end|>

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2,337

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Subjective experience suggests that we are able to direct our auditory attention independent of our visual gaze, e.g when shadowing a nearby conversation at a cocktail party. But what are the consequences at the behavioural and neural level? While numerous studies have investigated both auditory attention and visual gaze independently, little is known about their interaction during selective listening. In the present EEG study, we manipulated visual gaze independently of auditory attention while participants detected targets presented from one of three loudspeakers. We observed increased response times when gaze was directed away from the locus of auditory attention. Further, we found an increase in occipital alpha-band power contralateral to the direction of gaze, indicative of a suppression of distracting input. Finally, this condition also led to stronger central theta-band power, which correlated with the observed effect in response times, indicative of differences in top-down processing. Our data suggest that a misalignment between gaze and auditory attention both reduce behavioural performance and modulate underlying neural processes. The involvement of central theta-band and occipital alpha-band effects are in line with compensatory neural mechanisms such as increased cognitive control and the suppression of task irrelevant inputs. Introduction In most natural listening situations, the focus of auditory attention (“where we are listening to”) is aligned with visual gaze direction (“where we are looking at”). However, there are many instances in everyday life, for example while driving, in which we can listen to somewhere else than where we are looking. At least subjectively, it appears that we are capable of directing the locus of our auditory attention independently of visual gaze. Here, we seek to understand how gazing toward versus away from the locus of auditory attention affects behavioural and neural responses to sounds, and its impact on global measures of brain states such as ongoing oscillatory activity. Visual gaze is usually an overt manifestation of selective visual attention 1 , 2 , and often tightly linked with attention in other modalities 3 , 4 . During dichotic listening tasks, spontaneous eye movements have been shown to occur preferentially toward the attended side 5 , 6 . Research in animals has shown that the direction of visual gaze modifies concurrent auditory processing. For example, Werner-Reiss et al . 7 found that eye position changes both the spontaneous activity and responses to sounds of neurons in the auditory cortex of awake macaques, even in complete darkness. Similarly, Groh et al . 8 demonstrated that in macaques eye position affects firing rates of auditory neurons already at the level of the inferior colliculus. In humans, research on the impact of gaze direction on auditory processing has mostly been limited to its effects on sound localization. For instance, Maddox et al . 9 reported that directing gaze toward a sound significantly enhances discrimination of both interaural level and time differences, whereas directing auditory spatial attention alone does not. Irrespective of gaze direction, a large number of electroencephalographic (EEG) studies in humans have shown that endogenous auditory attention can amplify event related potentials (ERPs) to sounds as early as 20 ms after stimulus onset 10 , 11 , 12 , 13 . These early attentional effects are thought to reflect a sensory selection mechanism, based on readily discriminable features such as spatial location 10 , 14 . In addition to unisensory auditory attention, covert visual attention to the location of a sound can both amplify ERPs, as well as facilitate behavioural responses to auditory targets 15 , 16 , 17 , demonstrating the potential impact of visual information on auditory processing. Apart from influencing phasic responses to single sounds, auditory attention also affects oscillatory neural activity in the alpha-band range (8–14 Hz) 18 , 19 . For example, Obleser and Weisz 19 presented human listeners with degraded speech, and found that occipital alpha band activity correlated with speech intelligibility and listening effort. More generally, alpha-band activity has been suggested to act as a local sensory gating mechanism, by which processing of relevant sensory inputs is enhanced and irrelevant input is suppressed 20 . Indicative of this, both visual and auditory spatial attention have been shown to induce lateralized changes in occipital alpha-band activity, with larger power contra- versus ipsilateral to the attended side 21 , 22 , 23 . While the topography of alpha-band modulation for visual and auditory attention overlaps, the underlying networks for the two modalities are likely distinct 18 , 21 . Prolonged attention and demanding cognitive performance has additionally been linked to increased central theta-band activity (4–7 Hz) 24 , 25 , and has been demonstrated for tasks in the auditory 26 , and visual 27 domain, as well as during multisensory processing 28 . For instance, Friese et al . 28 found increased fronto-medial theta-band activity during attended versus unattended trials in an audio-visual congruency detection paradigm. In summary, auditory attention in humans increases ERPs to sounds and modulates posterior alpha-band oscillations, while the amount of cognitive control required during a given task seems to be reflected in central theta-band activity. However, while there is increasing knowledge about the mechanisms of auditory attention as well as the mediating influence of visual gaze in other animals, the impact of gaze direction on human auditory processing is still largely unexplored. To our knowledge, the only previous electrophysiological study investigating gaze dependent changes in the quality of auditory processing in humans was performed by Okita and Wei 29 . Using EEG recordings from four electrodes, the authors show enhanced ERPs between 100 and 500 ms following a tone, when participants gazed towards versus away from the spatial source of the tone. This was interpreted as an increase of selectivity between relevant and irrelevant auditory inputs. However, this experiment suffers from a number of methodological limitations including the lack of quantifiable eye position monitoring. Furthermore, it did not find any behavioural effects of gaze direction on auditory processing. In the present EEG study, we used a full factorial design to investigate the impact of task irrelevant gaze", "role": "user" }, { "content": "Listening to something while looking in a different direction can slow down reaction times while the brain works harder to suppress distractions, finds a new UCL study. In a study published in Scientific Reports, UCL researchers found that a misalignment between the direction of the eyes and the focus of auditory attention leads to slower reactions and increased listening effort. \"We frequently listen away from where our eyes are directed, such as when driving, or eavesdropping to a conversation at a party. So in this study we asked a simple question: How does the mere direction of gaze, even in the absence of visual information, affect listening?\" said the study's first author, Dr Ulrich Pomper (UCL Ear Institute). \"We found that gazing away from what we are listening to is mentally taxing, and has detrimental consequences to performance.\" The study design aimed to re-create a simple everyday listening situation—attempting to follow a single sound from a mixture of several - but within a controlled lab environment. The 19 study participants each sat facing three loudspeakers arranged in front of them in a darkened, soundproof room. They were instructed to follow sounds from one of the loudspeakers while ignoring sounds from the other two loudspeakers. Simultaneously, they were directed to look at either the 'followed' loudspeaker or at one of the other (ignored) loudspeakers. A special camera was used to confirm that they were looking in the direction requested. As the participants concentrated, their brain activity was monitored with electroencephalography (EEG). The researchers found that the participants' reaction times were slower when they were instructed to look away from the attended loudspeaker and this was also accompanied by an increase in oscillatory neural activity (also known as 'brain waves'). \"We found that the participants' brains were working hard to counteract the misalignment between gaze and auditory attention, even though the setup and tasks were very simple,\" said senior author Dr Maria Chait (UCL Ear Institute). \"It is striking that simply shifting the direction of gaze a few degrees away from a sound source can have such a remarkable effect on brain activity. We think this is because our brains are wired to expect visual gaze direction and auditory attention to be aligned. The intuitive feeling that our auditory attention is independent from gaze is an illusion.\" \"While our cohort of young participants exhibited only a relatively small slowing of reaction times, inconsistent gaze might have more severe consequences in older or hearing-impaired listeners and could lead to serious implications for safety when engaged in demanding tasks, like driving,\" she said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Subjective experience suggests that we are able to direct our auditory attention independent of our visual gaze, e.g when shadowing a nearby conversation at a cocktail party. But what are the consequences at the behavioural and neural level? While numerous studies have investigated both auditory attention and visual gaze independently, little is known about their interaction during selective listening. In the present EEG study, we manipulated visual gaze independently of auditory attention while participants detected targets presented from one of three loudspeakers. We observed increased response times when gaze was directed away from the locus of auditory attention. Further, we found an increase in occipital alpha-band power contralateral to the direction of gaze, indicative of a suppression of distracting input. Finally, this condition also led to stronger central theta-band power, which correlated with the observed effect in response times, indicative of differences in top-down processing. Our data suggest that a misalignment between gaze and auditory attention both reduce behavioural performance and modulate underlying neural processes. The involvement of central theta-band and occipital alpha-band effects are in line with compensatory neural mechanisms such as increased cognitive control and the suppression of task irrelevant inputs. Introduction In most natural listening situations, the focus of auditory attention (“where we are listening to”) is aligned with visual gaze direction (“where we are looking at”). However, there are many instances in everyday life, for example while driving, in which we can listen to somewhere else than where we are looking. At least subjectively, it appears that we are capable of directing the locus of our auditory attention independently of visual gaze. Here, we seek to understand how gazing toward versus away from the locus of auditory attention affects behavioural and neural responses to sounds, and its impact on global measures of brain states such as ongoing oscillatory activity. Visual gaze is usually an overt manifestation of selective visual attention 1 , 2 , and often tightly linked with attention in other modalities 3 , 4 . During dichotic listening tasks, spontaneous eye movements have been shown to occur preferentially toward the attended side 5 , 6 . Research in animals has shown that the direction of visual gaze modifies concurrent auditory processing. For example, Werner-Reiss et al . 7 found that eye position changes both the spontaneous activity and responses to sounds of neurons in the auditory cortex of awake macaques, even in complete darkness. Similarly, Groh et al . 8 demonstrated that in macaques eye position affects firing rates of auditory neurons already at the level of the inferior colliculus. In humans, research on the impact of gaze direction on auditory processing has mostly been limited to its effects on sound localization. For instance, Maddox et al . 9 reported that directing gaze toward a sound significantly enhances discrimination of both interaural level and time differences, whereas directing auditory spatial attention alone does not. Irrespective of gaze direction, a large number of electroencephalographic (EEG) studies in humans have shown that endogenous auditory attention can amplify event related potentials (ERPs) to sounds as early as 20 ms after stimulus onset 10 , 11 , 12 , 13 . These early attentional effects are thought to reflect a sensory selection mechanism, based on readily discriminable features such as spatial location 10 , 14 . In addition to unisensory auditory attention, covert visual attention to the location of a sound can both amplify ERPs, as well as facilitate behavioural responses to auditory targets 15 , 16 , 17 , demonstrating the potential impact of visual information on auditory processing. Apart from influencing phasic responses to single sounds, auditory attention also affects oscillatory neural activity in the alpha-band range (8–14 Hz) 18 , 19 . For example, Obleser and Weisz 19 presented human listeners with degraded speech, and found that occipital alpha band activity correlated with speech intelligibility and listening effort. More generally, alpha-band activity has been suggested to act as a local sensory gating mechanism, by which processing of relevant sensory inputs is enhanced and irrelevant input is suppressed 20 . Indicative of this, both visual and auditory spatial attention have been shown to induce lateralized changes in occipital alpha-band activity, with larger power contra- versus ipsilateral to the attended side 21 , 22 , 23 . While the topography of alpha-band modulation for visual and auditory attention overlaps, the underlying networks for the two modalities are likely distinct 18 , 21 . Prolonged attention and demanding cognitive performance has additionally been linked to increased central theta-band activity (4–7 Hz) 24 , 25 , and has been demonstrated for tasks in the auditory 26 , and visual 27 domain, as well as during multisensory processing 28 . For instance, Friese et al . 28 found increased fronto-medial theta-band activity during attended versus unattended trials in an audio-visual congruency detection paradigm. In summary, auditory attention in humans increases ERPs to sounds and modulates posterior alpha-band oscillations, while the amount of cognitive control required during a given task seems to be reflected in central theta-band activity. However, while there is increasing knowledge about the mechanisms of auditory attention as well as the mediating influence of visual gaze in other animals, the impact of gaze direction on human auditory processing is still largely unexplored. To our knowledge, the only previous electrophysiological study investigating gaze dependent changes in the quality of auditory processing in humans was performed by Okita and Wei 29 . Using EEG recordings from four electrodes, the authors show enhanced ERPs between 100 and 500 ms following a tone, when participants gazed towards versus away from the spatial source of the tone. This was interpreted as an increase of selectivity between relevant and irrelevant auditory inputs. However, this experiment suffers from a number of methodological limitations including the lack of quantifiable eye position monitoring. Furthermore, it did not find any behavioural effects of gaze direction on auditory processing. In the present EEG study, we used a full factorial design to investigate the impact of task irrelevant gaze<|im_end|> <|im_start|>assistant Listening to something while looking in a different direction can slow down reaction times while the brain works harder to suppress distractions, finds a new UCL study. In a study published in Scientific Reports, UCL researchers found that a misalignment between the direction of the eyes and the focus of auditory attention leads to slower reactions and increased listening effort. "We frequently listen away from where our eyes are directed, such as when driving, or eavesdropping to a conversation at a party. So in this study we asked a simple question: How does the mere direction of gaze, even in the absence of visual information, affect listening?" said the study's first author, Dr Ulrich Pomper (UCL Ear Institute). "We found that gazing away from what we are listening to is mentally taxing, and has detrimental consequences to performance." The study design aimed to re-create a simple everyday listening situation—attempting to follow a single sound from a mixture of several - but within a controlled lab environment. The 19 study participants each sat facing three loudspeakers arranged in front of them in a darkened, soundproof room. They were instructed to follow sounds from one of the loudspeakers while ignoring sounds from the other two loudspeakers. Simultaneously, they were directed to look at either the 'followed' loudspeaker or at one of the other (ignored) loudspeakers. A special camera was used to confirm that they were looking in the direction requested. As the participants concentrated, their brain activity was monitored with electroencephalography (EEG). The researchers found that the participants' reaction times were slower when they were instructed to look away from the attended loudspeaker and this was also accompanied by an increase in oscillatory neural activity (also known as 'brain waves'). "We found that the participants' brains were working hard to counteract the misalignment between gaze and auditory attention, even though the setup and tasks were very simple," said senior author Dr Maria Chait (UCL Ear Institute). "It is striking that simply shifting the direction of gaze a few degrees away from a sound source can have such a remarkable effect on brain activity. We think this is because our brains are wired to expect visual gaze direction and auditory attention to be aligned. The intuitive feeling that our auditory attention is independent from gaze is an illusion." "While our cohort of young participants exhibited only a relatively small slowing of reaction times, inconsistent gaze might have more severe consequences in older or hearing-impaired listeners and could lead to serious implications for safety when engaged in demanding tasks, like driving," she said. <|im_end|>

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1,795

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Computational modeling has been indispensable for understanding how subcellular neuronal features influence circuit processing. However, the role of dendritic computations in network-level operations remains largely unexplored. This is partly because existing tools do not allow the development of realistic and efficient network models that account for dendrites. Current spiking neural networks, although efficient, are usually quite simplistic, overlooking essential dendritic properties. Conversely, circuit models with morphologically detailed neuron models are computationally costly, thus impractical for large-network simulations. To bridge the gap between these two extremes and facilitate the adoption of dendritic features in spiking neural networks, we introduce Dendrify, an open-source Python package based on Brian 2. Dendrify, through simple commands, automatically generates reduced compartmental neuron models with simplified yet biologically relevant dendritic and synaptic integrative properties. Such models strike a good balance between flexibility, performance, and biological accuracy, allowing us to explore dendritic contributions to network-level functions while paving the way for developing more powerful neuromorphic systems. Introduction Simulations of spiking neural networks (SNNs) are widely used to understand how brain functions arise from area-specific network dynamics 1 , 2 , 3 . Moreover, SNNs have recently gained much attention for their value in low-power neuromorphic computing and practical machine learning applications 4 , 5 . SNNs typically comprise point, integrate-and-fire (I&F) neurons and replicate basic biological features such as specific connectivity motifs, excitation-inhibition dynamics, and learning via synaptic plasticity rules 6 , 7 , 8 , 9 . However, SNNs often ignore dendrites, the thin membranous extensions of neurons that receive the vast majority of incoming inputs. Numerous studies have shown that the dendrites of excitatory and inhibitory neurons possess compelling computational capabilities 10 , 11 that can significantly influence both neuronal and circuit function 12 , 13 , 14 , 15 and cannot be captured by point-neuron SNNs (for a recent review, see ref. 16 ). First, dendrites can act as semi-independent thresholding units, producing local regenerative events termed dendritic spikes (dSpikes). These spikes are generated by local voltage-gated mechanisms (e.g., Na + /Ca 2+ channels and NMDA receptors) and influence synaptic input integration and plasticity 10 , 11 . Moreover, dendritic mechanisms operate in multiple timescales, ranging from a few up to hundreds of milliseconds, allowing complex computations, including coincidence detection, low-pass filtering, input segregation/amplification, parallel nonlinear processing, and logical operations 17 , 18 , 19 , 20 , 21 , 22 . Due to these nonlinear phenomena, the arrangement of synapses along dendrites becomes a key determinant of local and somatic responses. For example, the impact of inhibitory pathways depends on their exact location relative to excitatory inputs 23 , 24 . Moreover, functionally related synapses can form anatomical clusters, which facilitate the induction of dSpikes, thus increasing computational efficiency and storage capacity 25 , 26 , 27 . Finally, dendritic morphology and passive properties shape the general electrotonic properties of neurons 10 . For example, dendritic filtering affects both the amplitude and the kinetics of synaptic currents traveling toward the soma in a location-dependent manner. Given the complexity of dendritic processing, SNNs that lack dendrites may fail to account for important dendritic contributions to neuronal integration and output, limiting their true computational power. Conversely, biophysical models of neurons with a detailed morphology are ideal for studying how dendritic processing affects neuronal computations at the single-cell level 16 . Such models comprise hundreds of compartments, each furnished with numerous ionic mechanisms to faithfully replicate the electrophysiological profile of simulated neurons. However, achieving high model accuracy is typically accompanied by increased complexity (e.g., higher CPU/GPU demands and larger run times), as numerous differential equations have to be solved at each simulation time step 16 . Therefore, this category of models is unsuitable for large-network simulations, where computational efficiency is a key priority. A middle-ground solution utilizes simplified models that capture only the essential electrophysiological characteristics of real neurons 28 , 29 , 30 , 31 , 32 , 33 . Notable examples of this approach are found in recent theoretical studies showing that dendritic mechanisms convey significant advantages to simplified network models of varying levels of abstraction. These include improved associative learning 12 , 27 , better input discrimination (pattern separation 34 ), efficient binding/linking of information 12 , 35 , and increased memory storage and recall capacity 14 , 36 . Similar advantages were recently seen in the machine learning field: adding dendritic nodes in artificial neural networks (ANNs) reduced the number of trainable parameters required to achieve high-performance accuracy 37 (also see 38 , 39 ). Moreover, incorporating dendritic nodes in Self Organizing Map classifiers 40 and other neuro-inspired networks 41 improved their continuous learning ability. Overall, while dendrites confer advanced computational power to simulated biological networks and these benefits are likely to extend to machine learning systems, SNNs remain largely dendrite-ignorant. A likely reason is that the current theoretical framework for modeling dendritic properties consists of overly complex equations with numerous free parameters, making it mathematically intractable and impractical for use in SNNs. To address the abovementioned complexity issues and provide a framework that allows the seamless incorporation of dendrites in SNN models, we developed Dendrify (Fig. 1 ). Dendrify is a free, open-source Python package that facilitates the addition of dendrites and various dendritic mechanisms in SNNs. Importantly, Dendrify works with the Brian 2 simulator 42 ; it builds upon the latter’s powerful and flexible features while automating some potentially complex and error-prone steps related to compartmental modeling. Specifically, through simple and intuitive commands, Dendrify automatically generates and handles all the equations (and most parameters) needed by Brian 2 to build simplified compartmental neurons. Its internal library of premade models supports a broad range of neuronal mechanisms yet allows users to provide their own model equations. Among other optimizations, we also introduce a novel phenomenological approach for modeling dSpikes, significantly more efficient and mathematically tractable than the Hodgkin–Huxley formalism. Moreover, we provide a step-by-step guide for designing reduced compartmental models that capture the key electrophysiological and anatomical properties of their biological", "role": "user" }, { "content": "FORTH-IMBB researchers have developed innovative computational tools to unravel the role of dendrites; complex neuronal brain structures with a key role in information processing. The new software allows the incorporation of important dendritic properties into neural network models. This work has important applications both in understanding brain function and in the field of artificial intelligence. Deciphering the secrets of the brain is considered to be one of the most important scientific endeavors of the 21st century. A better understanding of the mechanisms underlying brain function will contribute to research on the treatment of neurological diseases as well as the field of artificial intelligence, which has become an integral part of our society. In a recent publication, in Nature Communications, the team of Dr. Panayiota Poirazi, a Research Director at the Institute of Molecular Biology and Biotechnology (IMBB) of the Foundation for Research and Technology-Hellas (FORTH), presents a new software framework that allows the incorporation of dendrites and their key mechanisms into large-scale neural network models. Dendrites are the branched extensions of nerve cells that morphologically resemble the branches of a tree (hence their name). Their main function is to receive information from other neurons (in the form of electrical or chemical signals) and transmit it to the main body of the cell. For decades since their discovery, their role in information processing remained unknown, due to technological limitations in research. But recent studies reveal that dendrites have a wealth of mechanisms that allow them to perform complex mathematical calculations independent of the main neuron. At the same time, dendrites are equally important for the plasticity of the nervous system, i.e., the ability of the brain to change and adapt to its environment. This process plays a dominant role in complex brain functions, such as learning, memory, decision making and cognition. Although we now largely understand the contribution of dendrites to the behavior of a single neuron, their implications at the level of networks or entire brain regions remain unexplored. A small number of studies correlate dendritic complexity with various cognitive markers, and dendrites are known to decline during aging or in neurodegenerative diseases such as Alzheimer's. In addition, research on AI has already benefited from the use of dendritic mechanisms as a source of inspiration for the development of new improved and more efficient algorithms. However, many open questions remain and Dr. Poirazi's team hopes that the tools they are developing will facilitate the work of those attempting to understand the role of dendrites in brain function. This study introduces a new software framework that allows even naive users to build neuronal models with dendrites in a simple and efficient manner, thus minimizing computational complexity. Such computational models help to elucidate the role of dendrites in complex brain functions while also facilitating their incorporation in neuromorphic devices, a type of neuro-inspired artificial intelligence architecture. This effort was led by Michalis Pangalos, Ph.D. candidate in the Department of Biology of the University of Crete, in collaboration with Dr. Spiros Chavlis, postdoctoral researcher at IMBB, under the supervision of Dr. Poirazi. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Computational modeling has been indispensable for understanding how subcellular neuronal features influence circuit processing. However, the role of dendritic computations in network-level operations remains largely unexplored. This is partly because existing tools do not allow the development of realistic and efficient network models that account for dendrites. Current spiking neural networks, although efficient, are usually quite simplistic, overlooking essential dendritic properties. Conversely, circuit models with morphologically detailed neuron models are computationally costly, thus impractical for large-network simulations. To bridge the gap between these two extremes and facilitate the adoption of dendritic features in spiking neural networks, we introduce Dendrify, an open-source Python package based on Brian 2. Dendrify, through simple commands, automatically generates reduced compartmental neuron models with simplified yet biologically relevant dendritic and synaptic integrative properties. Such models strike a good balance between flexibility, performance, and biological accuracy, allowing us to explore dendritic contributions to network-level functions while paving the way for developing more powerful neuromorphic systems. Introduction Simulations of spiking neural networks (SNNs) are widely used to understand how brain functions arise from area-specific network dynamics 1 , 2 , 3 . Moreover, SNNs have recently gained much attention for their value in low-power neuromorphic computing and practical machine learning applications 4 , 5 . SNNs typically comprise point, integrate-and-fire (I&F) neurons and replicate basic biological features such as specific connectivity motifs, excitation-inhibition dynamics, and learning via synaptic plasticity rules 6 , 7 , 8 , 9 . However, SNNs often ignore dendrites, the thin membranous extensions of neurons that receive the vast majority of incoming inputs. Numerous studies have shown that the dendrites of excitatory and inhibitory neurons possess compelling computational capabilities 10 , 11 that can significantly influence both neuronal and circuit function 12 , 13 , 14 , 15 and cannot be captured by point-neuron SNNs (for a recent review, see ref. 16 ). First, dendrites can act as semi-independent thresholding units, producing local regenerative events termed dendritic spikes (dSpikes). These spikes are generated by local voltage-gated mechanisms (e.g., Na + /Ca 2+ channels and NMDA receptors) and influence synaptic input integration and plasticity 10 , 11 . Moreover, dendritic mechanisms operate in multiple timescales, ranging from a few up to hundreds of milliseconds, allowing complex computations, including coincidence detection, low-pass filtering, input segregation/amplification, parallel nonlinear processing, and logical operations 17 , 18 , 19 , 20 , 21 , 22 . Due to these nonlinear phenomena, the arrangement of synapses along dendrites becomes a key determinant of local and somatic responses. For example, the impact of inhibitory pathways depends on their exact location relative to excitatory inputs 23 , 24 . Moreover, functionally related synapses can form anatomical clusters, which facilitate the induction of dSpikes, thus increasing computational efficiency and storage capacity 25 , 26 , 27 . Finally, dendritic morphology and passive properties shape the general electrotonic properties of neurons 10 . For example, dendritic filtering affects both the amplitude and the kinetics of synaptic currents traveling toward the soma in a location-dependent manner. Given the complexity of dendritic processing, SNNs that lack dendrites may fail to account for important dendritic contributions to neuronal integration and output, limiting their true computational power. Conversely, biophysical models of neurons with a detailed morphology are ideal for studying how dendritic processing affects neuronal computations at the single-cell level 16 . Such models comprise hundreds of compartments, each furnished with numerous ionic mechanisms to faithfully replicate the electrophysiological profile of simulated neurons. However, achieving high model accuracy is typically accompanied by increased complexity (e.g., higher CPU/GPU demands and larger run times), as numerous differential equations have to be solved at each simulation time step 16 . Therefore, this category of models is unsuitable for large-network simulations, where computational efficiency is a key priority. A middle-ground solution utilizes simplified models that capture only the essential electrophysiological characteristics of real neurons 28 , 29 , 30 , 31 , 32 , 33 . Notable examples of this approach are found in recent theoretical studies showing that dendritic mechanisms convey significant advantages to simplified network models of varying levels of abstraction. These include improved associative learning 12 , 27 , better input discrimination (pattern separation 34 ), efficient binding/linking of information 12 , 35 , and increased memory storage and recall capacity 14 , 36 . Similar advantages were recently seen in the machine learning field: adding dendritic nodes in artificial neural networks (ANNs) reduced the number of trainable parameters required to achieve high-performance accuracy 37 (also see 38 , 39 ). Moreover, incorporating dendritic nodes in Self Organizing Map classifiers 40 and other neuro-inspired networks 41 improved their continuous learning ability. Overall, while dendrites confer advanced computational power to simulated biological networks and these benefits are likely to extend to machine learning systems, SNNs remain largely dendrite-ignorant. A likely reason is that the current theoretical framework for modeling dendritic properties consists of overly complex equations with numerous free parameters, making it mathematically intractable and impractical for use in SNNs. To address the abovementioned complexity issues and provide a framework that allows the seamless incorporation of dendrites in SNN models, we developed Dendrify (Fig. 1 ). Dendrify is a free, open-source Python package that facilitates the addition of dendrites and various dendritic mechanisms in SNNs. Importantly, Dendrify works with the Brian 2 simulator 42 ; it builds upon the latter’s powerful and flexible features while automating some potentially complex and error-prone steps related to compartmental modeling. Specifically, through simple and intuitive commands, Dendrify automatically generates and handles all the equations (and most parameters) needed by Brian 2 to build simplified compartmental neurons. Its internal library of premade models supports a broad range of neuronal mechanisms yet allows users to provide their own model equations. Among other optimizations, we also introduce a novel phenomenological approach for modeling dSpikes, significantly more efficient and mathematically tractable than the Hodgkin–Huxley formalism. Moreover, we provide a step-by-step guide for designing reduced compartmental models that capture the key electrophysiological and anatomical properties of their biological<|im_end|> <|im_start|>assistant FORTH-IMBB researchers have developed innovative computational tools to unravel the role of dendrites; complex neuronal brain structures with a key role in information processing. The new software allows the incorporation of important dendritic properties into neural network models. This work has important applications both in understanding brain function and in the field of artificial intelligence. Deciphering the secrets of the brain is considered to be one of the most important scientific endeavors of the 21st century. A better understanding of the mechanisms underlying brain function will contribute to research on the treatment of neurological diseases as well as the field of artificial intelligence, which has become an integral part of our society. In a recent publication, in Nature Communications, the team of Dr. Panayiota Poirazi, a Research Director at the Institute of Molecular Biology and Biotechnology (IMBB) of the Foundation for Research and Technology-Hellas (FORTH), presents a new software framework that allows the incorporation of dendrites and their key mechanisms into large-scale neural network models. Dendrites are the branched extensions of nerve cells that morphologically resemble the branches of a tree (hence their name). Their main function is to receive information from other neurons (in the form of electrical or chemical signals) and transmit it to the main body of the cell. For decades since their discovery, their role in information processing remained unknown, due to technological limitations in research. But recent studies reveal that dendrites have a wealth of mechanisms that allow them to perform complex mathematical calculations independent of the main neuron. At the same time, dendrites are equally important for the plasticity of the nervous system, i.e., the ability of the brain to change and adapt to its environment. This process plays a dominant role in complex brain functions, such as learning, memory, decision making and cognition. Although we now largely understand the contribution of dendrites to the behavior of a single neuron, their implications at the level of networks or entire brain regions remain unexplored. A small number of studies correlate dendritic complexity with various cognitive markers, and dendrites are known to decline during aging or in neurodegenerative diseases such as Alzheimer's. In addition, research on AI has already benefited from the use of dendritic mechanisms as a source of inspiration for the development of new improved and more efficient algorithms. However, many open questions remain and Dr. Poirazi's team hopes that the tools they are developing will facilitate the work of those attempting to understand the role of dendrites in brain function. This study introduces a new software framework that allows even naive users to build neuronal models with dendrites in a simple and efficient manner, thus minimizing computational complexity. Such computational models help to elucidate the role of dendrites in complex brain functions while also facilitating their incorporation in neuromorphic devices, a type of neuro-inspired artificial intelligence architecture. This effort was led by Michalis Pangalos, Ph.D. candidate in the Department of Biology of the University of Crete, in collaboration with Dr. Spiros Chavlis, postdoctoral researcher at IMBB, under the supervision of Dr. Poirazi. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Advances in machine learning and contactless sensors have given rise to ambient intelligence—physical spaces that are sensitive and responsive to the presence of humans. Here we review how this technology could improve our understanding of the metaphorically dark, unobserved spaces of healthcare. In hospital spaces, early applications could soon enable more efficient clinical workflows and improved patient safety in intensive care units and operating rooms. In daily living spaces, ambient intelligence could prolong the independence of older individuals and improve the management of individuals with a chronic disease by understanding everyday behaviour. Similar to other technologies, transformation into clinical applications at scale must overcome challenges such as rigorous clinical validation, appropriate data privacy and model transparency. Thoughtful use of this technology would enable us to understand the complex interplay between the physical environment and health-critical human behaviours. Main Boosted by innovations in data science and artificial intelligence 1 , 2 , decision-support systems are beginning to help clinicians to correct suboptimal and, in some cases, dangerous diagnostic and treatment decisions 3 , 4 , 5 . By contrast, the translation of better decisions into the physical actions performed by clinicians, patients and families remains largely unassisted 6 . Health-critical activities that occur in physical spaces, including hospitals and private homes, remain obscure. To gain the full dividends of medical advancements requires—in part—that affordable, human-centred approaches are continuously highlighted to assist clinicians in these metaphorically dark spaces. Despite numerous improvement initiatives, such as surgical safety checklists 7 , by the National Institutes of Health (NIH), Centres for Disease Control and Prevention (CDC), World Health Organization (WHO) and private organizations, as many as 400,000 people die every year in the United States owing to lapses and defects in clinical decision-making and physical actions 8 . Similar preventable suffering occurs in other countries, as well-motivated clinicians struggle with the rapidly growing complexity of modern healthcare 9 , 10 . To avoid overwhelming the cognitive capabilities of clinicians, advances in artificial intelligence hold the promise of assisting clinicians, not only with clinical decisions but also with the physical steps of clinical decisions 6 . Advances in machine learning and low-cost sensors can complement existing clinical decision-support systems by providing a computer-assisted understanding of the physical activities of healthcare. Passive, contactless sensors (Fig. 1 ) embedded in the environment can form an ambient intelligence that is aware of people’s movements and adapt to their continuing health needs 11 , 12 , 13 , 14 . Similar to modern driver-assistance systems, this form of ambient intelligence can help clinicians and in-home caregivers to perfect the physical motions that comprise the final steps of modern healthcare. Already enabling better manufacturing, safer autonomous vehicles and smarter sports entertainment 15 , clinical physical-action support can more reliably translate the rapid flow of biomedical discoveries into error-free healthcare delivery and worldwide human benefits. Fig. 1: Contactless sensors for ambient intelligence. Brightly coloured pixels denote objects that are closer to the depth sensor. Black pixels denote sensor noise caused by reflective, metallic objects. The radio sensor shows a micro-Doppler signature of a moving object, for which the x axis denotes time (5 s) and the y axis denotes the Doppler frequency. The radio sensor image is reproduced from ref. 89 . The acoustic sensor displays an audio waveform of a person speaking, for which the x axis denotes time (5 s) and the y axis denotes the signal amplitude. Full size image This Review explores how ambient, contactless sensors, in addition to contact-based wearable devices, can illuminate two health-critical environments: hospitals and daily living spaces. With several illustrative clinical-use cases, we review recent algorithmic research and clinical validation studies, citing key patient outcomes and technical challenges. We conclude with a discussion of broader social and ethical considerations including privacy, fairness, transparency and ethics. Additional references can be found in Supplementary Note 1 . Hospital spaces In 2018, approximately 7.4% of the US population required an overnight hospital stay 16 . In the same year, 17 million admission episodes were reported by the National Health Service (NHS) in the UK 17 . Yet, healthcare workers are often overworked, and hospitals understaffed and resource-limited 18 , 19 . We discuss a number of hospital spaces in which ambient intelligence may have an important role in improving the quality of healthcare delivery, the productivity of clinicians, and business operations (Fig. 2 ). These improvements could be of great assistance during healthcare crises, such as pandemics, during which time hospitals encounter a surge of patients 20 . Fig. 2: Ambient intelligence for hospitals. a , Commercial ambient sensor for which the coverage area is shown in green (that is, the field of view of visual sensors and range for acoustic and radio sensors). b , Sensors deployed inside a patient room can capture conversations and the physical motions of patients, clinicians and visitors. c , Sensors can be deployed throughout a hospital. d , Comparison of predictions and ground truth of activity from depth sensor data. Top, data from a depth sensor. Middle, the prediction of the algorithm of mobilization activity, duration and the number of staff who assist the patient. Bottom, human-annotated ground truth from a retrospective video review. d , Adapted from ref. 29 . Full size image Intensive care units Intensive care units (ICUs) are specialized hospital departments in which patients with life-threatening illnesses or critical organ failures are treated. In the United States, ICUs cost the health system US$108 billion per year 21 and account for up to 13% of all hospital costs 22 . One promising use case of ambient intelligence in ICUs is the computer-assisted monitoring of patient mobilization. ICU-acquired weaknesses are a common neuromuscular impairment in critically ill patients, potentially leading to a twofold increase in one-year mortality rate and 30% higher hospital costs 23 . Early patient mobilization could reduce the relative incidence of ICU-acquired weaknesses by 40% 24 . Currently, the standard mobility assessment is through direct, in-person observation, although its use is limited by", "role": "user" }, { "content": "As many as 400,000 Americans die each year because of medical errors, but many of these deaths could be prevented by using electronic sensors and artificial intelligence to help medical professionals monitor and treat vulnerable patients in ways that improve outcomes while respecting privacy. \"We have the ability to build technologies into the physical spaces where health care is delivered to help cut the rate of fatal errors that occur today due to the sheer volume of patients and the complexity of their care,\" said Arnold Milstein, a professor of medicine and director of Stanford's Clinical Excellence Research Center (CERC). Milstein, along with computer science professor Fei-Fei Li and graduate student Albert Haque, are co-authors of a Nature paper that reviews the field of \"ambient intelligence\" in health care—an interdisciplinary effort to create such smart hospital rooms equipped with AI systems that can do a range of things to improve outcomes. For example, sensors and AI can immediately alert clinicians and patient visitors when they fail to sanitize their hands before entering a hospital room. AI tools can be built into smart homes where technology could unobtrusively monitor the frail elderly for behavioral clues of impending health crises. And they prompt in-home caregivers, remotely located clinicians and patients themselves to make timely, life-saving interventions. Li, who is co-director of the Stanford Institute for Human-Centered Artificial Intelligence (HAI), said ambient technologies have many potential benefits, but they also raise legal and regulatory issues, as well as privacy concerns that must be identified and addressed in a public way to win the trust of patients and providers, as well as the various agencies and institutions that pay health care costs. \"Technology to protect the health of medically fragile populations is inherently human-centered,\" Li said. \"Researchers must listen to all the stakeholders in order to create systems that supplement and complement the efforts of nurses, doctors and other caregivers, as well as patients themselves.\" Li and Milstein co-direct the 8-year-old Stanford Partnership in AI-Assisted Care (PAC), one of a growing number of centers, including those at Johns Hopkins University and the University of Toronto, where technologists and clinicians have teamed up to develop ambient intelligence technologies to help health care providers manage patient volumes so huge—roughly 24 million Americans required an overnight hospital stay in 2018—that even the tiniest margin of error can cost many lives. \"We are in a foot race with the complexity of bedside care,\" Milstein said. \"By one recent count, clinicians in a hospital's neonatal intensive care unit took 600 bedside actions, per patient, per day. Without technology assistance, perfect execution of this volume of complex actions is well beyond what is reasonable to expect of even the most conscientious clinical teams.\" The Fix: Invisible light guided by AI? Haque, who compiled the 170 scientific papers cited in the Nature article, said the field is based largely on the convergence of two technological trends: the availability of infrared sensors that are inexpensive enough to build into high-risk care-giving environments, and the rise of machine learning systems as a way to use sensor input to train specialized AI applications in health care. The infrared technologies are of two types. The first is active infrared, such as the invisible light beams used by TV remote controls. But instead of simply beaming invisible light in one direction, like a TV remote, new active infrared systems use AI to compute how long it takes the invisible rays to bounce back to the source, like a light-based form of radar that maps the 3-D outlines of a person or object. Such infrared depth sensors are already being used outside hospital rooms, for instance, to discern whether a person washed their hands before entering and, if not, issue an alert. In one Stanford experiment, a tablet computer hung near the door shows a solid green screen that transitions to red, or some other alert color that might be tested, should a hygiene failure occur. Researchers had considered using audible warnings until medical professionals advised otherwise. \"Hospitals are already full of buzzes and beeps,\" Milstein said. \"Our human-centered design interviews with clinicians taught us that a visual cue would likely be more effective and less annoying.\" These alert systems are being tested to see if they can reduce the number of ICU patients who get nosocomial infections—potentially deadly illnesses contracted by patients due to failure of other people in the hospital to fully adhere to infection prevention protocols. The second type of infrared technology are passive detectors, of the sort that allow night vision goggles to create thermal images from the infrared rays generated by body heat. In a hospital setting, a thermal sensor above an ICU bed would enable the governing AI to detect twitching or writhing beneath the sheets, and alert clinical team members to impending health crises without constantly going from room to room. So far, the researchers have avoided using high-definition video sensors, such as those in smartphones, as capturing video imagery could unnecessarily intrude on the privacy of clinicians and patients. \"The silhouette images provided by infrared sensors may provide data that is sufficiently accurate to train AI algorithms for many clinically important applications,\" Haque said. Constant monitoring by ambient intelligence systems in a home environment could also be used to detect clues of serious illness or potential accidents, and alert caregivers to make timely interventions. For instance, when frail seniors start moving more slowly or stop eating regularly, such behaviors can presage depression, a greater likelihood of a fall or the rapid onset of a dangerous health crisis. Researchers are developing activity recognition algorithms that can sift through infrared sensing data to detect changes in habitual behaviors, and help caregivers get a more holistic view of patient well-being. Privacy is of particular concern in homes, assisted living settings and nursing homes, but \"the preliminary results we're getting from hospitals and daily living spaces confirm that ambient sensing technologies can provide the data we need to curb medical errors,\" Milstein said. \"Our Nature review tells the field that we're on the right track.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Advances in machine learning and contactless sensors have given rise to ambient intelligence—physical spaces that are sensitive and responsive to the presence of humans. Here we review how this technology could improve our understanding of the metaphorically dark, unobserved spaces of healthcare. In hospital spaces, early applications could soon enable more efficient clinical workflows and improved patient safety in intensive care units and operating rooms. In daily living spaces, ambient intelligence could prolong the independence of older individuals and improve the management of individuals with a chronic disease by understanding everyday behaviour. Similar to other technologies, transformation into clinical applications at scale must overcome challenges such as rigorous clinical validation, appropriate data privacy and model transparency. Thoughtful use of this technology would enable us to understand the complex interplay between the physical environment and health-critical human behaviours. Main Boosted by innovations in data science and artificial intelligence 1 , 2 , decision-support systems are beginning to help clinicians to correct suboptimal and, in some cases, dangerous diagnostic and treatment decisions 3 , 4 , 5 . By contrast, the translation of better decisions into the physical actions performed by clinicians, patients and families remains largely unassisted 6 . Health-critical activities that occur in physical spaces, including hospitals and private homes, remain obscure. To gain the full dividends of medical advancements requires—in part—that affordable, human-centred approaches are continuously highlighted to assist clinicians in these metaphorically dark spaces. Despite numerous improvement initiatives, such as surgical safety checklists 7 , by the National Institutes of Health (NIH), Centres for Disease Control and Prevention (CDC), World Health Organization (WHO) and private organizations, as many as 400,000 people die every year in the United States owing to lapses and defects in clinical decision-making and physical actions 8 . Similar preventable suffering occurs in other countries, as well-motivated clinicians struggle with the rapidly growing complexity of modern healthcare 9 , 10 . To avoid overwhelming the cognitive capabilities of clinicians, advances in artificial intelligence hold the promise of assisting clinicians, not only with clinical decisions but also with the physical steps of clinical decisions 6 . Advances in machine learning and low-cost sensors can complement existing clinical decision-support systems by providing a computer-assisted understanding of the physical activities of healthcare. Passive, contactless sensors (Fig. 1 ) embedded in the environment can form an ambient intelligence that is aware of people’s movements and adapt to their continuing health needs 11 , 12 , 13 , 14 . Similar to modern driver-assistance systems, this form of ambient intelligence can help clinicians and in-home caregivers to perfect the physical motions that comprise the final steps of modern healthcare. Already enabling better manufacturing, safer autonomous vehicles and smarter sports entertainment 15 , clinical physical-action support can more reliably translate the rapid flow of biomedical discoveries into error-free healthcare delivery and worldwide human benefits. Fig. 1: Contactless sensors for ambient intelligence. Brightly coloured pixels denote objects that are closer to the depth sensor. Black pixels denote sensor noise caused by reflective, metallic objects. The radio sensor shows a micro-Doppler signature of a moving object, for which the x axis denotes time (5 s) and the y axis denotes the Doppler frequency. The radio sensor image is reproduced from ref. 89 . The acoustic sensor displays an audio waveform of a person speaking, for which the x axis denotes time (5 s) and the y axis denotes the signal amplitude. Full size image This Review explores how ambient, contactless sensors, in addition to contact-based wearable devices, can illuminate two health-critical environments: hospitals and daily living spaces. With several illustrative clinical-use cases, we review recent algorithmic research and clinical validation studies, citing key patient outcomes and technical challenges. We conclude with a discussion of broader social and ethical considerations including privacy, fairness, transparency and ethics. Additional references can be found in Supplementary Note 1 . Hospital spaces In 2018, approximately 7.4% of the US population required an overnight hospital stay 16 . In the same year, 17 million admission episodes were reported by the National Health Service (NHS) in the UK 17 . Yet, healthcare workers are often overworked, and hospitals understaffed and resource-limited 18 , 19 . We discuss a number of hospital spaces in which ambient intelligence may have an important role in improving the quality of healthcare delivery, the productivity of clinicians, and business operations (Fig. 2 ). These improvements could be of great assistance during healthcare crises, such as pandemics, during which time hospitals encounter a surge of patients 20 . Fig. 2: Ambient intelligence for hospitals. a , Commercial ambient sensor for which the coverage area is shown in green (that is, the field of view of visual sensors and range for acoustic and radio sensors). b , Sensors deployed inside a patient room can capture conversations and the physical motions of patients, clinicians and visitors. c , Sensors can be deployed throughout a hospital. d , Comparison of predictions and ground truth of activity from depth sensor data. Top, data from a depth sensor. Middle, the prediction of the algorithm of mobilization activity, duration and the number of staff who assist the patient. Bottom, human-annotated ground truth from a retrospective video review. d , Adapted from ref. 29 . Full size image Intensive care units Intensive care units (ICUs) are specialized hospital departments in which patients with life-threatening illnesses or critical organ failures are treated. In the United States, ICUs cost the health system US$108 billion per year 21 and account for up to 13% of all hospital costs 22 . One promising use case of ambient intelligence in ICUs is the computer-assisted monitoring of patient mobilization. ICU-acquired weaknesses are a common neuromuscular impairment in critically ill patients, potentially leading to a twofold increase in one-year mortality rate and 30% higher hospital costs 23 . Early patient mobilization could reduce the relative incidence of ICU-acquired weaknesses by 40% 24 . Currently, the standard mobility assessment is through direct, in-person observation, although its use is limited by<|im_end|> <|im_start|>assistant As many as 400,000 Americans die each year because of medical errors, but many of these deaths could be prevented by using electronic sensors and artificial intelligence to help medical professionals monitor and treat vulnerable patients in ways that improve outcomes while respecting privacy. "We have the ability to build technologies into the physical spaces where health care is delivered to help cut the rate of fatal errors that occur today due to the sheer volume of patients and the complexity of their care," said Arnold Milstein, a professor of medicine and director of Stanford's Clinical Excellence Research Center (CERC). Milstein, along with computer science professor Fei-Fei Li and graduate student Albert Haque, are co-authors of a Nature paper that reviews the field of "ambient intelligence" in health care—an interdisciplinary effort to create such smart hospital rooms equipped with AI systems that can do a range of things to improve outcomes. For example, sensors and AI can immediately alert clinicians and patient visitors when they fail to sanitize their hands before entering a hospital room. AI tools can be built into smart homes where technology could unobtrusively monitor the frail elderly for behavioral clues of impending health crises. And they prompt in-home caregivers, remotely located clinicians and patients themselves to make timely, life-saving interventions. Li, who is co-director of the Stanford Institute for Human-Centered Artificial Intelligence (HAI), said ambient technologies have many potential benefits, but they also raise legal and regulatory issues, as well as privacy concerns that must be identified and addressed in a public way to win the trust of patients and providers, as well as the various agencies and institutions that pay health care costs. "Technology to protect the health of medically fragile populations is inherently human-centered," Li said. "Researchers must listen to all the stakeholders in order to create systems that supplement and complement the efforts of nurses, doctors and other caregivers, as well as patients themselves." Li and Milstein co-direct the 8-year-old Stanford Partnership in AI-Assisted Care (PAC), one of a growing number of centers, including those at Johns Hopkins University and the University of Toronto, where technologists and clinicians have teamed up to develop ambient intelligence technologies to help health care providers manage patient volumes so huge—roughly 24 million Americans required an overnight hospital stay in 2018—that even the tiniest margin of error can cost many lives. "We are in a foot race with the complexity of bedside care," Milstein said. "By one recent count, clinicians in a hospital's neonatal intensive care unit took 600 bedside actions, per patient, per day. Without technology assistance, perfect execution of this volume of complex actions is well beyond what is reasonable to expect of even the most conscientious clinical teams." The Fix: Invisible light guided by AI? Haque, who compiled the 170 scientific papers cited in the Nature article, said the field is based largely on the convergence of two technological trends: the availability of infrared sensors that are inexpensive enough to build into high-risk care-giving environments, and the rise of machine learning systems as a way to use sensor input to train specialized AI applications in health care. The infrared technologies are of two types. The first is active infrared, such as the invisible light beams used by TV remote controls. But instead of simply beaming invisible light in one direction, like a TV remote, new active infrared systems use AI to compute how long it takes the invisible rays to bounce back to the source, like a light-based form of radar that maps the 3-D outlines of a person or object. Such infrared depth sensors are already being used outside hospital rooms, for instance, to discern whether a person washed their hands before entering and, if not, issue an alert. In one Stanford experiment, a tablet computer hung near the door shows a solid green screen that transitions to red, or some other alert color that might be tested, should a hygiene failure occur. Researchers had considered using audible warnings until medical professionals advised otherwise. "Hospitals are already full of buzzes and beeps," Milstein said. "Our human-centered design interviews with clinicians taught us that a visual cue would likely be more effective and less annoying." These alert systems are being tested to see if they can reduce the number of ICU patients who get nosocomial infections—potentially deadly illnesses contracted by patients due to failure of other people in the hospital to fully adhere to infection prevention protocols. The second type of infrared technology are passive detectors, of the sort that allow night vision goggles to create thermal images from the infrared rays generated by body heat. In a hospital setting, a thermal sensor above an ICU bed would enable the governing AI to detect twitching or writhing beneath the sheets, and alert clinical team members to impending health crises without constantly going from room to room. So far, the researchers have avoided using high-definition video sensors, such as those in smartphones, as capturing video imagery could unnecessarily intrude on the privacy of clinicians and patients. "The silhouette images provided by infrared sensors may provide data that is sufficiently accurate to train AI algorithms for many clinically important applications," Haque said. Constant monitoring by ambient intelligence systems in a home environment could also be used to detect clues of serious illness or potential accidents, and alert caregivers to make timely interventions. For instance, when frail seniors start moving more slowly or stop eating regularly, such behaviors can presage depression, a greater likelihood of a fall or the rapid onset of a dangerous health crisis. Researchers are developing activity recognition algorithms that can sift through infrared sensing data to detect changes in habitual behaviors, and help caregivers get a more holistic view of patient well-being. Privacy is of particular concern in homes, assisted living settings and nursing homes, but "the preliminary results we're getting from hospitals and daily living spaces confirm that ambient sensing technologies can provide the data we need to curb medical errors," Milstein said. "Our Nature review tells the field that we're on the right track." <|im_end|>

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2,481

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Engineered living materials (ELMs) based on bacterial cellulose (BC) offer a promising avenue for cheap-to-produce materials that can be programmed with genetically encoded functionalities. Here we explore how ELMs can be fabricated in a modular fashion from millimetre-scale biofilm spheroids grown from shaking cultures of Komagataeibacter rhaeticus . Here we define a reproducible protocol to produce BC spheroids with the high yield bacterial cellulose producer K. rhaeticus and demonstrate for the first time their potential for their use as building blocks to grow ELMs in 3D shapes. Using genetically engineered K. rhaeticus , we produce functionalized BC spheroids and use these to make and grow patterned BC-based ELMs that signal within a material and can sense and report on chemical inputs. We also investigate the use of BC spheroids as a method to regenerate damaged BC materials and as a way to fuse together smaller material sections of cellulose and synthetic materials into a larger piece. This work improves our understanding of BC spheroid formation and showcases their great potential for fabricating, patterning and repairing ELMs based on the promising biomaterial of bacterial cellulose. Introduction Engineered living materials (ELMs) are those containing cells on or within the material that play a role in its functionalisation or can produce the material itself 1 , 2 , 3 , 4 . Bacterial cellulose (BC) is a carbohydrate polymer produced by many bacterial species as a structural element of their biofilm and offers excellent opportunities for developing new ELMs 5 . In the past decade, progress in understanding and producing BC has now led to its use in a broad range of applications, including products used in textiles, cosmetics, healthcare, audio-visual technology and architecture 6 , 7 , 8 , 9 . The BC produced by several Acetobacteriacea species are of particular interest as these are quickly and cheaply made as pellicles—a large mass of thick BC—when the cells are grown in static rich media 10 , 11 . BC inherently has attractive high-performance mechanical properties and crystallinity, has a high water-retention capacity and is ultra-pure compared to plant cellulose 12 , 13 . These outstanding properties of BC make it an excellent candidate for developing new materials with improved technical and environmental benefits. Most of applications use sterile, purified BC as a bulk specialised material; however, BC has also shown promise as an ELM 14 , 15 . In one recent example, incorporating Bacillus subtilis cells into BC-based wound dressings helped to prevent wound infections by blocking the growth of several pathogenic bacteria 16 . Two desirable features of ELMs not routinely seen in normal materials are modular design and regeneration in response to damage. Easy and cheap repair of damaged materials (or their automatic regeneration) is an important consideration for the sustainability of all new materials 17 . BC offers excellent opportunities in this regard, because the bacteria trapped in the grown material have the potential to regenerate it by further growth and cellulose production in the future. Hypothetically, by providing nutrients, water and oxygen, the bacteria can keep growing and seal gaps and tears when they arise, so long as the material has not been dehydrated or sterilised after growth. For patterned functionalities, this can also theoretically be achieved with BC-based materials by growing these from genetically engineered cells 5 . However, another possibility to tackle this problem could be to use modular ELM building blocks and pattern these physically as a mosaic to make larger materials. Such a ‘building block’ approach to novel materials has been taken before in nanotechnology to increase the complexity of materials and to facilitate industrial scaling of complex pieces 18 . Modular BC-based building blocks have not been explored before in an ELM context, but BC and in particular its rapid production from living cells within the material structure offers an excellent opportunity to tackle this challenge. Past work has shown several solutions for building BC into shapes other than the standard flat pellicles. Growing BC in hyper-hydrophobic moulds has allowed researchers to create a versatile range of three-dimensional (3D) shapes with high accuracy 19 , 20 . However, moulds are limited in what they can achieve in terms of size, require mould design and fabrication and typically work just for growing one material at a time. Creating patterns of functionalised BC grown from several different cell types would prove unattainable with this approach and so limits its use for creating 3D functionalised patterned BC-based ELMs. 3D printing of cells with semi-solid growth support materials is more promising in terms of creating 3D ELMs incorporating multiple strains in patterns 21 . However, the additive manufacturing approach relies on specialised equipment and the majority of the product is support material, rather than living material. A building-block approach where modular units of living material grow and self-connect into 3D shapes would be less cumbersome. BC grows as floating pellicles in the air–liquid interphase of glucose-rich media. Under shaking conditions, some strains may produce millimetre-scale rounded BC particles named variously in the literature as spheroids, spherical granules, sphere-like BC or sphere-like BC particles 22 , 23 , 24 . Here we introduce the concept of using BC spheroids as a building block to make and engineer 3D BC-based ELMs. Growth of BC spheroids has remained poorly understood and is typically characterised as being strain dependent or inconsistently produced 22 . Here we now define a reproducible method to produce BC spheroids from the bacterium Komagataeibacter rhaeticus . We use these BC spheroids as building blocks to build 3D shapes and to create patterned ELMs made of spheroids containing genetically functionalised bacteria that impart fluorescence and send and receive signals. We further demonstrate that spheroid building blocks can be used to regenerate damaged BC materials as fresh, stored or purified spheroids and that this can be used to fuse and assemble independent BC pieces in a mosaic fashion. Results BC spheroids BC spheroids have been reported in several previous studies 22 , 23 , 24 , but", "role": "user" }, { "content": "Imperial College London researchers have created 3D building blocks that can heal themselves in response to damage. The engineered living materials (ELMs) exploit biology's ability to heal and replenish material and could respond to damage in harsh environments using a sense-and-response system. This work, published in Nature Communications, could lead to the creation of real-world materials that detect and heal their own damage, such as fixing a crack in a windshield, a tear in the fuselage of an aircraft or a pothole in the road. By integrating the building blocks into self-healing building materials, scientists could reduce the amount of maintenance needed and extend a material's life and usefulness. Lead author Professor Tom Ellis of the Department of Bioengineering at Imperial says that \"in the past we've created living materials with inbuilt sensors that can detect environmental cues and changes. Now we've created living materials that can detect damage and respond to it by healing themselves.\" In the same way that architecture uses modular pieces that can be assembled into a variety of building structures, this research demonstrates that the same principle can be applied to the design and construction of bacterial cellulose-based materials. To create ELMs, the researchers genetically engineered bacteria called Komagataeibacter rhaeticus to have them produce fluorescent 3D sphere-shaped cell cultures, known as spheroids, and to give them sensors which detect damage. They arranged the spheroids into different shapes and patterns, demonstrating the potential of spheroids as modular building blocks. Patterns and 3D shapes made from the spheroids. Credit: Imperial College London They used a hole punch to damage a thick layer of bacterial cellulose—the scaffold-like material made by some bacteria on which ELMs are produced. They then inserted the freshly grown spheroids into the holes and, after incubating them for three days, saw excellent repair that was structurally stable and restored the consistency and appearance of the material. Professor Ellis says that \"by placing the spheroids into the damaged area and incubating the cultures, the blocks were able to both sense the damage and regrow the material to repair it.\" First author Dr. Joaquin Caro-Astorga of Imperial's Department of Bioengineering says that their \"discovery opens a new approach where grown materials can be used as modules with different functions like in construction. We are currently working on hosting other living organisms within the spheroids that can live together with the cellulose-producing bacteria. \"The possible living materials that can come from this are diverse: for example, with yeast cells that secrete medically-relevant proteins, we could generate wound-healing films where hormones and enzymes are produced by a bandage to improve skin repair.\" The growth in popularity of bacterial cellulose for its outstanding properties is the response to the worldwide challenge to find new materials with better-tailored functional behaviors. Dr. Patrick Rose, science director of US Office of Naval Research Global London, which part-funded the research, says that \"the challenge is to mimic and combine the distinct features biology has to offer. We are not only trying to emulate those systems, but engineer biology to have additional features that are more amenable to the needs we seek without direct intervention. Ultimately, we want to increase the lifetime of a product, prevent failures of systems before the problem is visible to the naked eye and have the material think for itself.\" The next step for this group of researchers is to develop new spheroid building blocks with different properties, such as combining them with materials like cotton, graphite and gelatins to create more complex designs. This could lead to new applications like biological filters, implantable electronics or medical biosensor patches. \"Bacterial cellulose spheroids as building blocks for 3D and patterned living materials and for regeneration\" by Ellis et al., published 19 August 2021 in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Engineered living materials (ELMs) based on bacterial cellulose (BC) offer a promising avenue for cheap-to-produce materials that can be programmed with genetically encoded functionalities. Here we explore how ELMs can be fabricated in a modular fashion from millimetre-scale biofilm spheroids grown from shaking cultures of Komagataeibacter rhaeticus . Here we define a reproducible protocol to produce BC spheroids with the high yield bacterial cellulose producer K. rhaeticus and demonstrate for the first time their potential for their use as building blocks to grow ELMs in 3D shapes. Using genetically engineered K. rhaeticus , we produce functionalized BC spheroids and use these to make and grow patterned BC-based ELMs that signal within a material and can sense and report on chemical inputs. We also investigate the use of BC spheroids as a method to regenerate damaged BC materials and as a way to fuse together smaller material sections of cellulose and synthetic materials into a larger piece. This work improves our understanding of BC spheroid formation and showcases their great potential for fabricating, patterning and repairing ELMs based on the promising biomaterial of bacterial cellulose. Introduction Engineered living materials (ELMs) are those containing cells on or within the material that play a role in its functionalisation or can produce the material itself 1 , 2 , 3 , 4 . Bacterial cellulose (BC) is a carbohydrate polymer produced by many bacterial species as a structural element of their biofilm and offers excellent opportunities for developing new ELMs 5 . In the past decade, progress in understanding and producing BC has now led to its use in a broad range of applications, including products used in textiles, cosmetics, healthcare, audio-visual technology and architecture 6 , 7 , 8 , 9 . The BC produced by several Acetobacteriacea species are of particular interest as these are quickly and cheaply made as pellicles—a large mass of thick BC—when the cells are grown in static rich media 10 , 11 . BC inherently has attractive high-performance mechanical properties and crystallinity, has a high water-retention capacity and is ultra-pure compared to plant cellulose 12 , 13 . These outstanding properties of BC make it an excellent candidate for developing new materials with improved technical and environmental benefits. Most of applications use sterile, purified BC as a bulk specialised material; however, BC has also shown promise as an ELM 14 , 15 . In one recent example, incorporating Bacillus subtilis cells into BC-based wound dressings helped to prevent wound infections by blocking the growth of several pathogenic bacteria 16 . Two desirable features of ELMs not routinely seen in normal materials are modular design and regeneration in response to damage. Easy and cheap repair of damaged materials (or their automatic regeneration) is an important consideration for the sustainability of all new materials 17 . BC offers excellent opportunities in this regard, because the bacteria trapped in the grown material have the potential to regenerate it by further growth and cellulose production in the future. Hypothetically, by providing nutrients, water and oxygen, the bacteria can keep growing and seal gaps and tears when they arise, so long as the material has not been dehydrated or sterilised after growth. For patterned functionalities, this can also theoretically be achieved with BC-based materials by growing these from genetically engineered cells 5 . However, another possibility to tackle this problem could be to use modular ELM building blocks and pattern these physically as a mosaic to make larger materials. Such a ‘building block’ approach to novel materials has been taken before in nanotechnology to increase the complexity of materials and to facilitate industrial scaling of complex pieces 18 . Modular BC-based building blocks have not been explored before in an ELM context, but BC and in particular its rapid production from living cells within the material structure offers an excellent opportunity to tackle this challenge. Past work has shown several solutions for building BC into shapes other than the standard flat pellicles. Growing BC in hyper-hydrophobic moulds has allowed researchers to create a versatile range of three-dimensional (3D) shapes with high accuracy 19 , 20 . However, moulds are limited in what they can achieve in terms of size, require mould design and fabrication and typically work just for growing one material at a time. Creating patterns of functionalised BC grown from several different cell types would prove unattainable with this approach and so limits its use for creating 3D functionalised patterned BC-based ELMs. 3D printing of cells with semi-solid growth support materials is more promising in terms of creating 3D ELMs incorporating multiple strains in patterns 21 . However, the additive manufacturing approach relies on specialised equipment and the majority of the product is support material, rather than living material. A building-block approach where modular units of living material grow and self-connect into 3D shapes would be less cumbersome. BC grows as floating pellicles in the air–liquid interphase of glucose-rich media. Under shaking conditions, some strains may produce millimetre-scale rounded BC particles named variously in the literature as spheroids, spherical granules, sphere-like BC or sphere-like BC particles 22 , 23 , 24 . Here we introduce the concept of using BC spheroids as a building block to make and engineer 3D BC-based ELMs. Growth of BC spheroids has remained poorly understood and is typically characterised as being strain dependent or inconsistently produced 22 . Here we now define a reproducible method to produce BC spheroids from the bacterium Komagataeibacter rhaeticus . We use these BC spheroids as building blocks to build 3D shapes and to create patterned ELMs made of spheroids containing genetically functionalised bacteria that impart fluorescence and send and receive signals. We further demonstrate that spheroid building blocks can be used to regenerate damaged BC materials as fresh, stored or purified spheroids and that this can be used to fuse and assemble independent BC pieces in a mosaic fashion. Results BC spheroids BC spheroids have been reported in several previous studies 22 , 23 , 24 , but<|im_end|> <|im_start|>assistant Imperial College London researchers have created 3D building blocks that can heal themselves in response to damage. The engineered living materials (ELMs) exploit biology's ability to heal and replenish material and could respond to damage in harsh environments using a sense-and-response system. This work, published in Nature Communications, could lead to the creation of real-world materials that detect and heal their own damage, such as fixing a crack in a windshield, a tear in the fuselage of an aircraft or a pothole in the road. By integrating the building blocks into self-healing building materials, scientists could reduce the amount of maintenance needed and extend a material's life and usefulness. Lead author Professor Tom Ellis of the Department of Bioengineering at Imperial says that "in the past we've created living materials with inbuilt sensors that can detect environmental cues and changes. Now we've created living materials that can detect damage and respond to it by healing themselves." In the same way that architecture uses modular pieces that can be assembled into a variety of building structures, this research demonstrates that the same principle can be applied to the design and construction of bacterial cellulose-based materials. To create ELMs, the researchers genetically engineered bacteria called Komagataeibacter rhaeticus to have them produce fluorescent 3D sphere-shaped cell cultures, known as spheroids, and to give them sensors which detect damage. They arranged the spheroids into different shapes and patterns, demonstrating the potential of spheroids as modular building blocks. Patterns and 3D shapes made from the spheroids. Credit: Imperial College London They used a hole punch to damage a thick layer of bacterial cellulose—the scaffold-like material made by some bacteria on which ELMs are produced. They then inserted the freshly grown spheroids into the holes and, after incubating them for three days, saw excellent repair that was structurally stable and restored the consistency and appearance of the material. Professor Ellis says that "by placing the spheroids into the damaged area and incubating the cultures, the blocks were able to both sense the damage and regrow the material to repair it." First author Dr. Joaquin Caro-Astorga of Imperial's Department of Bioengineering says that their "discovery opens a new approach where grown materials can be used as modules with different functions like in construction. We are currently working on hosting other living organisms within the spheroids that can live together with the cellulose-producing bacteria. "The possible living materials that can come from this are diverse: for example, with yeast cells that secrete medically-relevant proteins, we could generate wound-healing films where hormones and enzymes are produced by a bandage to improve skin repair." The growth in popularity of bacterial cellulose for its outstanding properties is the response to the worldwide challenge to find new materials with better-tailored functional behaviors. Dr. Patrick Rose, science director of US Office of Naval Research Global London, which part-funded the research, says that "the challenge is to mimic and combine the distinct features biology has to offer. We are not only trying to emulate those systems, but engineer biology to have additional features that are more amenable to the needs we seek without direct intervention. Ultimately, we want to increase the lifetime of a product, prevent failures of systems before the problem is visible to the naked eye and have the material think for itself." The next step for this group of researchers is to develop new spheroid building blocks with different properties, such as combining them with materials like cotton, graphite and gelatins to create more complex designs. This could lead to new applications like biological filters, implantable electronics or medical biosensor patches. "Bacterial cellulose spheroids as building blocks for 3D and patterned living materials and for regeneration" by Ellis et al., published 19 August 2021 in Nature Communications. <|im_end|>

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21483, 323, 311, 1893, 5497, 291, 469, 11237, 82, 1903, 315, 274, 29182, 17390, 8649, 52033, 16003, 4147, 24032, 430, 70772, 97332, 323, 3708, 323, 5371, 17738, 13, 1226, 4726, 20461, 430, 274, 29182, 590, 4857, 10215, 649, 387, 1511, 311, 80551, 20727, 18531, 7384, 439, 7878, 11, 9967, 477, 92600, 274, 29182, 17390, 323, 430, 420, 649, 387, 1511, 311, 32802, 323, 42840, 9678, 18531, 9863, 304, 264, 71624, 11401, 13, 18591, 18531, 274, 29182, 17390, 18531, 274, 29182, 17390, 617, 1027, 5068, 304, 3892, 3766, 7978, 220, 1313, 1174, 220, 1419, 1174, 220, 1187, 1174, 719, 128257, 198, 128256, 78191, 198, 1453, 68327, 9304, 7295, 12074, 617, 3549, 220, 18, 35, 4857, 10215, 430, 649, 27661, 5694, 304, 2077, 311, 5674, 13, 578, 46036, 5496, 7384, 320, 2818, 22365, 8, 33294, 34458, 596, 5845, 311, 27661, 323, 70543, 819, 3769, 323, 1436, 6013, 311, 5674, 304, 25984, 22484, 1701, 264, 5647, 9976, 59569, 1887, 13, 1115, 990, 11, 4756, 304, 22037, 26545, 11, 1436, 3063, 311, 279, 9886, 315, 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323, 369, 60517, 1, 555, 44707, 1880, 453, 2637, 4756, 220, 777, 6287, 220, 2366, 16, 304, 22037, 26545, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum. Introduction Ashkenazi Jews (AJ), identified as Jewish individuals of Central- and Eastern European ancestry, form the largest genetic isolate in the United States. AJ demonstrate distinctive genetic characteristics 1 , 2 , including high prevalence of autosomal recessive diseases and relatively high frequency of alleles that confer a strong risk of common diseases, such as Parkinson’s disease 3 and breast and ovarian cancer 4 . Several recent studies have employed common polymorphisms 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 to characterize AJ as a genetically distinct population, close to other Jewish populations as well as to present-day Middle Eastern and European populations. Previous analyses of recent AJ history highlighted a narrow population bottleneck of only hundreds of individuals in late medieval times, followed by rapid expansion 12 , 14 . The AJ population is much larger and/or experienced a more severe bottleneck than other founder populations, such as Amish, Hutterites or Icelanders 15 , whose demographic histories facilitated a steady stream of genetic discoveries. This suggests the potential for cataloguing nearly all founder variants in a large extant population by sequencing a limited number of samples, who represent the diversity in the founding group (for example, ref. 16 ). Such a catalogue of variants can make a threefold contribution: First, it will enable clinical interpretation of personal genomes in the sizeable AJ population by distinguishing between background variation and recent, potentially more deleterious mutations. Second, it will improve disease mapping in AJ by increasing the accuracy of imputation. Third, the ability to extensively sample a population with ancient roots in the Levant is expected to provide insights regarding the histories of both Middle Eastern and European populations. Here we report a catalogue of 128 high coverage, whole-genome AJ sequences. Compared with a European reference panel, the AJ panel has more novel and population-specific variants, and we demonstrate that the AJ panel is necessary for interpretation and imputation of AJ personal genomes. Analysis of long shared segments, which are abundant in AJ, confirms a recent severe bottleneck and potential utility in future sequencing studies. The joint AJ–European allele frequency spectrum suggests that the AJ population is an even mix of European and Middle Eastern ancestral populations and quantifies ancient bottlenecks and population splits. Finally, we report the deleterious mutation load in AJ to be slightly higher than in Europeans. Results We sequenced a panel ( n =128) of controls of self-reported and empirically validated AJ ancestry ( Supplementary Note 1 ; Supplementary Table 1 ; Supplementary Fig. 1 ). The high coverage sequence (>50 × ), generated by Complete Genomics 17 , showed multiple quality control (QC) indicators supporting both high quality and completeness of the single-nucleotide variant (SNV) data: 97% coverage of the genome ( Supplementary Note 2 ; Supplementary Table 2 ), inferred discordance of 0.047% to high quality genotypes in SNP arrays ( Supplementary Note 2 ; Supplementary Data 1 ), transition/transversion ratio of 2.14, and consistency of QC measures across potential sources of bias ( Supplementary Note 2 ; Supplementary Data 2 ; Supplementary Figs 1 and 2 ). The average raw number of non-reference SNVs called per individual was 3.412 M, including 10.5K coding synonymous changes and 9.7K non-synonymous ones ( Supplementary Data 2 ). An additional 538K multinucleotide variants, 4.1K mobile element insertions, and 302 copy number variants (spanning 6.7 Mbp) were observed, on average, in each sample ( Supplementary Data 2 ). However, inspection of novel non-SNVs demonstrated high false-positive rates ( Supplementary Note 2 ), and we thus focused on autosomal, bi-allelic SNVs for all subsequent analyses. We applied strict multisample filters ( Supplementary Note 2 ) to generate a working set of 12,326,197 high quality SNVs, of which 2,891,414 were novel (23.5%; dbSNP135). Quality was gauged by a sequenced duplicate as well as runs-of-homozygosity, which are sufficiently frequent in AJ for this purpose, providing estimates of ≈6,000–8,000 false positives genome wide ( Supplementary Note 2 ), in line with previous benchmarks of this technology 17 . Principal component analysis of common variants in the sequenced AJ samples confirmed previous observations 5 , 6 , 9 , 10 , namely, that AJ form a distinct cluster with proximity to other Jewish, European and Middle Eastern populations ( Supplementary Fig. 1 ). Our reference panel is expected to improve the ability to catalogue variants and haplotypes in the Ashkenazi population, beyond what is possible with non-ancestry-matched reference samples. A natural panel for comparison would be the European samples from the 1000 Genomes Project 18 . However, to match the high depth of our data and the sequencing platform used to obtain it, we chose as our primary comparison data set a cohort of Flemish (FL) personal genomes ( n =26) from Belgium ( Supplementary Note 2 ). We merged our first batch of AJ genomes ( n =57) with the FL data, applying a QC pipeline attempting to remove all potentially artifactual population-specific variants ( Supplementary Note 2 ).", "role": "user" }, { "content": "Led by Itsik Pe'er, associate professor of computer science at Columbia Engineering, a team of researchers has created a data resource that will improve genomic research in the Ashkenazi Jewish population and lead to more effective personalized medicine. The team, which includes experts from 11 labs in the New York City area and Israel, focused on the Ashkenazi Jewish population because of its demographic history of genetic isolation and the resulting abundance of population-specific mutations and high prevalence of rare genetic disorders. The Ashkenazi Jewish population has played an important role in human genetics, with notable successes in gene mapping as well as prenatal and cancer screening. The study was published online on Nature Communications today. \"Our study is the first full DNA sequence dataset available for Ashkenazi Jewish genomes,\" says Pe'er, who is also a co-chair of the Health Analytics Center at Columbia's Institute for Data Sciences and Engineering, as well as a member of its Foundations of Data Science Center. \"With this comprehensive catalog of mutations present in the Ashkenazi Jewish population, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders. We see this study serving as a vehicle for personalized medicine and a model for researchers working with other populations.\" To help in his hunt for disease genes, Pe'er founded The Ashkenazi Genome Consortium (TAGC) in September 2011 with Todd Lencz, an investigator at The Feinstein Institute for Medical Research, director of the Laboratory of Analytic Genomics at the Zucker Hillside Hospital, and associate professor of molecular medicine and psychiatry at the Hofstra North Shore-LIJ School of Medicine. The other TAGC members, who are providing expertise in the diseases they are studying, are: Gil Atzmon, associate professor of medicine and genetics, Albert Einstein College of Medicine (genetics of longevity and diabetes);Lorraine Clark, associate professor of clinical pathology and cell biology and co-director, Personalized Genomic Medicine Laboratory, Columbia University Medical Center, Laurie Ozelius, associate professor at Icahn School of Medicine at Mount Sinai, and Susan Bressman, chair of neurology at Mount Sinai Beth Israel (Parkinson's disease and related neurological phenotypes);Harry Ostrer, professor of pathology, genetics, and pediatrics, Albert Einstein College of Medicine (radiogenomics, cancers and rare genetic disorders);Ken Offit, chief of clinical genetics at Memorial Sloan Kettering Cancer Center (breast, ovarian, colon and prostate cancers, lymphoma);Inga Peter, associate professor of genetics and genomic sciences, and Judy Cho, professor of medicine and professor of genetics and genomic sciences, both at The Mount Sinai Hospital (inflammatory bowel disease); andAriel Darvasi, vice-dean of The Faculty of Life Sciences at The Hebrew University of Jerusalem (multiple diseases). Before the TAGC study, data was available for a limited number of DNA markers (only approximately one in every 3000 letters of DNA) that are mostly common in Europeans. The TAGC researchers performed high-depth sequencing of 128 complete genomes of Ashkenazi Jewish healthy individuals. They compared their data to European samples, and found that Ashkenazi Jewish genomes had significantly more mutations that had not yet been mapped. Pe'er and his team analyzed the raw data and created a comprehensive catalog of mutations present in the Ashkenazi Jewish population. The TAGC database is already proving useful for clinical genomics, identifying specific new mutations for carrier screening. Lencz explains: \"TAGC advances the goal of bringing personal genomics to the clinic, as it tells the physician whether a mutation in a patient's genome is shared by healthy individuals, and can alleviate concerns that it is causing disease. Without our work, a patient's genome sequence is much harder to interpret, and more prone to create false alarms. We have eliminated two thirds of these false alarms.\" The TAGC study further enables more effective discovery of disease-causing mutations, since some genetic factors are observable in Ashkenazi individuals but essentially absent elsewhere. Moreover, the demography of the Ashkenazi population, the largest isolated population in the U.S., enables large-scale recruitment of study patients and hence more genetic discoveries than in other well-known isolated populations like the Amish and Hutterites locally, or the Icelanders overseas. The researchers expect that medical insights from studies of specific populations will also be relevant to general populations as well. The TAGC team's findings also shed light on the long-debated origin of Ashkenazi Jews and Europeans. The genetic data indicates that the Ashkenazi Jewish population was founded in the late medieval times by a small number, effectively only hundreds of individuals, whose descendants expanded rapidly while remaining mostly isolated genetically. \"Our analysis shows that Ashkenazi Jewish medieval founders were ethnically admixed, with origins in Europe and in the Middle East, roughly in equal parts,\" says Shai Carmi, a post-doctoral scientist who works with Pe'er and who conducted the analysis. \"TAGC data are more comprehensive than what was previously available, and we believe the data settle the dispute regarding European and Middle Eastern ancestry in Ashkenazi Jews. In addition to illuminating medieval Jewish history, our results further pave the way to better understanding European origins, millennia before. For example, our data provides evidence for today's European population being genetically descendant primarily from late mid-eastern migrations that took place after the last ice age, rather than from the first humans to arrive to the continent, more than 40,000 years ago.\" The researchers note that their results also raise a number of hypotheses regarding Ashkenazi origin, which they have now begun exploring. They are looking at, for example, the identity of the Ashkenazi founders: who are the modern populations most similar to them in Europe and in the Middle East? When did the admixture process take place and to what extent was that process sex-biased, where men with one origin mated with women from another? Pe'er adds, \"Equally important to us is making our data available to the entire research community. We've released it to public-access databases and fully expect the creativity of the scientific world to come up with additional uses for the data. What's especially gratifying is the idea that our work will pave the way for personalized genomics in other populations as well.\" Pe'er and his TAGC colleagues are already working on their next step: to study specific diseases in the Ashkenazi population, including schizophrenia, Parkinson's, Crohn's, diabetes, and cancer, as well as other inherited traits such as longevity. They are also working with additional collaborators, including the New York Genome Center, to sequence approximately 500 more Ashkenazi genomes to make the catalog of mutations even more comprehensive. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum. Introduction Ashkenazi Jews (AJ), identified as Jewish individuals of Central- and Eastern European ancestry, form the largest genetic isolate in the United States. AJ demonstrate distinctive genetic characteristics 1 , 2 , including high prevalence of autosomal recessive diseases and relatively high frequency of alleles that confer a strong risk of common diseases, such as Parkinson’s disease 3 and breast and ovarian cancer 4 . Several recent studies have employed common polymorphisms 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 to characterize AJ as a genetically distinct population, close to other Jewish populations as well as to present-day Middle Eastern and European populations. Previous analyses of recent AJ history highlighted a narrow population bottleneck of only hundreds of individuals in late medieval times, followed by rapid expansion 12 , 14 . The AJ population is much larger and/or experienced a more severe bottleneck than other founder populations, such as Amish, Hutterites or Icelanders 15 , whose demographic histories facilitated a steady stream of genetic discoveries. This suggests the potential for cataloguing nearly all founder variants in a large extant population by sequencing a limited number of samples, who represent the diversity in the founding group (for example, ref. 16 ). Such a catalogue of variants can make a threefold contribution: First, it will enable clinical interpretation of personal genomes in the sizeable AJ population by distinguishing between background variation and recent, potentially more deleterious mutations. Second, it will improve disease mapping in AJ by increasing the accuracy of imputation. Third, the ability to extensively sample a population with ancient roots in the Levant is expected to provide insights regarding the histories of both Middle Eastern and European populations. Here we report a catalogue of 128 high coverage, whole-genome AJ sequences. Compared with a European reference panel, the AJ panel has more novel and population-specific variants, and we demonstrate that the AJ panel is necessary for interpretation and imputation of AJ personal genomes. Analysis of long shared segments, which are abundant in AJ, confirms a recent severe bottleneck and potential utility in future sequencing studies. The joint AJ–European allele frequency spectrum suggests that the AJ population is an even mix of European and Middle Eastern ancestral populations and quantifies ancient bottlenecks and population splits. Finally, we report the deleterious mutation load in AJ to be slightly higher than in Europeans. Results We sequenced a panel ( n =128) of controls of self-reported and empirically validated AJ ancestry ( Supplementary Note 1 ; Supplementary Table 1 ; Supplementary Fig. 1 ). The high coverage sequence (>50 × ), generated by Complete Genomics 17 , showed multiple quality control (QC) indicators supporting both high quality and completeness of the single-nucleotide variant (SNV) data: 97% coverage of the genome ( Supplementary Note 2 ; Supplementary Table 2 ), inferred discordance of 0.047% to high quality genotypes in SNP arrays ( Supplementary Note 2 ; Supplementary Data 1 ), transition/transversion ratio of 2.14, and consistency of QC measures across potential sources of bias ( Supplementary Note 2 ; Supplementary Data 2 ; Supplementary Figs 1 and 2 ). The average raw number of non-reference SNVs called per individual was 3.412 M, including 10.5K coding synonymous changes and 9.7K non-synonymous ones ( Supplementary Data 2 ). An additional 538K multinucleotide variants, 4.1K mobile element insertions, and 302 copy number variants (spanning 6.7 Mbp) were observed, on average, in each sample ( Supplementary Data 2 ). However, inspection of novel non-SNVs demonstrated high false-positive rates ( Supplementary Note 2 ), and we thus focused on autosomal, bi-allelic SNVs for all subsequent analyses. We applied strict multisample filters ( Supplementary Note 2 ) to generate a working set of 12,326,197 high quality SNVs, of which 2,891,414 were novel (23.5%; dbSNP135). Quality was gauged by a sequenced duplicate as well as runs-of-homozygosity, which are sufficiently frequent in AJ for this purpose, providing estimates of ≈6,000–8,000 false positives genome wide ( Supplementary Note 2 ), in line with previous benchmarks of this technology 17 . Principal component analysis of common variants in the sequenced AJ samples confirmed previous observations 5 , 6 , 9 , 10 , namely, that AJ form a distinct cluster with proximity to other Jewish, European and Middle Eastern populations ( Supplementary Fig. 1 ). Our reference panel is expected to improve the ability to catalogue variants and haplotypes in the Ashkenazi population, beyond what is possible with non-ancestry-matched reference samples. A natural panel for comparison would be the European samples from the 1000 Genomes Project 18 . However, to match the high depth of our data and the sequencing platform used to obtain it, we chose as our primary comparison data set a cohort of Flemish (FL) personal genomes ( n =26) from Belgium ( Supplementary Note 2 ). We merged our first batch of AJ genomes ( n =57) with the FL data, applying a QC pipeline attempting to remove all potentially artifactual population-specific variants ( Supplementary Note 2 ).<|im_end|> <|im_start|>assistant Led by Itsik Pe'er, associate professor of computer science at Columbia Engineering, a team of researchers has created a data resource that will improve genomic research in the Ashkenazi Jewish population and lead to more effective personalized medicine. The team, which includes experts from 11 labs in the New York City area and Israel, focused on the Ashkenazi Jewish population because of its demographic history of genetic isolation and the resulting abundance of population-specific mutations and high prevalence of rare genetic disorders. The Ashkenazi Jewish population has played an important role in human genetics, with notable successes in gene mapping as well as prenatal and cancer screening. The study was published online on Nature Communications today. "Our study is the first full DNA sequence dataset available for Ashkenazi Jewish genomes," says Pe'er, who is also a co-chair of the Health Analytics Center at Columbia's Institute for Data Sciences and Engineering, as well as a member of its Foundations of Data Science Center. "With this comprehensive catalog of mutations present in the Ashkenazi Jewish population, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders. We see this study serving as a vehicle for personalized medicine and a model for researchers working with other populations." To help in his hunt for disease genes, Pe'er founded The Ashkenazi Genome Consortium (TAGC) in September 2011 with Todd Lencz, an investigator at The Feinstein Institute for Medical Research, director of the Laboratory of Analytic Genomics at the Zucker Hillside Hospital, and associate professor of molecular medicine and psychiatry at the Hofstra North Shore-LIJ School of Medicine. The other TAGC members, who are providing expertise in the diseases they are studying, are: Gil Atzmon, associate professor of medicine and genetics, Albert Einstein College of Medicine (genetics of longevity and diabetes);Lorraine Clark, associate professor of clinical pathology and cell biology and co-director, Personalized Genomic Medicine Laboratory, Columbia University Medical Center, Laurie Ozelius, associate professor at Icahn School of Medicine at Mount Sinai, and Susan Bressman, chair of neurology at Mount Sinai Beth Israel (Parkinson's disease and related neurological phenotypes);Harry Ostrer, professor of pathology, genetics, and pediatrics, Albert Einstein College of Medicine (radiogenomics, cancers and rare genetic disorders);Ken Offit, chief of clinical genetics at Memorial Sloan Kettering Cancer Center (breast, ovarian, colon and prostate cancers, lymphoma);Inga Peter, associate professor of genetics and genomic sciences, and Judy Cho, professor of medicine and professor of genetics and genomic sciences, both at The Mount Sinai Hospital (inflammatory bowel disease); andAriel Darvasi, vice-dean of The Faculty of Life Sciences at The Hebrew University of Jerusalem (multiple diseases). Before the TAGC study, data was available for a limited number of DNA markers (only approximately one in every 3000 letters of DNA) that are mostly common in Europeans. The TAGC researchers performed high-depth sequencing of 128 complete genomes of Ashkenazi Jewish healthy individuals. They compared their data to European samples, and found that Ashkenazi Jewish genomes had significantly more mutations that had not yet been mapped. Pe'er and his team analyzed the raw data and created a comprehensive catalog of mutations present in the Ashkenazi Jewish population. The TAGC database is already proving useful for clinical genomics, identifying specific new mutations for carrier screening. Lencz explains: "TAGC advances the goal of bringing personal genomics to the clinic, as it tells the physician whether a mutation in a patient's genome is shared by healthy individuals, and can alleviate concerns that it is causing disease. Without our work, a patient's genome sequence is much harder to interpret, and more prone to create false alarms. We have eliminated two thirds of these false alarms." The TAGC study further enables more effective discovery of disease-causing mutations, since some genetic factors are observable in Ashkenazi individuals but essentially absent elsewhere. Moreover, the demography of the Ashkenazi population, the largest isolated population in the U.S., enables large-scale recruitment of study patients and hence more genetic discoveries than in other well-known isolated populations like the Amish and Hutterites locally, or the Icelanders overseas. The researchers expect that medical insights from studies of specific populations will also be relevant to general populations as well. The TAGC team's findings also shed light on the long-debated origin of Ashkenazi Jews and Europeans. The genetic data indicates that the Ashkenazi Jewish population was founded in the late medieval times by a small number, effectively only hundreds of individuals, whose descendants expanded rapidly while remaining mostly isolated genetically. "Our analysis shows that Ashkenazi Jewish medieval founders were ethnically admixed, with origins in Europe and in the Middle East, roughly in equal parts," says Shai Carmi, a post-doctoral scientist who works with Pe'er and who conducted the analysis. "TAGC data are more comprehensive than what was previously available, and we believe the data settle the dispute regarding European and Middle Eastern ancestry in Ashkenazi Jews. In addition to illuminating medieval Jewish history, our results further pave the way to better understanding European origins, millennia before. For example, our data provides evidence for today's European population being genetically descendant primarily from late mid-eastern migrations that took place after the last ice age, rather than from the first humans to arrive to the continent, more than 40,000 years ago." The researchers note that their results also raise a number of hypotheses regarding Ashkenazi origin, which they have now begun exploring. They are looking at, for example, the identity of the Ashkenazi founders: who are the modern populations most similar to them in Europe and in the Middle East? When did the admixture process take place and to what extent was that process sex-biased, where men with one origin mated with women from another? Pe'er adds, "Equally important to us is making our data available to the entire research community. We've released it to public-access databases and fully expect the creativity of the scientific world to come up with additional uses for the data. What's especially gratifying is the idea that our work will pave the way for personalized genomics in other populations as well." Pe'er and his TAGC colleagues are already working on their next step: to study specific diseases in the Ashkenazi population, including schizophrenia, Parkinson's, Crohn's, diabetes, and cancer, as well as other inherited traits such as longevity. They are also working with additional collaborators, including the New York Genome Center, to sequence approximately 500 more Ashkenazi genomes to make the catalog of mutations even more comprehensive. <|im_end|>

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2,715

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In cuprate superconductors, the doping of carriers into the parent Mott insulator induces superconductivity and various other phases whose characteristic temperatures are typically plotted versus the doping level p . In most materials, p cannot be determined from the chemical composition, but it is derived from the superconducting transition temperature, T c , using the assumption that the T c dependence on doping is universal. Here, we present angle-resolved photoemission studies of Bi 2 Sr 2 CaCu 2 O 8+ δ , cleaved and annealed in vacuum or in ozone to reduce or increase the doping from the initial value corresponding to T c = 91 K. We show that p can be determined from the underlying Fermi surfaces and that in-situ annealing allows mapping of a wide doping regime, covering the superconducting dome and the non-superconducting phase on the overdoped side. Our results show a surprisingly smooth dependence of the inferred Fermi surface with doping. In the highly overdoped regime, the superconducting gap approaches the value of 2Δ 0 = (4 ± 1) k B T c Introduction Bi 2 Sr 2 CaCu 2 O 8+ δ (Bi2212) is a prototypical cuprate high-Tc superconductor (HTSC) and one of the most studied materials in condensed matter physics. Its phase diagram has been heavily studied by many different techniques. In particular, Bi2212 has been the perfect subject for studies by Angle Resolved Photoemission Spectroscopy (ARPES) and Spectroscopic Imaging - Scanning Tunneling Microscopy (SI-STM) due to its ease of cleaving. These techniques have contributed significantly to our current understanding of the cuprates by providing invaluable information on different phenomena and their development with doping, mostly in Bi2212. The d -wave symmetry of the superconducting (SC) gap 1 , 2 , the normal state gap (pseudogap) 3 , 4 , 5 , the quasiparticle (QP) self-energy 2 , 6 , 7 and, more recently, the transition in topology of the Fermi surface (FS) from open to closed 8 , 9 are a few notable examples of such contributions. However, Bi2212 can only be doped within a relatively limited range, especially on the overdoped side, where the superconducting transition temperature ( T c ) cannot be reduced beyond ~50 K, leaving a large and important region of the phase diagram out of reach. Even within the covered region, the actual doping level p is not independently determined, but it is usually calculated from the measured T c by assuming the putative parabolic T c − p dependence that is considered universal for all the cuprates 10 . Only in a very limited number of materials such as La 2− x Sr x CuO 4 and La 2− x Ba x CuO 4 , can the doping be approximately determined from chemical composition as p ≈ x . These two materials however, have very different T c − p dependences, illustrating the invalidity of the universal parabolic T c − p dome 11 . Here, we revisit the Bi2212 phase diagram by modifying the doping level of the as-grown crystal, by annealing in situ cleaved samples either in vacuum, resulting in homogeneous underdoping, or in ozone, resulting in overdoping of the near-surface region. We were able to span a wide region of the phase diagram, ranging from strongly underdoped, with the T c reduced down to 30 K (UD30), to strongly overdoped, where the superconductivity was completely suppressed (OD0). In addition, we were able to infer the doping level directly from ARPES, by measuring the volume of the underlying FS. In that way, we follow the development of spectral features with doping with unprecedented clarity and detail and construct the phase diagram of Bi2212. Results Fermi surface Figure 1 shows the photoemission intensity integrated within ±2.5 meV around the Fermi level for the as-grown sample and for several different doping levels, induced by annealing in vacuum, or ozone. Due to the presence of the spectral gap, only the near-nodal segments are visible, while the intensity is strongly reduced or absent in most of the Brillouin zone (BZ), except in the highly overdoped samples with reduced gaps. As we move down in energy, more and more of the missing intensity is recovered, and at the energy of the maximal spectral gap (Δ 0 ), the full, closed contour of the underlying FS is recovered. Although the Luttinger theorem requires that, to determine the carrier density, one measures the closed contours only for QPs at E = 0 (Fermi level), this is rendered impossible by the existence of the spectral gap. Therefore, we hypothesize that the contour of minimum gap energy may be used for the same purpose. This hypothesis assumes particle-hole symmetry of the gapped state about the chemical potential. In that case, connecting the ( k x , k y ) points where the intensity first appears, yields the curves of minimal gap loci, which we refer to throughout as the underlying FSs. Mapping at higher temperatures, above T c and above the pseudogap temperature, T * , that was performed at several doping levels (see Methods section), shows exactly the same Fermi contours, supporting our approach. We do not see any change in shape between the low-temperature and high-temperature Fermi contours that were previously reported in ref. 12 . Figure 1 also shows tight binding (TB) contours, with solid (dashed) lines representing the bonding (antibonding) states 13 , 14 , 15 . The TB parameters for several doping levels are given in Table 1. The number of carriers forming the underlying FS is obtained from the Luttinger count of the area enclosed by the Fermi contour, p L = 2 A FS . To express this in terms of doping that usually serves as the abscissa in phase diagrams of the cuprates, we calculate the number of additional holes doped into the parent Mott insulator as p A = p L − 1 = 2 A FS − 1. Here, both the bonding and the antibonding states are counted, A FS = (", "role": "user" }, { "content": "Scientists mapping out the quantum characteristics of superconductors—materials that conduct electricity with no energy loss—have entered a new regime. Using newly connected tools named OASIS at the U.S. Department of Energy's Brookhaven National Laboratory, they've uncovered previously inaccessible details of the \"phase diagram\" of one of the most commonly studied \"high-temperature\" superconductors. The newly mapped data includes signals of what happens when superconductivity vanishes. \"In terms of superconductivity, this may sound bad, but if you study some phenomenon, it is always good to be able to approach it from its origin,\" said Brookhaven physicist Tonica Valla, who led the study just published in the journal Nature Communications. \"If you have a chance to see how superconductivity disappears, that in turn might give insight into what causes superconductivity in the first place.\" Unlocking the secrets of superconductivity holds great promise in addressing energy challenges. Materials able to carry current over long distances with no loss would revolutionize power transmission, eliminate the need for cooling computer-packed data centers, and lead to new forms of energy storage, for example. The hitch is that, at present, most known superconductors, even the \"high-temperature\" varieties, must themselves be kept super cold to perform their current-carrying magic. So, scientists have been trying to understand the key characteristics that cause superconductivity in these materials with the goal of discovering or creating new materials that can operate at temperatures more practical for these everyday applications. The Brookhaven team was studying a well-known high-temperature superconductor made of layers that include bismuth-oxide, strontium-oxide, calcium, and copper-oxide (abbreviated as BSCCO). Cleaving crystals of this material creates pristine bismuth-oxide surfaces. When they analyzed the electronic structure of the pristine cleaved surface, they saw telltale signs of superconductivity at a transition temperature (Tc) of 94 Kelvin (-179 degrees Celsius)—the highest temperature at which superconductivity sets in for this well-studied material. The team then heated samples in ozone (O3) and found that they could achieve high doping levels and explore previously unexplored portions of this material's phase diagram, which is a map-like graph showing how the material changes its properties at different temperatures under different conditions (similar to the way you can map out the temperature and pressure coordinates at which liquid water freezes when it is cooled, or changes to steam when heated). In this case, the variable the scientists were interested in was how many charge vacancies, or \"holes,\" were added, or \"doped\" into the material by the exposure to ozone. Holes facilitate the flow of current by giving the charges (electrons) somewhere to go. \"For this material, if you start with the crystal of 'parent' compound, which is an insulator (meaning no conductivity), the introduction of holes results in superconductivity,\" Valla said. As more holes are added, the superconductivity gets stronger and at higher temperatures up to a maximum at 94 Kelvin, he explained. \"Then, with more holes, the material becomes 'over-doped,' and Tc goes down—for this material, to 50 K. This phase diagram for BSCCO plots the temperature (T, in degrees Kelvin, on the y axis) at which superconductivity sets in as more and more charge vacancies, or \"holes,\" are doped into the material (horizontal, x axis). On the underdoped side of the \"dome\" (left), as more holes are added, the transition temperate increases to a maximum of 94 K, but as more holes are added, the transition temperature drops off. The red dashed line represents previously assumed dependence of superconductivity \"dome,\" while the black line represents the correct dependence, obtained from the new data (black dots). This was the first time scientists were able to create highly overdoped samples, allowing them to explore the part of the phase diagram shaded in yellow where superconductivity disappears. Tracking the disappearance may help them understand what causes superconductivity to occur in the first place. Credit: Brookhaven National Laboratory \"Until this study, nothing past that point was known because we couldn't get crystals doped above that level. But our new data takes us to a point of doping way beyond the previous limit, to a point where Tc is not measurable.\" Said Valla, \"That means we can now explore the entire dome-shaped curve of superconductivity in this material, which is something that nobody has been able to do before.\" The team created samples heated in a vacuum (to produce underdoped material) and in ozone (to make overdoped samples) and plotted points along the entire superconducting dome. They discovered some interesting characteristics in the previously unexplored \"far side\" of the phase diagram. \"What we saw is that things become much simpler,\" Valla said. Some of the quirkier characteristics that exist on the well-explored side of the map and complicate scientists' understanding of high-temperature superconductivity—things like a \"pseudogap\" in the electronic signature, and variations in particle spin and charge densities—disappear on the overdoped far side of the dome. Brookhaven Lab physicists Tonica Valla and Ilya Drozdov in the OASIS laboratory at Brookhaven National Laboratory. Credit: Brookhaven National Laboratory \"This side of the phase diagram is somewhat like what we expect to see in more conventional superconductivity,\" Valla said, referring to the oldest known metal-based superconductors. \"When superconductivity is free of these other things that complicate the picture, then what is left is superconductivity that perhaps is not that unconventional,\" he added. \"We still might not know its origin, but on this side of the phase diagram, it looks like something that theory can handle more easily, and it gives you a simpler way of looking at the problem to try to understand what is going on.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In cuprate superconductors, the doping of carriers into the parent Mott insulator induces superconductivity and various other phases whose characteristic temperatures are typically plotted versus the doping level p . In most materials, p cannot be determined from the chemical composition, but it is derived from the superconducting transition temperature, T c , using the assumption that the T c dependence on doping is universal. Here, we present angle-resolved photoemission studies of Bi 2 Sr 2 CaCu 2 O 8+ δ , cleaved and annealed in vacuum or in ozone to reduce or increase the doping from the initial value corresponding to T c = 91 K. We show that p can be determined from the underlying Fermi surfaces and that in-situ annealing allows mapping of a wide doping regime, covering the superconducting dome and the non-superconducting phase on the overdoped side. Our results show a surprisingly smooth dependence of the inferred Fermi surface with doping. In the highly overdoped regime, the superconducting gap approaches the value of 2Δ 0 = (4 ± 1) k B T c Introduction Bi 2 Sr 2 CaCu 2 O 8+ δ (Bi2212) is a prototypical cuprate high-Tc superconductor (HTSC) and one of the most studied materials in condensed matter physics. Its phase diagram has been heavily studied by many different techniques. In particular, Bi2212 has been the perfect subject for studies by Angle Resolved Photoemission Spectroscopy (ARPES) and Spectroscopic Imaging - Scanning Tunneling Microscopy (SI-STM) due to its ease of cleaving. These techniques have contributed significantly to our current understanding of the cuprates by providing invaluable information on different phenomena and their development with doping, mostly in Bi2212. The d -wave symmetry of the superconducting (SC) gap 1 , 2 , the normal state gap (pseudogap) 3 , 4 , 5 , the quasiparticle (QP) self-energy 2 , 6 , 7 and, more recently, the transition in topology of the Fermi surface (FS) from open to closed 8 , 9 are a few notable examples of such contributions. However, Bi2212 can only be doped within a relatively limited range, especially on the overdoped side, where the superconducting transition temperature ( T c ) cannot be reduced beyond ~50 K, leaving a large and important region of the phase diagram out of reach. Even within the covered region, the actual doping level p is not independently determined, but it is usually calculated from the measured T c by assuming the putative parabolic T c − p dependence that is considered universal for all the cuprates 10 . Only in a very limited number of materials such as La 2− x Sr x CuO 4 and La 2− x Ba x CuO 4 , can the doping be approximately determined from chemical composition as p ≈ x . These two materials however, have very different T c − p dependences, illustrating the invalidity of the universal parabolic T c − p dome 11 . Here, we revisit the Bi2212 phase diagram by modifying the doping level of the as-grown crystal, by annealing in situ cleaved samples either in vacuum, resulting in homogeneous underdoping, or in ozone, resulting in overdoping of the near-surface region. We were able to span a wide region of the phase diagram, ranging from strongly underdoped, with the T c reduced down to 30 K (UD30), to strongly overdoped, where the superconductivity was completely suppressed (OD0). In addition, we were able to infer the doping level directly from ARPES, by measuring the volume of the underlying FS. In that way, we follow the development of spectral features with doping with unprecedented clarity and detail and construct the phase diagram of Bi2212. Results Fermi surface Figure 1 shows the photoemission intensity integrated within ±2.5 meV around the Fermi level for the as-grown sample and for several different doping levels, induced by annealing in vacuum, or ozone. Due to the presence of the spectral gap, only the near-nodal segments are visible, while the intensity is strongly reduced or absent in most of the Brillouin zone (BZ), except in the highly overdoped samples with reduced gaps. As we move down in energy, more and more of the missing intensity is recovered, and at the energy of the maximal spectral gap (Δ 0 ), the full, closed contour of the underlying FS is recovered. Although the Luttinger theorem requires that, to determine the carrier density, one measures the closed contours only for QPs at E = 0 (Fermi level), this is rendered impossible by the existence of the spectral gap. Therefore, we hypothesize that the contour of minimum gap energy may be used for the same purpose. This hypothesis assumes particle-hole symmetry of the gapped state about the chemical potential. In that case, connecting the ( k x , k y ) points where the intensity first appears, yields the curves of minimal gap loci, which we refer to throughout as the underlying FSs. Mapping at higher temperatures, above T c and above the pseudogap temperature, T * , that was performed at several doping levels (see Methods section), shows exactly the same Fermi contours, supporting our approach. We do not see any change in shape between the low-temperature and high-temperature Fermi contours that were previously reported in ref. 12 . Figure 1 also shows tight binding (TB) contours, with solid (dashed) lines representing the bonding (antibonding) states 13 , 14 , 15 . The TB parameters for several doping levels are given in Table 1. The number of carriers forming the underlying FS is obtained from the Luttinger count of the area enclosed by the Fermi contour, p L = 2 A FS . To express this in terms of doping that usually serves as the abscissa in phase diagrams of the cuprates, we calculate the number of additional holes doped into the parent Mott insulator as p A = p L − 1 = 2 A FS − 1. Here, both the bonding and the antibonding states are counted, A FS = (<|im_end|> <|im_start|>assistant Scientists mapping out the quantum characteristics of superconductors—materials that conduct electricity with no energy loss—have entered a new regime. Using newly connected tools named OASIS at the U.S. Department of Energy's Brookhaven National Laboratory, they've uncovered previously inaccessible details of the "phase diagram" of one of the most commonly studied "high-temperature" superconductors. The newly mapped data includes signals of what happens when superconductivity vanishes. "In terms of superconductivity, this may sound bad, but if you study some phenomenon, it is always good to be able to approach it from its origin," said Brookhaven physicist Tonica Valla, who led the study just published in the journal Nature Communications. "If you have a chance to see how superconductivity disappears, that in turn might give insight into what causes superconductivity in the first place." Unlocking the secrets of superconductivity holds great promise in addressing energy challenges. Materials able to carry current over long distances with no loss would revolutionize power transmission, eliminate the need for cooling computer-packed data centers, and lead to new forms of energy storage, for example. The hitch is that, at present, most known superconductors, even the "high-temperature" varieties, must themselves be kept super cold to perform their current-carrying magic. So, scientists have been trying to understand the key characteristics that cause superconductivity in these materials with the goal of discovering or creating new materials that can operate at temperatures more practical for these everyday applications. The Brookhaven team was studying a well-known high-temperature superconductor made of layers that include bismuth-oxide, strontium-oxide, calcium, and copper-oxide (abbreviated as BSCCO). Cleaving crystals of this material creates pristine bismuth-oxide surfaces. When they analyzed the electronic structure of the pristine cleaved surface, they saw telltale signs of superconductivity at a transition temperature (Tc) of 94 Kelvin (-179 degrees Celsius)—the highest temperature at which superconductivity sets in for this well-studied material. The team then heated samples in ozone (O3) and found that they could achieve high doping levels and explore previously unexplored portions of this material's phase diagram, which is a map-like graph showing how the material changes its properties at different temperatures under different conditions (similar to the way you can map out the temperature and pressure coordinates at which liquid water freezes when it is cooled, or changes to steam when heated). In this case, the variable the scientists were interested in was how many charge vacancies, or "holes," were added, or "doped" into the material by the exposure to ozone. Holes facilitate the flow of current by giving the charges (electrons) somewhere to go. "For this material, if you start with the crystal of 'parent' compound, which is an insulator (meaning no conductivity), the introduction of holes results in superconductivity," Valla said. As more holes are added, the superconductivity gets stronger and at higher temperatures up to a maximum at 94 Kelvin, he explained. "Then, with more holes, the material becomes 'over-doped,' and Tc goes down—for this material, to 50 K. This phase diagram for BSCCO plots the temperature (T, in degrees Kelvin, on the y axis) at which superconductivity sets in as more and more charge vacancies, or "holes," are doped into the material (horizontal, x axis). On the underdoped side of the "dome" (left), as more holes are added, the transition temperate increases to a maximum of 94 K, but as more holes are added, the transition temperature drops off. The red dashed line represents previously assumed dependence of superconductivity "dome," while the black line represents the correct dependence, obtained from the new data (black dots). This was the first time scientists were able to create highly overdoped samples, allowing them to explore the part of the phase diagram shaded in yellow where superconductivity disappears. Tracking the disappearance may help them understand what causes superconductivity to occur in the first place. Credit: Brookhaven National Laboratory "Until this study, nothing past that point was known because we couldn't get crystals doped above that level. But our new data takes us to a point of doping way beyond the previous limit, to a point where Tc is not measurable." Said Valla, "That means we can now explore the entire dome-shaped curve of superconductivity in this material, which is something that nobody has been able to do before." The team created samples heated in a vacuum (to produce underdoped material) and in ozone (to make overdoped samples) and plotted points along the entire superconducting dome. They discovered some interesting characteristics in the previously unexplored "far side" of the phase diagram. "What we saw is that things become much simpler," Valla said. Some of the quirkier characteristics that exist on the well-explored side of the map and complicate scientists' understanding of high-temperature superconductivity—things like a "pseudogap" in the electronic signature, and variations in particle spin and charge densities—disappear on the overdoped far side of the dome. Brookhaven Lab physicists Tonica Valla and Ilya Drozdov in the OASIS laboratory at Brookhaven National Laboratory. Credit: Brookhaven National Laboratory "This side of the phase diagram is somewhat like what we expect to see in more conventional superconductivity," Valla said, referring to the oldest known metal-based superconductors. "When superconductivity is free of these other things that complicate the picture, then what is left is superconductivity that perhaps is not that unconventional," he added. "We still might not know its origin, but on this side of the phase diagram, it looks like something that theory can handle more easily, and it gives you a simpler way of looking at the problem to try to understand what is going on." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Thermal interactions between Earth’s core and mantle provide the power that maintains the geomagnetic field. However, the effect of these interactions and, in particular, the thermochemical piles at the base of the mantle on magnetic field behaviour remains uncertain. Here we present numerical dynamo simulations with strong lateral variations in heat flow imposed at the core–mantle boundary to reproduce conditions within Earth and indicate how the mantle controls core dynamics. Comparing these simulations to recent global magnetic field models, based on observational data spanning tens of thousands of years, they successfully reproduce the morphology and secular variation of Earth’s modern field and the inferred large-scale flow structure at the top of the core. These simulations reveal that the long-term geomagnetic signatures of thermal core–mantle interactions are evident in the longitudinal structure of the geomagnetic field as equatorial patches of reverse flux, rather than the high-latitude patches suggested by less Earth-like simulations. Comparison of these simulations with the field models also suggests that the amplitude of the present-day longitudinal hemispheric imbalance in secular variation is anomalously large, indicating our present-day geomagnetic field may be unusual. Main Earth’s global magnetic field has persisted for billions of years, generated by a dynamo process in the liquid core that derives power from the slow loss of heat to the mantle 1 . Convection within the mantle is characterized by much longer timescales and much longer wavelengths than core convection and lateral variations in the temperature distribution of the lowermost mantle result in a heterogeneous pattern of heat flow at the core–mantle boundary (CMB), with suppressed heat flux where the lowermost mantle is anomalously hot, such as the African and Pacific large low velocity provinces (LLVPs) 2 , 3 . The extent to which mantle heat flow controls the geodynamo and geomagnetic field has been debated for decades. Variations in reversal frequency 4 , apparent preferred longitudes of transitional virtual geomagnetic poles 5 and persistently weak field changes in the Pacific 6 , all argued to result from the mantle’s influence on core dynamics, have been disputed by both observational and modelling studies 7 . Recently, a major observational limitation—the lack of continuous global time-dependent representations of the field covering more than a few core turnover times—has been addressed by new models, such as GGF100k, which represents the Global Geomagnetic Field over the past 100 thousand years (kyr) (ref. 8 ). By combining these observations with numerical simulations of core dynamics, we find that it is now possible to identify the magnetic signature of thermal core–mantle interaction and its links to core dynamics. A prominent feature of the geomagnetic field in high-resolution models covering the last 400 years (ref. 9 ) are four high-latitude flux patches that appear at longitudes where mantle heat flow is expected to be anomalously high. Convergent downwelling resulting from locally elevated heat flow could cause intense flux patches to persistently concentrate around preferred longitudes 7 . However, while similar patches must be represented in realistic simulations of core dynamics, observational models that extend much deeper in time 10 find that patches are not stationary, indicating that they could be transient features. Nevertheless, observational studies agree that the long-wavelength structure of Earth’s time-averaged magnetic field contains substantial non-zonal structure 10 . Free convection in the core may give rise to magnetic field structures with lifetimes comparable to the advective timescale (a few centuries); however, because mantle structure persists over geologically long times, its influence should appear in sufficiently long-term averages of Earth’s magnetic field. Another feature of the recent magnetic field is the preference for stronger secular variation (SV) in the Atlantic hemisphere 11 , a signature that has persisted for at least a few centuries 9 . Palaeomagnetic reconstructions of Earth’s magnetic field do not recover instantaneous SV; however, they can provide measures of field variability throughout their duration. For example, the paleosecular variation index ( P i ) (ref. 12 ) is a non-dimensional measure of the palaeo-field’s deviation from the expected dipole strength and structure at a given location (Methods), and temporal evolution of P i provides insight into patterns of field variation over the last 100 kyr (ref. 10 ). Although periods of enhanced activity in the Atlantic hemisphere are seen in long-term records, so too are periods of enhanced Pacific activity 13 , 14 , 15 , 16 ; as with the structure of the field itself, successful simulations must contain non-zonal SV features that are relatively long lived but not strictly stationary. Secular variation arises from the interaction between the magnetic field and fluid flow at the top of the outer core. Inversion of SV data can thus provide insight into core flow, although the details of the recovered flow depend on the treatment of the data and the assumptions used to break the inherent non-uniqueness of the inversion 17 . Nevertheless, some features are consistently seen in these observationally derived models such as relatively strong westward flow beneath the equatorial Atlantic, whereas flow beneath the equatorial Pacific is generally weak or eastward 17 , 18 , 19 , 20 . Large-scale core flow has been characterized as an equatorially symmetric eccentric gyre, with the westward Atlantic flow deviating towards the poles near American longitudes, bypassing the Pacific at high latitudes and returning towards the Equator by Indian longitudes 19 , 21 , 22 . Previous dynamo studies have obtained simulated fields with morphology similar to the present geomagnetic field (for example, refs. 23 , 24 , 25 ); however, only one has also reported a match to the pattern of modern SV 26 . This result was obtained by adding two features to the standard geodynamo model set-up: gravitational coupling between the inner core and mantle and a hemispheric pattern of inner core growth due to convective translation. Although the strength of gravitational coupling is relatively well constrained 27 , recent determinations of core material properties suggest that purely thermal convection of the inner core is highly unlikely and that purely compositional and", "role": "user" }, { "content": "Compass readings that do not show the direction of true north and interference with the operations of satellites are a few of the problems caused by peculiarities of the Earth's magnetic field. The magnetic field radiates around the world and far into space, but it is set by processes that happen deep within the Earth's core, where temperatures exceed 5,000 degrees Celsius. New research from geophysicists at the University of Leeds suggests that the way this super-hot core is cooled is key to understanding the causes of the peculiarities—or anomalies, as scientists call them—of the Earth's magnetic field. Dynamo at the center of the Earth In the extremely hot temperatures found deep in the Earth, the core is a mass of swirling, molten iron which acts as a dynamo. As the molten iron moves, it generates the Earth's global magnetic field. Convective currents keep the dynamo turning as heat flows out of the core and into the mantle, a rock layer that extends 2,900 kilometers up to the Earth's crust. Research by Dr. Jonathan Mound and Professor Christopher Davies, from the School of Earth and Environment at Leeds, has found that this cooling process does not happen in a uniform way across the Earth—and these variations cause anomalies in the Earth's magnetic field. Variations in Earth's magnetic field Seismic analysis has identified that there are regions of the mantle, under Africa and the Pacific for instance, that are particularly hot. Computer simulations by the researchers have revealed that these hot zones reduce the cooling effect on the core—and this causes regional or localized changes to the properties of the magnetic field. For example, where the mantle is hotter, the magnetic field at the top of the core is likely to be weaker. And this results in a weaker magnetic field which is projected into space above the South Atlantic, which causes problems for orbiting satellites. Interference with space technology Dr. Mound, who led the study, said, \"One of the things that the magnetic field in space does is deflect charged particles emitted from the sun. When the magnetic field is weaker, this protective shield is not so effective. \"So, when satellites pass over that area, these charged particles can disrupt and interfere with their operations.\" Scientists have known about the anomaly over the South Atlantic since they started monitoring and observing the magnetic field, but it is not known if it is a long-lived feature or something that has happened more recently in the history of the Earth. As the study at Leeds has revealed, the anomalies are likely to be caused by differences in the rate at which heat is flowing from the Earth's core into the mantle. Whereabouts in the Earth's inner structure these heat flow differences happen is likely to dictate how long they could last. Dr. Mound added, \"Processes in the mantle happen very slowly, so we can expect the temperature anomalies in the lower mantle will have stayed the same for tens of millions of years. Therefore, we would expect the properties of the magnetic field they create also to have been similar over tens of millions of years. \"But the hotter, outer core is quite a dynamic fluid region. So, the heat flows and the magnetic field properties they cause will probably fluctuate on shorter time scales, perhaps for 100's to 1000's of years.\" The paper—Longitudinal structure of Earth's magnetic field controlled by lower mantle heat flow—is published in Nature Geoscience. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Thermal interactions between Earth’s core and mantle provide the power that maintains the geomagnetic field. However, the effect of these interactions and, in particular, the thermochemical piles at the base of the mantle on magnetic field behaviour remains uncertain. Here we present numerical dynamo simulations with strong lateral variations in heat flow imposed at the core–mantle boundary to reproduce conditions within Earth and indicate how the mantle controls core dynamics. Comparing these simulations to recent global magnetic field models, based on observational data spanning tens of thousands of years, they successfully reproduce the morphology and secular variation of Earth’s modern field and the inferred large-scale flow structure at the top of the core. These simulations reveal that the long-term geomagnetic signatures of thermal core–mantle interactions are evident in the longitudinal structure of the geomagnetic field as equatorial patches of reverse flux, rather than the high-latitude patches suggested by less Earth-like simulations. Comparison of these simulations with the field models also suggests that the amplitude of the present-day longitudinal hemispheric imbalance in secular variation is anomalously large, indicating our present-day geomagnetic field may be unusual. Main Earth’s global magnetic field has persisted for billions of years, generated by a dynamo process in the liquid core that derives power from the slow loss of heat to the mantle 1 . Convection within the mantle is characterized by much longer timescales and much longer wavelengths than core convection and lateral variations in the temperature distribution of the lowermost mantle result in a heterogeneous pattern of heat flow at the core–mantle boundary (CMB), with suppressed heat flux where the lowermost mantle is anomalously hot, such as the African and Pacific large low velocity provinces (LLVPs) 2 , 3 . The extent to which mantle heat flow controls the geodynamo and geomagnetic field has been debated for decades. Variations in reversal frequency 4 , apparent preferred longitudes of transitional virtual geomagnetic poles 5 and persistently weak field changes in the Pacific 6 , all argued to result from the mantle’s influence on core dynamics, have been disputed by both observational and modelling studies 7 . Recently, a major observational limitation—the lack of continuous global time-dependent representations of the field covering more than a few core turnover times—has been addressed by new models, such as GGF100k, which represents the Global Geomagnetic Field over the past 100 thousand years (kyr) (ref. 8 ). By combining these observations with numerical simulations of core dynamics, we find that it is now possible to identify the magnetic signature of thermal core–mantle interaction and its links to core dynamics. A prominent feature of the geomagnetic field in high-resolution models covering the last 400 years (ref. 9 ) are four high-latitude flux patches that appear at longitudes where mantle heat flow is expected to be anomalously high. Convergent downwelling resulting from locally elevated heat flow could cause intense flux patches to persistently concentrate around preferred longitudes 7 . However, while similar patches must be represented in realistic simulations of core dynamics, observational models that extend much deeper in time 10 find that patches are not stationary, indicating that they could be transient features. Nevertheless, observational studies agree that the long-wavelength structure of Earth’s time-averaged magnetic field contains substantial non-zonal structure 10 . Free convection in the core may give rise to magnetic field structures with lifetimes comparable to the advective timescale (a few centuries); however, because mantle structure persists over geologically long times, its influence should appear in sufficiently long-term averages of Earth’s magnetic field. Another feature of the recent magnetic field is the preference for stronger secular variation (SV) in the Atlantic hemisphere 11 , a signature that has persisted for at least a few centuries 9 . Palaeomagnetic reconstructions of Earth’s magnetic field do not recover instantaneous SV; however, they can provide measures of field variability throughout their duration. For example, the paleosecular variation index ( P i ) (ref. 12 ) is a non-dimensional measure of the palaeo-field’s deviation from the expected dipole strength and structure at a given location (Methods), and temporal evolution of P i provides insight into patterns of field variation over the last 100 kyr (ref. 10 ). Although periods of enhanced activity in the Atlantic hemisphere are seen in long-term records, so too are periods of enhanced Pacific activity 13 , 14 , 15 , 16 ; as with the structure of the field itself, successful simulations must contain non-zonal SV features that are relatively long lived but not strictly stationary. Secular variation arises from the interaction between the magnetic field and fluid flow at the top of the outer core. Inversion of SV data can thus provide insight into core flow, although the details of the recovered flow depend on the treatment of the data and the assumptions used to break the inherent non-uniqueness of the inversion 17 . Nevertheless, some features are consistently seen in these observationally derived models such as relatively strong westward flow beneath the equatorial Atlantic, whereas flow beneath the equatorial Pacific is generally weak or eastward 17 , 18 , 19 , 20 . Large-scale core flow has been characterized as an equatorially symmetric eccentric gyre, with the westward Atlantic flow deviating towards the poles near American longitudes, bypassing the Pacific at high latitudes and returning towards the Equator by Indian longitudes 19 , 21 , 22 . Previous dynamo studies have obtained simulated fields with morphology similar to the present geomagnetic field (for example, refs. 23 , 24 , 25 ); however, only one has also reported a match to the pattern of modern SV 26 . This result was obtained by adding two features to the standard geodynamo model set-up: gravitational coupling between the inner core and mantle and a hemispheric pattern of inner core growth due to convective translation. Although the strength of gravitational coupling is relatively well constrained 27 , recent determinations of core material properties suggest that purely thermal convection of the inner core is highly unlikely and that purely compositional and<|im_end|> <|im_start|>assistant Compass readings that do not show the direction of true north and interference with the operations of satellites are a few of the problems caused by peculiarities of the Earth's magnetic field. The magnetic field radiates around the world and far into space, but it is set by processes that happen deep within the Earth's core, where temperatures exceed 5,000 degrees Celsius. New research from geophysicists at the University of Leeds suggests that the way this super-hot core is cooled is key to understanding the causes of the peculiarities—or anomalies, as scientists call them—of the Earth's magnetic field. Dynamo at the center of the Earth In the extremely hot temperatures found deep in the Earth, the core is a mass of swirling, molten iron which acts as a dynamo. As the molten iron moves, it generates the Earth's global magnetic field. Convective currents keep the dynamo turning as heat flows out of the core and into the mantle, a rock layer that extends 2,900 kilometers up to the Earth's crust. Research by Dr. Jonathan Mound and Professor Christopher Davies, from the School of Earth and Environment at Leeds, has found that this cooling process does not happen in a uniform way across the Earth—and these variations cause anomalies in the Earth's magnetic field. Variations in Earth's magnetic field Seismic analysis has identified that there are regions of the mantle, under Africa and the Pacific for instance, that are particularly hot. Computer simulations by the researchers have revealed that these hot zones reduce the cooling effect on the core—and this causes regional or localized changes to the properties of the magnetic field. For example, where the mantle is hotter, the magnetic field at the top of the core is likely to be weaker. And this results in a weaker magnetic field which is projected into space above the South Atlantic, which causes problems for orbiting satellites. Interference with space technology Dr. Mound, who led the study, said, "One of the things that the magnetic field in space does is deflect charged particles emitted from the sun. When the magnetic field is weaker, this protective shield is not so effective. "So, when satellites pass over that area, these charged particles can disrupt and interfere with their operations." Scientists have known about the anomaly over the South Atlantic since they started monitoring and observing the magnetic field, but it is not known if it is a long-lived feature or something that has happened more recently in the history of the Earth. As the study at Leeds has revealed, the anomalies are likely to be caused by differences in the rate at which heat is flowing from the Earth's core into the mantle. Whereabouts in the Earth's inner structure these heat flow differences happen is likely to dictate how long they could last. Dr. Mound added, "Processes in the mantle happen very slowly, so we can expect the temperature anomalies in the lower mantle will have stayed the same for tens of millions of years. Therefore, we would expect the properties of the magnetic field they create also to have been similar over tens of millions of years. "But the hotter, outer core is quite a dynamic fluid region. So, the heat flows and the magnetic field properties they cause will probably fluctuate on shorter time scales, perhaps for 100's to 1000's of years." The paper—Longitudinal structure of Earth's magnetic field controlled by lower mantle heat flow—is published in Nature Geoscience. <|im_end|>

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1,974

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract By using near-infrared fluorescent protein (iRFP)-expressing hematopoietic cells, we established a novel, quantitative, in vivo , noninvasive atherosclerosis imaging system. This murine atherosclerosis imaging approach targets macrophages expressing iRFP in plaques. Low-density lipoprotein receptor-deficient ( LDLR −/− ) mice transplanted with beta-actin promoter-derived iRFP transgenic (TG) mouse bone marrow (BM) cells (iRFP → LDLR −/− ) were used. Atherosclerosis was induced by a nonfluorescent 1.25% cholesterol diet (HCD). Atherosclerosis was compared among the three differently induced mouse groups. iRFP → LDLR −/− mice fed a normal diet (ND) and LDLR −/− mice transplanted with wild-type (WT) BM cells were used as controls. The in vivo imaging system (IVIS) detected an enhanced iRFP signal in the thoracic aorta of HCD-fed iRFP → LDLR −/− mice, whereas iRFP signals were not observed in the control mice. Time-course imaging showed a gradual increase in the signal area, which was correlated with atherosclerotic plaque progression. Oil red O (ORO) staining of aortas and histological analysis of plaques confirmed that the detected signal was strictly emitted from plaque-positive areas of the aorta. Our new murine atherosclerosis imaging system can noninvasively image atherosclerotic plaques in the aorta and generate longitudinal data, validating the ability of the system to monitor lesion progression. Introduction Despite considerable therapeutic advances over the past 50 years, atherosclerosis-related cardiovascular diseases (CVD) remain the leading cause of death worldwide 1 . Conventional structural and functional imaging methods play increasingly important roles in better understanding such diseases and can be used to validate current therapeutic measures and to develop novel drug therapies 2 . Improved imaging technologies hold promise for accelerating drug development 1 . Macrophages play essential roles in all phases of atherosclerosis, from the development of a fatty streak to processes that ultimately contribute to plaque rupture and myocardial infarction 3 . Leukocytes are central components of the inflammatory response, and plaque macrophages account for the majority of leukocytes in atherosclerotic plaques 4 , 5 , 6 . There is extensive evidence linking local macrophage infiltration with plaque characteristics and vulnerability 7 , and plaque macrophages have emerged as key imaging targets for inflammatory atheroma in animal models 8 , 9 , 10 , 11 , 12 . Consequently, techniques that can detect macrophages in vivo are useful for monitoring the development of atherosclerotic lesions. However, to our knowledge, there are few reports on direct methods that can be used to noninvasively measure the accumulation of macrophages without injecting imaging reagents. Therefore, user-friendly direct methods to noninvasively detect macrophage-rich plaques are in high demand in preclinical settings. Bioluminescent proteins and visible light fluorescent proteins are powerful technologies that have been extensively used to further our understanding of complex processes. However, such proteins have limited utility in vivo because of their poor deep tissue penetration and high autofluorescence. In contrast, imaging with near-infrared fluorescence proteins within the 700–900 nm range of spectral wavelengths offers several advantages, including its high-sensitivity, nonionizing radiation and relatively simple operation 11 , 13 . A new near-infrared fluorescent protein (iRFP), a fluorescent mutant of Rp BphP2 bacteriophytochrome, was generated by Filonov et al . 12 . iRFP is a nontoxic, stable protein with excitation and emission wavelengths of 690 nm and 713 nm, respectively. iRFP is brighter, stronger and more stable than previous generations of similar fluorescent proteins 12 . These qualities make iRFP useful for in vivo imaging with great deep tissue penetration and minimal autofluorescence. Previously, Tran et al . generated transgenic (TG) iRFP mice with ubiquitous iRFP expression 14 . Because the expression of iRFP in hematopoietic cells was observed even in bone marrow-transplanted mice, we hypothesized that high iRFP fluorescence could be observed with the accumulation of macrophages within the atherosclerotic plaque area after transplantation of iRFP TG born marrow cells into X-ray-irradiated low-density lipoprotein receptor knockout ( LDLR −/− ) mice under hyperlipidemia conditions. In this study, we established a noninvasive, in vivo atherosclerosis imaging system using iRFP hematopoietic cell-transplanted LDLR −/− mice. To our knowledge, this is the first reported use of the endogenous iRFP fluorescence expression to image atherosclerotic lesions from 0 to 8 weeks without an invasive method or injection of imaging reagents. We believe that this novel noninvasive imaging approach will prove to be very helpful for monitoring disease progression in drug intervention studies with animal models. Results In vitro fluorescence expression of iRFP TG macrophages Initially, to validate the fluorescence intensity of iRFP TG mouse macrophages, we collected peritoneal macrophages from both iRFP TG and wild-type (WT) mice 3 days after injection of thioglycolate. Then, the cultured macrophages were observed by fluorescence microscope under a Cy5.5 filter. Clear, bright iRFP fluorescence signals were observed in the iRFP TG mouse macrophages, while no iRFP signal was observed in the WT macrophages (Fig. 1A ). Next, we conducted an experiment to determine the minimum iRFP TG macrophage number that was required to produce a detectable fluorescent signal by IVIS in the in vitro conditions. iRFP TG peritoneal macrophages were collected in 0.2 ml tubes at amounts ranging from 1 × 10 3 cells to 1 × 10 7 cells. Clear fluorescence signals were detected even with 1 × 10 5 iRFP TG macrophages, while no fluorescence signal was observed from the WT peritoneal macrophages, even at 1 × 10 7 cells (Fig. 1B ). The signal intensity increased exponentially with an augmented number of cells (Fig. 1C ). The fluorescence signal intensity of 1 × 10 7 iRFP TG macrophages was even higher than that of indocyanine green, which was used as a positive control. These results demonstrate that the iRFP TG macrophages display a bright iRFP signal and that the fluorescence intensity increased in a cell number-dependent manner. Moreover, the IVIS system was capable of capturing the cellular iRFP signal, and under our imaging conditions, a minimum of 1 × 10 5 iRFP TG macrophages was required to detect a fluorescence signal in vitro . Figure 1 iRFP TG mouse macrophages express fluorescence in vitro . ( A", "role": "user" }, { "content": "Atherosclerosis, a process involving the buildup of arterial plaque and an associated reduction in blood flow, is a major feature of cardiovascular diseases. Although advances have been made in characterizing how this buildup occurs and ways to reduce it, diseases linked to atherosclerosis are still a major cause of mortality. In a major breakthrough in this field, researchers at the University of Tsukuba have developed a tool that can image the development of atherosclerotic plaque in the body and follow its progression over time, enabling accurate evaluation of drugs to treat atherosclerosis, and potentially, analysis of the likely risk posed by such plaque in individual patients. In this study, reported in the journal Scientific Reports, the team induced atherosclerosis in mice by inactivating a fat and cholesterol-related receptor and feeding them on a high-cholesterol diet. They also exposed these mice to X-rays to wipe out the native cells of their immune system, and then transplanted them with genetically engineered immune cells exhibiting fluorescence. \"A main advantage of our approach is that the introduced immune cells, as macrophages, congregate in atherosclerotic plaque, so the level of fluorescence emitted by them strongly correlates with the amount of plaque that has formed,\" Yoshihiro Miwa says. \"Because the expressed fluorescent proteins emit light in the near-infrared part of the spectrum, they can be detected at deeper locations within the body, such as the thoracic aorta.\" To confirm that this method can be used to identify the amount of atherosclerotic plaque within the mice, rather than just whether or not such plaque is present, the team established three groups with differing feeding patterns. They fed one group the high-cholesterol diet every day; another group was fed the high-cholesterol diet and a normal diet on alternate weeks; the third ate a normal diet. The findings based on the intensity of the fluorescent signal confirmed the expected stepwise differences in plaque quantity among these three groups, and also showed clear increases with a longer time spent consuming the unhealthy diets. \"Because we can now clearly analyze the amount of plaque present and its change over time, our work should lead to more effective monitoring of how well anti-atherosclerotic drugs work,\" corresponding author Michito Hamada says. \"This method can also reduce the number of experimental animals used because there's no need to sacrifice them and remove tissues for analysis at each time point within an experiment.\" The team hopes to further increase the sophistication of this tool, which could potentially lead to accurate analysis of the risk associated with the buildup of plaque in human patients and produce a range of associated medical benefits. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract By using near-infrared fluorescent protein (iRFP)-expressing hematopoietic cells, we established a novel, quantitative, in vivo , noninvasive atherosclerosis imaging system. This murine atherosclerosis imaging approach targets macrophages expressing iRFP in plaques. Low-density lipoprotein receptor-deficient ( LDLR −/− ) mice transplanted with beta-actin promoter-derived iRFP transgenic (TG) mouse bone marrow (BM) cells (iRFP → LDLR −/− ) were used. Atherosclerosis was induced by a nonfluorescent 1.25% cholesterol diet (HCD). Atherosclerosis was compared among the three differently induced mouse groups. iRFP → LDLR −/− mice fed a normal diet (ND) and LDLR −/− mice transplanted with wild-type (WT) BM cells were used as controls. The in vivo imaging system (IVIS) detected an enhanced iRFP signal in the thoracic aorta of HCD-fed iRFP → LDLR −/− mice, whereas iRFP signals were not observed in the control mice. Time-course imaging showed a gradual increase in the signal area, which was correlated with atherosclerotic plaque progression. Oil red O (ORO) staining of aortas and histological analysis of plaques confirmed that the detected signal was strictly emitted from plaque-positive areas of the aorta. Our new murine atherosclerosis imaging system can noninvasively image atherosclerotic plaques in the aorta and generate longitudinal data, validating the ability of the system to monitor lesion progression. Introduction Despite considerable therapeutic advances over the past 50 years, atherosclerosis-related cardiovascular diseases (CVD) remain the leading cause of death worldwide 1 . Conventional structural and functional imaging methods play increasingly important roles in better understanding such diseases and can be used to validate current therapeutic measures and to develop novel drug therapies 2 . Improved imaging technologies hold promise for accelerating drug development 1 . Macrophages play essential roles in all phases of atherosclerosis, from the development of a fatty streak to processes that ultimately contribute to plaque rupture and myocardial infarction 3 . Leukocytes are central components of the inflammatory response, and plaque macrophages account for the majority of leukocytes in atherosclerotic plaques 4 , 5 , 6 . There is extensive evidence linking local macrophage infiltration with plaque characteristics and vulnerability 7 , and plaque macrophages have emerged as key imaging targets for inflammatory atheroma in animal models 8 , 9 , 10 , 11 , 12 . Consequently, techniques that can detect macrophages in vivo are useful for monitoring the development of atherosclerotic lesions. However, to our knowledge, there are few reports on direct methods that can be used to noninvasively measure the accumulation of macrophages without injecting imaging reagents. Therefore, user-friendly direct methods to noninvasively detect macrophage-rich plaques are in high demand in preclinical settings. Bioluminescent proteins and visible light fluorescent proteins are powerful technologies that have been extensively used to further our understanding of complex processes. However, such proteins have limited utility in vivo because of their poor deep tissue penetration and high autofluorescence. In contrast, imaging with near-infrared fluorescence proteins within the 700–900 nm range of spectral wavelengths offers several advantages, including its high-sensitivity, nonionizing radiation and relatively simple operation 11 , 13 . A new near-infrared fluorescent protein (iRFP), a fluorescent mutant of Rp BphP2 bacteriophytochrome, was generated by Filonov et al . 12 . iRFP is a nontoxic, stable protein with excitation and emission wavelengths of 690 nm and 713 nm, respectively. iRFP is brighter, stronger and more stable than previous generations of similar fluorescent proteins 12 . These qualities make iRFP useful for in vivo imaging with great deep tissue penetration and minimal autofluorescence. Previously, Tran et al . generated transgenic (TG) iRFP mice with ubiquitous iRFP expression 14 . Because the expression of iRFP in hematopoietic cells was observed even in bone marrow-transplanted mice, we hypothesized that high iRFP fluorescence could be observed with the accumulation of macrophages within the atherosclerotic plaque area after transplantation of iRFP TG born marrow cells into X-ray-irradiated low-density lipoprotein receptor knockout ( LDLR −/− ) mice under hyperlipidemia conditions. In this study, we established a noninvasive, in vivo atherosclerosis imaging system using iRFP hematopoietic cell-transplanted LDLR −/− mice. To our knowledge, this is the first reported use of the endogenous iRFP fluorescence expression to image atherosclerotic lesions from 0 to 8 weeks without an invasive method or injection of imaging reagents. We believe that this novel noninvasive imaging approach will prove to be very helpful for monitoring disease progression in drug intervention studies with animal models. Results In vitro fluorescence expression of iRFP TG macrophages Initially, to validate the fluorescence intensity of iRFP TG mouse macrophages, we collected peritoneal macrophages from both iRFP TG and wild-type (WT) mice 3 days after injection of thioglycolate. Then, the cultured macrophages were observed by fluorescence microscope under a Cy5.5 filter. Clear, bright iRFP fluorescence signals were observed in the iRFP TG mouse macrophages, while no iRFP signal was observed in the WT macrophages (Fig. 1A ). Next, we conducted an experiment to determine the minimum iRFP TG macrophage number that was required to produce a detectable fluorescent signal by IVIS in the in vitro conditions. iRFP TG peritoneal macrophages were collected in 0.2 ml tubes at amounts ranging from 1 × 10 3 cells to 1 × 10 7 cells. Clear fluorescence signals were detected even with 1 × 10 5 iRFP TG macrophages, while no fluorescence signal was observed from the WT peritoneal macrophages, even at 1 × 10 7 cells (Fig. 1B ). The signal intensity increased exponentially with an augmented number of cells (Fig. 1C ). The fluorescence signal intensity of 1 × 10 7 iRFP TG macrophages was even higher than that of indocyanine green, which was used as a positive control. These results demonstrate that the iRFP TG macrophages display a bright iRFP signal and that the fluorescence intensity increased in a cell number-dependent manner. Moreover, the IVIS system was capable of capturing the cellular iRFP signal, and under our imaging conditions, a minimum of 1 × 10 5 iRFP TG macrophages was required to detect a fluorescence signal in vitro . Figure 1 iRFP TG mouse macrophages express fluorescence in vitro . ( A<|im_end|> <|im_start|>assistant Atherosclerosis, a process involving the buildup of arterial plaque and an associated reduction in blood flow, is a major feature of cardiovascular diseases. Although advances have been made in characterizing how this buildup occurs and ways to reduce it, diseases linked to atherosclerosis are still a major cause of mortality. In a major breakthrough in this field, researchers at the University of Tsukuba have developed a tool that can image the development of atherosclerotic plaque in the body and follow its progression over time, enabling accurate evaluation of drugs to treat atherosclerosis, and potentially, analysis of the likely risk posed by such plaque in individual patients. In this study, reported in the journal Scientific Reports, the team induced atherosclerosis in mice by inactivating a fat and cholesterol-related receptor and feeding them on a high-cholesterol diet. They also exposed these mice to X-rays to wipe out the native cells of their immune system, and then transplanted them with genetically engineered immune cells exhibiting fluorescence. "A main advantage of our approach is that the introduced immune cells, as macrophages, congregate in atherosclerotic plaque, so the level of fluorescence emitted by them strongly correlates with the amount of plaque that has formed," Yoshihiro Miwa says. "Because the expressed fluorescent proteins emit light in the near-infrared part of the spectrum, they can be detected at deeper locations within the body, such as the thoracic aorta." To confirm that this method can be used to identify the amount of atherosclerotic plaque within the mice, rather than just whether or not such plaque is present, the team established three groups with differing feeding patterns. They fed one group the high-cholesterol diet every day; another group was fed the high-cholesterol diet and a normal diet on alternate weeks; the third ate a normal diet. The findings based on the intensity of the fluorescent signal confirmed the expected stepwise differences in plaque quantity among these three groups, and also showed clear increases with a longer time spent consuming the unhealthy diets. "Because we can now clearly analyze the amount of plaque present and its change over time, our work should lead to more effective monitoring of how well anti-atherosclerotic drugs work," corresponding author Michito Hamada says. "This method can also reduce the number of experimental animals used because there's no need to sacrifice them and remove tissues for analysis at each time point within an experiment." The team hopes to further increase the sophistication of this tool, which could potentially lead to accurate analysis of the risk associated with the buildup of plaque in human patients and produce a range of associated medical benefits. <|im_end|>

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1176, 5068, 1005, 315, 279, 842, 53595, 602, 49, 11960, 97332, 7645, 311, 2217, 264, 91882, 566, 261, 14546, 63324, 505, 220, 15, 311, 220, 23, 5672, 2085, 459, 53354, 1749, 477, 26127, 315, 32758, 312, 55975, 13, 1226, 4510, 430, 420, 11775, 2536, 258, 78134, 32758, 5603, 690, 12391, 311, 387, 1633, 11190, 369, 16967, 8624, 33824, 304, 5623, 21623, 7978, 449, 10065, 4211, 13, 18591, 763, 55004, 97332, 7645, 315, 602, 49, 11960, 56972, 18563, 764, 1154, 59656, 11, 311, 9788, 279, 97332, 21261, 315, 602, 49, 11960, 56972, 8814, 18563, 764, 1154, 11, 584, 14890, 824, 85166, 278, 18563, 764, 1154, 505, 2225, 602, 49, 11960, 56972, 323, 8545, 10827, 320, 18961, 8, 24548, 220, 18, 2919, 1306, 26127, 315, 62428, 540, 398, 2119, 349, 13, 5112, 11, 279, 89948, 18563, 764, 1154, 1051, 13468, 555, 97332, 73757, 1234, 264, 18221, 20, 13, 20, 4141, 13, 12292, 11, 10107, 602, 49, 11960, 97332, 17738, 1051, 13468, 304, 279, 602, 49, 11960, 56972, 8814, 18563, 764, 1154, 11, 1418, 912, 602, 49, 11960, 8450, 574, 13468, 304, 279, 59199, 18563, 764, 1154, 320, 30035, 13, 220, 16, 32, 7609, 9479, 11, 584, 13375, 459, 9526, 311, 8417, 279, 8187, 602, 49, 11960, 56972, 18563, 764, 425, 1396, 430, 574, 2631, 311, 8356, 264, 11388, 481, 74864, 8450, 555, 17244, 1669, 304, 279, 304, 55004, 4787, 13, 602, 49, 11960, 56972, 824, 85166, 278, 18563, 764, 1154, 1051, 14890, 304, 220, 15, 13, 17, 16116, 34083, 520, 15055, 24950, 505, 220, 16, 25800, 220, 605, 220, 18, 7917, 311, 220, 16, 25800, 220, 605, 220, 22, 7917, 13, 12292, 97332, 17738, 1051, 16914, 1524, 449, 220, 16, 25800, 220, 605, 220, 20, 602, 49, 11960, 56972, 18563, 764, 1154, 11, 1418, 912, 97332, 8450, 574, 13468, 505, 279, 59199, 824, 85166, 278, 18563, 764, 1154, 11, 1524, 520, 220, 16, 25800, 220, 605, 220, 22, 7917, 320, 30035, 13, 220, 16, 33, 7609, 578, 8450, 21261, 7319, 75251, 449, 459, 57088, 1396, 315, 7917, 320, 30035, 13, 220, 16, 34, 7609, 578, 97332, 8450, 21261, 315, 220, 16, 25800, 220, 605, 220, 22, 602, 49, 11960, 56972, 18563, 764, 1154, 574, 1524, 5190, 1109, 430, 315, 1280, 511, 8503, 483, 6307, 11, 902, 574, 1511, 439, 264, 6928, 2585, 13, 4314, 3135, 20461, 430, 279, 602, 49, 11960, 56972, 18563, 764, 1154, 3113, 264, 10107, 602, 49, 11960, 8450, 323, 430, 279, 97332, 21261, 7319, 304, 264, 2849, 1396, 43918, 11827, 13, 23674, 11, 279, 17244, 1669, 1887, 574, 13171, 315, 40880, 279, 35693, 602, 49, 11960, 8450, 11, 323, 1234, 1057, 32758, 4787, 11, 264, 8187, 315, 220, 16, 25800, 220, 605, 220, 20, 602, 49, 11960, 56972, 18563, 764, 1154, 574, 2631, 311, 11388, 264, 97332, 8450, 304, 55004, 662, 19575, 220, 16, 602, 49, 11960, 56972, 8814, 18563, 764, 1154, 3237, 97332, 304, 55004, 662, 320, 362, 128257, 198, 128256, 78191, 198, 32, 91882, 91711, 11, 264, 1920, 16239, 279, 86765, 315, 80935, 61464, 323, 459, 5938, 14278, 304, 6680, 6530, 11, 374, 264, 3682, 4668, 315, 41713, 19338, 13, 10541, 31003, 617, 1027, 1903, 304, 3752, 4954, 1268, 420, 86765, 13980, 323, 5627, 311, 8108, 433, 11, 19338, 10815, 311, 264, 91882, 91711, 527, 2103, 264, 3682, 5353, 315, 29528, 13, 763, 264, 3682, 42445, 304, 420, 2115, 11, 12074, 520, 279, 3907, 315, 26132, 3178, 31529, 617, 8040, 264, 5507, 430, 649, 2217, 279, 4500, 315, 264, 91882, 566, 261, 14546, 61464, 304, 279, 2547, 323, 1833, 1202, 33824, 927, 892, 11, 28462, 13687, 16865, 315, 11217, 311, 4322, 264, 91882, 91711, 11, 323, 13893, 11, 6492, 315, 279, 4461, 5326, 37260, 555, 1778, 61464, 304, 3927, 6978, 13, 763, 420, 4007, 11, 5068, 304, 279, 8486, 38130, 29140, 11, 279, 2128, 36572, 264, 91882, 91711, 304, 24548, 555, 304, 9035, 1113, 264, 8834, 323, 39086, 14228, 35268, 323, 26040, 1124, 389, 264, 1579, 12, 971, 273, 33282, 10173, 13, 2435, 1101, 15246, 1521, 24548, 311, 1630, 82817, 311, 40194, 704, 279, 10068, 7917, 315, 872, 22852, 1887, 11, 323, 1243, 1380, 501, 7719, 1124, 449, 52033, 46036, 22852, 7917, 87719, 97332, 13, 330, 32, 1925, 9610, 315, 1057, 5603, 374, 430, 279, 11784, 22852, 7917, 11, 439, 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2,060

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The chemical order and disorder of solids have a decisive influence on the material properties. There are numerous materials exhibiting chemical order/disorder of atoms with similar X-ray atomic scattering factors and similar neutron scattering lengths. It is difficult to investigate such order/disorder hidden in the data obtained from conventional diffraction methods. Herein, we quantitatively determined the Mo/Nb order in the high ion conductor Ba 7 Nb 4 MoO 20 by a technique combining resonant X-ray diffraction, solid-state nuclear magnetic resonance (NMR) and first-principle calculations. NMR provided direct evidence that Mo atoms occupy only the M 2 site near the intrinsically oxygen-deficient ion-conducting layer. Resonant X-ray diffraction determined the occupancy factors of Mo atoms at the M 2 and other sites to be 0.50 and 0.00, respectively. These findings provide a basis for the development of ion conductors. This combined technique would open a new avenue for in-depth investigation of the hidden chemical order/disorder in materials. Introduction Structural order and disorder have attracted considerable attention because of their correlation with material properties 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Chemical (occupational) order and disorder have been studied mainly by crystal structure analysis using diffraction data. Such order and disorder are often observed among elements demonstrating similar X-ray atomic scattering factors and similar neutron scattering lengths. Here, we consider the chemical order between two elements X and Y ( X/Y order) and define the Scattering Contrast Score of elements X and Y , SCS( X , Y ) as a measure of the contrasts in X-ray and neutron scattering powers between the X and Y elements. $${{{{{\\rm{SCS}}}}}}\\left(X,Y\\right)=\\left | \\frac{N\\left(X\\right)-N\\left(Y\\right)}{N\\left(X\\right)+N\\left(Y\\right)}\\right |+\\left | \\frac{{{{{{\\rm{Re}}}}}}\\left[b\\left(X\\right)\\right]-{{{{{\\rm{Re}}}}}}\\left[b\\left(Y\\right)\\right]}{{{{{{\\rm{Re}}}}}}\\left[b\\left(X\\right)\\right]+{{{{{\\rm{Re}}}}}}\\left[b\\left(Y\\right)\\right]}\\right | $$ (1) Here N ( X ) and Re[ b ( X )] are the number of electrons and real part of the coherent neutron scattering length b of atom X , respectively. There are numerous pairs of X and Y elements with low SCS values (ex. ~300 X/Y pairs with SCS lower than 0.15; red parts in Fig. 1 ). However, it is difficult to investigate the X/Y chemical order hidden in conventional X-ray and neutron diffraction. Thus, the chemical order is an important unresolved issue with numerous materials (Supplementary Table 1 ). Herein, we propose a technique to elucidate the chemical order, which is a combination of resonant X-ray powder diffraction (RXRD) 17 , 18 , 19 , 20 , 21 and solid-state nuclear magnetic resonance (NMR) 22 , 23 , 24 , 25 assisted by density functional theory (DFT) calculations 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . Most materials are polycrystalline or powdered. In contrast to single-crystal X-ray and neutron diffraction, this combined technique can be widely applied to both polycrystalline and powdered samples. Direct evidence of the chemical order can be obtained by NMR 23 ; however, it is difficult to quantitatively analyse the chemical order among the constituent elements. In contrast, RXRD enables the quantitative determination of the chemical order by the refinement of occupancy factors, although the refinement results using powder diffraction data are often dependent on the initial structural model. A reliable, quantitative chemical order can be obtained by the present combined technique of NMR and RXRD. We call this combined technique as RXRD/NMR method. Fig. 1: Numerous pairs of X and Y elements having low scattering contrast score SCS( X , Y ). Each number stands for the SCS( X , Y ) value. Neutron scattering lengths are taken from the NIST website 68 . All the SCS( X , Y ) values are available in Supplementary Data 1 and Supplementary Table 16 . Full size image In this study, we aim to elucidate the Mo/Nb order/disorder in a high ion conductor Ba 7 Nb 4 MoO 20 ·0.15 H 2 O using the RXRD/NMR method (Fig. 2a ). We chose Ba 7 Nb 4 MoO 20 ·0.15 H 2 O, because Ba 7 Nb 4 MoO 20 -based oxides and related compounds are emerging materials with high ion conduction, structural disorder and high chemical stability 11 , 34 , 35 , 36 , 37 , 38 , 39 , 40 . The crystal structures of Ba 7 Nb 4 MoO 20 -based oxides have been extensively investigated. However, all the structural refinements were performed assuming the complete Mo/Nb disorder 11 , 34 , 35 , 36 , 38 , 39 , because the Mo 6+ and Nb 5+ cations have both (i) the same number of electrons leading to almost the same X-ray atomic scattering factors and (ii) almost the same neutron scattering lengths (6.715 and 7.054 fm for Mo and Nb, respectively). This indicates a small SCS value for the Mo/Nb pair of 0.037. Because the ions migrate in the oxygen-deficient c′ layers of Ba 7 Nb 4 MoO 20 -based oxides 34 , 36 , 38 , 39 , the determination of the chemical order/disorder of Mo and Nb atoms at the crystallographic M 2 site near the c′ layer is essential (Fig. 2b ). Thus, the chemical order of Mo and Nb atoms at the M 2 site is an important unsolved issue. Herein, we report the chemical order of Mo atoms at the M 2 site near the c′ layer, which offers unprecedented insight into the understanding of the ion diffusion mechanism in hexagonal perovskite-related oxides. Fig. 2: Strategies for the elucidation of the Mo/Nb order and complete crystal structure of Ba 7 Nb 4 MoO 20 ·0.15 H 2 O. a Combined technique to determine the crystal structure and Mo/Nb order of Ba 7 Nb 4 MoO 20 ·0.15 H 2 O. b Refined crystal structure showing the M 1, M 2, M 3 and M 4 sites of Mo and Nb atoms in Ba 7 Nb 4 MoO 20 ·0.15 H 2 O where the Mo and Nb atoms", "role": "user" }, { "content": "Researchers at Tokyo Tech have discovered hidden chemical order of the Mo and Nb atoms in disordered Ba7Nb4MoO20, by combining state-of-the-art techniques, including resonant X-ray diffraction and solid-state nuclear magnetic resonance. This study provides valuable insights into how a material's properties, such as ionic conduction, can be heavily influenced by its hidden chemical order. These results would stimulate significant advances in materials science and engineering. Determining the precise structure of a crystalline solid is a challenging endeavor. Materials properties such as ion conduction and chemical stability, are heavily influenced by the chemical (occupational) order and disorder. However, the techniques that scientists typically use to elucidate unknown crystal structures suffer from serious limitations. For instance, X-ray and neutron diffraction methods are powerful techniques to reveal the atomic positions and arrangement in the crystal lattice. However, they may not be adequate for distinguishing different atomic species with similar X-ray scattering factors and similar neutron scattering lengths. To tackle this issue, a research team led by Professor Masatomo Yashima of Tokyo Institute of Technology (Tokyo Tech) in Japan sought to develop a novel and more powerful approach to analyze the order and disorder in crystals. They combined four different techniques to analyze the crystal structure of an important ionic conductor, Ba7Nb4MoO20. \"We chose Ba7Nb4MoO20 as Ba7Nb4MoO20-based oxides and related compounds are a class of emerging materials with interesting properties such as high ionic conduction and high chemical stability,\" explains Prof. Yashima. \"However, given that both the Mo6+ and Nb5+ cations have similar scattering powers, all structural analyses of Ba7Nb4MoO20 until now have been performed assuming complete Mo/Nb disorder.\" As described in their recent paper published in Nature Communications, the researchers used an approach that combined two experimental techniques, resonant X-ray diffraction (RXRD) and solid-state nuclear magnetic resonance (NMR) aided by computational calculations based on density functional theory (DFT). The NMR provided direct experimental evidence that the Mo atoms occupy only the crystallographic M2 site in Ba7Nb4MoO20, indicating the chemical order of Mo atoms. Next, the researchers used RXRD to quantify the occupancy factors of Mo and Nb atoms. They found that the occupancy factor of Mo atoms was 0.5 at the M2 site but zero at all other sites. Interestingly, the M2 site is close to the oxide-ion conducting, oxygen-deficient layer of Ba7Nb4MoO20. This suggests that the Mo atoms at the M2 site have key role in the high ion conduction of Ba7Nb4MoO20. Furthermore, DFT calculations indicated that the Mo ordering stabilizes Mo excess composition exhibiting high ionic conductivity. Positions, occupancy, and atomic displacements of protons and oxide ions were also determined by neutron diffraction. \"Our results demonstrate that the Mo order affects the material properties of Ba7Nb4MoO20,\" says Prof. Yashima. \"In this regard, our work represents a major advance in our understanding of the correlation between the crystal structure and the material properties of ionic conductors.\" Further, in contrast to single-crystal X-ray and neutron diffraction, the proposed approach can even be extended to other polycrystalline and powdered samples. Overall, the methodology presented in this study can open up new avenues for an in-depth analysis of chemical order/disorder in materials. In turn, this could lead to the development of physics, chemistry, and materials science and technology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The chemical order and disorder of solids have a decisive influence on the material properties. There are numerous materials exhibiting chemical order/disorder of atoms with similar X-ray atomic scattering factors and similar neutron scattering lengths. It is difficult to investigate such order/disorder hidden in the data obtained from conventional diffraction methods. Herein, we quantitatively determined the Mo/Nb order in the high ion conductor Ba 7 Nb 4 MoO 20 by a technique combining resonant X-ray diffraction, solid-state nuclear magnetic resonance (NMR) and first-principle calculations. NMR provided direct evidence that Mo atoms occupy only the M 2 site near the intrinsically oxygen-deficient ion-conducting layer. Resonant X-ray diffraction determined the occupancy factors of Mo atoms at the M 2 and other sites to be 0.50 and 0.00, respectively. These findings provide a basis for the development of ion conductors. This combined technique would open a new avenue for in-depth investigation of the hidden chemical order/disorder in materials. Introduction Structural order and disorder have attracted considerable attention because of their correlation with material properties 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Chemical (occupational) order and disorder have been studied mainly by crystal structure analysis using diffraction data. Such order and disorder are often observed among elements demonstrating similar X-ray atomic scattering factors and similar neutron scattering lengths. Here, we consider the chemical order between two elements X and Y ( X/Y order) and define the Scattering Contrast Score of elements X and Y , SCS( X , Y ) as a measure of the contrasts in X-ray and neutron scattering powers between the X and Y elements. $${{{{{\rm{SCS}}}}}}\left(X,Y\right)=\left | \frac{N\left(X\right)-N\left(Y\right)}{N\left(X\right)+N\left(Y\right)}\right |+\left | \frac{{{{{{\rm{Re}}}}}}\left[b\left(X\right)\right]-{{{{{\rm{Re}}}}}}\left[b\left(Y\right)\right]}{{{{{{\rm{Re}}}}}}\left[b\left(X\right)\right]+{{{{{\rm{Re}}}}}}\left[b\left(Y\right)\right]}\right | $$ (1) Here N ( X ) and Re[ b ( X )] are the number of electrons and real part of the coherent neutron scattering length b of atom X , respectively. There are numerous pairs of X and Y elements with low SCS values (ex. ~300 X/Y pairs with SCS lower than 0.15; red parts in Fig. 1 ). However, it is difficult to investigate the X/Y chemical order hidden in conventional X-ray and neutron diffraction. Thus, the chemical order is an important unresolved issue with numerous materials (Supplementary Table 1 ). Herein, we propose a technique to elucidate the chemical order, which is a combination of resonant X-ray powder diffraction (RXRD) 17 , 18 , 19 , 20 , 21 and solid-state nuclear magnetic resonance (NMR) 22 , 23 , 24 , 25 assisted by density functional theory (DFT) calculations 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . Most materials are polycrystalline or powdered. In contrast to single-crystal X-ray and neutron diffraction, this combined technique can be widely applied to both polycrystalline and powdered samples. Direct evidence of the chemical order can be obtained by NMR 23 ; however, it is difficult to quantitatively analyse the chemical order among the constituent elements. In contrast, RXRD enables the quantitative determination of the chemical order by the refinement of occupancy factors, although the refinement results using powder diffraction data are often dependent on the initial structural model. A reliable, quantitative chemical order can be obtained by the present combined technique of NMR and RXRD. We call this combined technique as RXRD/NMR method. Fig. 1: Numerous pairs of X and Y elements having low scattering contrast score SCS( X , Y ). Each number stands for the SCS( X , Y ) value. Neutron scattering lengths are taken from the NIST website 68 . All the SCS( X , Y ) values are available in Supplementary Data 1 and Supplementary Table 16 . Full size image In this study, we aim to elucidate the Mo/Nb order/disorder in a high ion conductor Ba 7 Nb 4 MoO 20 ·0.15 H 2 O using the RXRD/NMR method (Fig. 2a ). We chose Ba 7 Nb 4 MoO 20 ·0.15 H 2 O, because Ba 7 Nb 4 MoO 20 -based oxides and related compounds are emerging materials with high ion conduction, structural disorder and high chemical stability 11 , 34 , 35 , 36 , 37 , 38 , 39 , 40 . The crystal structures of Ba 7 Nb 4 MoO 20 -based oxides have been extensively investigated. However, all the structural refinements were performed assuming the complete Mo/Nb disorder 11 , 34 , 35 , 36 , 38 , 39 , because the Mo 6+ and Nb 5+ cations have both (i) the same number of electrons leading to almost the same X-ray atomic scattering factors and (ii) almost the same neutron scattering lengths (6.715 and 7.054 fm for Mo and Nb, respectively). This indicates a small SCS value for the Mo/Nb pair of 0.037. Because the ions migrate in the oxygen-deficient c′ layers of Ba 7 Nb 4 MoO 20 -based oxides 34 , 36 , 38 , 39 , the determination of the chemical order/disorder of Mo and Nb atoms at the crystallographic M 2 site near the c′ layer is essential (Fig. 2b ). Thus, the chemical order of Mo and Nb atoms at the M 2 site is an important unsolved issue. Herein, we report the chemical order of Mo atoms at the M 2 site near the c′ layer, which offers unprecedented insight into the understanding of the ion diffusion mechanism in hexagonal perovskite-related oxides. Fig. 2: Strategies for the elucidation of the Mo/Nb order and complete crystal structure of Ba 7 Nb 4 MoO 20 ·0.15 H 2 O. a Combined technique to determine the crystal structure and Mo/Nb order of Ba 7 Nb 4 MoO 20 ·0.15 H 2 O. b Refined crystal structure showing the M 1, M 2, M 3 and M 4 sites of Mo and Nb atoms in Ba 7 Nb 4 MoO 20 ·0.15 H 2 O where the Mo and Nb atoms<|im_end|> <|im_start|>assistant Researchers at Tokyo Tech have discovered hidden chemical order of the Mo and Nb atoms in disordered Ba7Nb4MoO20, by combining state-of-the-art techniques, including resonant X-ray diffraction and solid-state nuclear magnetic resonance. This study provides valuable insights into how a material's properties, such as ionic conduction, can be heavily influenced by its hidden chemical order. These results would stimulate significant advances in materials science and engineering. Determining the precise structure of a crystalline solid is a challenging endeavor. Materials properties such as ion conduction and chemical stability, are heavily influenced by the chemical (occupational) order and disorder. However, the techniques that scientists typically use to elucidate unknown crystal structures suffer from serious limitations. For instance, X-ray and neutron diffraction methods are powerful techniques to reveal the atomic positions and arrangement in the crystal lattice. However, they may not be adequate for distinguishing different atomic species with similar X-ray scattering factors and similar neutron scattering lengths. To tackle this issue, a research team led by Professor Masatomo Yashima of Tokyo Institute of Technology (Tokyo Tech) in Japan sought to develop a novel and more powerful approach to analyze the order and disorder in crystals. They combined four different techniques to analyze the crystal structure of an important ionic conductor, Ba7Nb4MoO20. "We chose Ba7Nb4MoO20 as Ba7Nb4MoO20-based oxides and related compounds are a class of emerging materials with interesting properties such as high ionic conduction and high chemical stability," explains Prof. Yashima. "However, given that both the Mo6+ and Nb5+ cations have similar scattering powers, all structural analyses of Ba7Nb4MoO20 until now have been performed assuming complete Mo/Nb disorder." As described in their recent paper published in Nature Communications, the researchers used an approach that combined two experimental techniques, resonant X-ray diffraction (RXRD) and solid-state nuclear magnetic resonance (NMR) aided by computational calculations based on density functional theory (DFT). The NMR provided direct experimental evidence that the Mo atoms occupy only the crystallographic M2 site in Ba7Nb4MoO20, indicating the chemical order of Mo atoms. Next, the researchers used RXRD to quantify the occupancy factors of Mo and Nb atoms. They found that the occupancy factor of Mo atoms was 0.5 at the M2 site but zero at all other sites. Interestingly, the M2 site is close to the oxide-ion conducting, oxygen-deficient layer of Ba7Nb4MoO20. This suggests that the Mo atoms at the M2 site have key role in the high ion conduction of Ba7Nb4MoO20. Furthermore, DFT calculations indicated that the Mo ordering stabilizes Mo excess composition exhibiting high ionic conductivity. Positions, occupancy, and atomic displacements of protons and oxide ions were also determined by neutron diffraction. "Our results demonstrate that the Mo order affects the material properties of Ba7Nb4MoO20," says Prof. Yashima. "In this regard, our work represents a major advance in our understanding of the correlation between the crystal structure and the material properties of ionic conductors." Further, in contrast to single-crystal X-ray and neutron diffraction, the proposed approach can even be extended to other polycrystalline and powdered samples. Overall, the methodology presented in this study can open up new avenues for an in-depth analysis of chemical order/disorder in materials. In turn, this could lead to the development of physics, chemistry, and materials science and technology. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Superconducting circuits are a competitive platform for quantum computation because they offer controllability, long coherence times and strong interactions—properties that are essential for the study of quantum materials comprising microwave photons. However, intrinsic photon losses in these circuits hinder the realization of quantum many-body phases. Here we use superconducting circuits to explore strongly correlated quantum matter by building a Bose–Hubbard lattice for photons in the strongly interacting regime. We develop a versatile method for dissipative preparation of incompressible many-body phases through reservoir engineering and apply it to our system to stabilize a Mott insulator of photons against losses. Site- and time-resolved readout of the lattice allows us to investigate the microscopic details of the thermalization process through the dynamics of defect propagation and removal in the Mott phase. Our experiments demonstrate the power of superconducting circuits for studying strongly correlated matter in both coherent and engineered dissipative settings. In conjunction with recently demonstrated superconducting microwave Chern insulators, we expect that our approach will enable the exploration of topologically ordered phases of matter. Main The richness of quantum materials originates from the competition between quantum fluctuations arising from strong interactions, motional dynamics and the topology of the system. The results of this competition manifest as strong correlations and entanglement, which are observed both in the equilibrium ground state and in non-equilibrium dynamical evolution. In most condensed matter systems, efficient thermalization to a cold reservoir that has a well-defined chemical potential leads naturally to the preparation of the system near its many-body ground state, so understanding of the path to strong correlations—how particles order themselves under the system Hamiltonian—is limited. Synthetic quantum materials provide an opportunity to investigate this paradigm. Built from highly coherent constituents with precisely controlled and tunable interactions and dynamics, such materials have emerged as ideal platforms to explore quantum correlations, owing to their slowed dynamics and in high-resolution-imaging capabilities 1 , 2 . Low-entropy strongly correlated states are typically reached adiabatically in a many-body analogue of the Landau–Zener process by slowly tuning the system Hamiltonian through a quantum phase transition while the system is isolated from the environment, starting with a low-entropy state prepared in a weakly interacting or weakly correlated regime. As a prominent example from atomic physics, laser and evaporative cooling remove entropy from weakly interacting atomic gases to create Bose–Einstein condensates 3 , 4 , which are then used to adiabatically reach phases such as Mott insulators 5 , quantum magnets 6 , 7 and potentially even topologically ordered states 8 . These coherent isolated systems have prompted studies of relaxation in closed quantum systems, including observation of pre-thermalization 9 , many-body localization 10 and quantum self-thermalization 11 . Nonetheless, the challenge in such a ‘cool, then adiabatically evolve’ approach is the competition between the limited coherence time and the adiabatic criterion at the smallest many-body gaps, which shrink in the quantum critical region and often vanish at topological phase transitions. This suggests that dissipative stabilization of many-body states, which works directly in the strongly correlated phase with a potentially larger many-body gap, is a promising alternative approach. So far, though, thermalization of synthetic matter into strongly correlated phases has remained largely unexplored. Recently, photonic systems have emerged as a platform of interest for the exploration of synthetic quantum matter 12 , 13 , 14 , 15 , 16 , 17 . In particular, superconducting circuits have been used to study many-body physics of microwave photons, taking advantage of the individual control of strongly interacting qubits in these circuits. This approach builds on the circuit quantum electrodynamics toolbox developed for quantum computing 18 and has been applied to digital simulation of spin models 19 , fermionic dynamics 20 and quantum chemistry 21 , 22 . Equally of interest are analogue simulation experiments in these circuits, studying low-disorder lattices 23 , low-loss synthetic gauge fields 24 , 25 , dissipative lattices 26 , 27 and many-body localization in disorder potentials 28 . In the circuit platform, the particles that populate the system are microwave photons, which are inevitably subject to intrinsic particle losses. Without an imposed chemical potential, the photonic system eventually decays to the vacuum state, naturally posing the challenge of how to achieve strongly correlated matter in the absence of particle-number conservation. To this end, dissipative preparation and manipulation of quantum states via tailored reservoirs have become an active area of research both theoretically and experimentally, in which dissipative coupling to the environment serves as a resource 29 , 30 , 31 . Such engineered dissipation has been used to stabilize entangled states of ions 32 , single-qubit states 33 and entangled two-qubit states 34 , and holds promise for autonomous quantum error correction 35 , 36 , 37 . Here, we present a circuit platform for the exploration of quantum matter composed of strongly interacting microwave photons and use it to demonstrate direct dissipative stabilization of a strongly correlated phase of photons. Our scheme 38 builds on and simplifies previous proposals 39 , 40 , 41 , 42 , and is agnostic to the target phase as long as it is incompressible and exhibits mobile quasi-holes. To understand the protocol, illustrated in Fig. 1 , we consider a target ground state comprising N 0 photons that is spectrally gapped from excited states with the same particle number by the many-body gap Δ mb . Additionally, this state must be incompressible with respect to change in particle number, in the sense that inserting each of the first N 0 particles requires about the same energy, whereas adding the ( N 0 + 1)th particle requires an energy that differs by the compressibility gap Δ comp . Using a combination of coherent drive and engineered dissipation, we irreversibly inject particles into the system near the energy (per particle) of the target state. As long as the target state has good wavefunction overlap with both the initial state (for example, the vacuum N = 0) and the locally injected particles, the system will be continuously", "role": "user" }, { "content": "A team of researchers at the University of Chicago has developed a circuit platform for the exploration of quantum matter made of strongly interacting microwave photons. In their paper published in the journal Nature, the group outlines their platform and how it might be used. As part of the effort to create a useful quantum computer, scientists have been investigating superconducting circuits, which are controllable, have long coherence times and have strong interactions—characteristics required when studying quantum materials with microwave photons. The researchers note also that photon losses in such circuits (dissipation) can hold back the formation of many-body phases. To address this issue, they have developed a versatile circuit platform for handling many-body phases via reservoir engineering, resulting in a Mott insulator to reduce losses. The scheme involves imagining a tiny location called a transmon and considering how it could house a single photon. In such a scenario, when the transmon is empty, it is a simple matter to add a photon by pushing with a microwave generated electric field, but doing so could also remove any photon that is already housed. Instead, the researchers suggest adding a reservoir and pushing photons into the transmon as pairs—any extra photon would move naturally into the reservoir. In the case that there is already a photon in the transmon, it would remain in place rather than move to the reservoir. Next, the researchers imagined extending the scheme by adding more transmons to form a chain. An added photon would make its way down the chain, and if no locations were empty, it would wind up in the reservoir. Eventually, the system reaches a point at which all the locations in the chain are filled with single photons—this would represent a Mott insulator state. The researchers note that such a scheme would be flexible and thus could be applied to systems with different shapes, sizes and couplings. They note also that the scheme could be used to prepare any gapped phase of matter. They point out that for such a scheme to be practical, two new advances are still needed: a way to extend it to a larger system and a means of improving the quality of preparation. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Superconducting circuits are a competitive platform for quantum computation because they offer controllability, long coherence times and strong interactions—properties that are essential for the study of quantum materials comprising microwave photons. However, intrinsic photon losses in these circuits hinder the realization of quantum many-body phases. Here we use superconducting circuits to explore strongly correlated quantum matter by building a Bose–Hubbard lattice for photons in the strongly interacting regime. We develop a versatile method for dissipative preparation of incompressible many-body phases through reservoir engineering and apply it to our system to stabilize a Mott insulator of photons against losses. Site- and time-resolved readout of the lattice allows us to investigate the microscopic details of the thermalization process through the dynamics of defect propagation and removal in the Mott phase. Our experiments demonstrate the power of superconducting circuits for studying strongly correlated matter in both coherent and engineered dissipative settings. In conjunction with recently demonstrated superconducting microwave Chern insulators, we expect that our approach will enable the exploration of topologically ordered phases of matter. Main The richness of quantum materials originates from the competition between quantum fluctuations arising from strong interactions, motional dynamics and the topology of the system. The results of this competition manifest as strong correlations and entanglement, which are observed both in the equilibrium ground state and in non-equilibrium dynamical evolution. In most condensed matter systems, efficient thermalization to a cold reservoir that has a well-defined chemical potential leads naturally to the preparation of the system near its many-body ground state, so understanding of the path to strong correlations—how particles order themselves under the system Hamiltonian—is limited. Synthetic quantum materials provide an opportunity to investigate this paradigm. Built from highly coherent constituents with precisely controlled and tunable interactions and dynamics, such materials have emerged as ideal platforms to explore quantum correlations, owing to their slowed dynamics and in high-resolution-imaging capabilities 1 , 2 . Low-entropy strongly correlated states are typically reached adiabatically in a many-body analogue of the Landau–Zener process by slowly tuning the system Hamiltonian through a quantum phase transition while the system is isolated from the environment, starting with a low-entropy state prepared in a weakly interacting or weakly correlated regime. As a prominent example from atomic physics, laser and evaporative cooling remove entropy from weakly interacting atomic gases to create Bose–Einstein condensates 3 , 4 , which are then used to adiabatically reach phases such as Mott insulators 5 , quantum magnets 6 , 7 and potentially even topologically ordered states 8 . These coherent isolated systems have prompted studies of relaxation in closed quantum systems, including observation of pre-thermalization 9 , many-body localization 10 and quantum self-thermalization 11 . Nonetheless, the challenge in such a ‘cool, then adiabatically evolve’ approach is the competition between the limited coherence time and the adiabatic criterion at the smallest many-body gaps, which shrink in the quantum critical region and often vanish at topological phase transitions. This suggests that dissipative stabilization of many-body states, which works directly in the strongly correlated phase with a potentially larger many-body gap, is a promising alternative approach. So far, though, thermalization of synthetic matter into strongly correlated phases has remained largely unexplored. Recently, photonic systems have emerged as a platform of interest for the exploration of synthetic quantum matter 12 , 13 , 14 , 15 , 16 , 17 . In particular, superconducting circuits have been used to study many-body physics of microwave photons, taking advantage of the individual control of strongly interacting qubits in these circuits. This approach builds on the circuit quantum electrodynamics toolbox developed for quantum computing 18 and has been applied to digital simulation of spin models 19 , fermionic dynamics 20 and quantum chemistry 21 , 22 . Equally of interest are analogue simulation experiments in these circuits, studying low-disorder lattices 23 , low-loss synthetic gauge fields 24 , 25 , dissipative lattices 26 , 27 and many-body localization in disorder potentials 28 . In the circuit platform, the particles that populate the system are microwave photons, which are inevitably subject to intrinsic particle losses. Without an imposed chemical potential, the photonic system eventually decays to the vacuum state, naturally posing the challenge of how to achieve strongly correlated matter in the absence of particle-number conservation. To this end, dissipative preparation and manipulation of quantum states via tailored reservoirs have become an active area of research both theoretically and experimentally, in which dissipative coupling to the environment serves as a resource 29 , 30 , 31 . Such engineered dissipation has been used to stabilize entangled states of ions 32 , single-qubit states 33 and entangled two-qubit states 34 , and holds promise for autonomous quantum error correction 35 , 36 , 37 . Here, we present a circuit platform for the exploration of quantum matter composed of strongly interacting microwave photons and use it to demonstrate direct dissipative stabilization of a strongly correlated phase of photons. Our scheme 38 builds on and simplifies previous proposals 39 , 40 , 41 , 42 , and is agnostic to the target phase as long as it is incompressible and exhibits mobile quasi-holes. To understand the protocol, illustrated in Fig. 1 , we consider a target ground state comprising N 0 photons that is spectrally gapped from excited states with the same particle number by the many-body gap Δ mb . Additionally, this state must be incompressible with respect to change in particle number, in the sense that inserting each of the first N 0 particles requires about the same energy, whereas adding the ( N 0 + 1)th particle requires an energy that differs by the compressibility gap Δ comp . Using a combination of coherent drive and engineered dissipation, we irreversibly inject particles into the system near the energy (per particle) of the target state. As long as the target state has good wavefunction overlap with both the initial state (for example, the vacuum N = 0) and the locally injected particles, the system will be continuously<|im_end|> <|im_start|>assistant A team of researchers at the University of Chicago has developed a circuit platform for the exploration of quantum matter made of strongly interacting microwave photons. In their paper published in the journal Nature, the group outlines their platform and how it might be used. As part of the effort to create a useful quantum computer, scientists have been investigating superconducting circuits, which are controllable, have long coherence times and have strong interactions—characteristics required when studying quantum materials with microwave photons. The researchers note also that photon losses in such circuits (dissipation) can hold back the formation of many-body phases. To address this issue, they have developed a versatile circuit platform for handling many-body phases via reservoir engineering, resulting in a Mott insulator to reduce losses. The scheme involves imagining a tiny location called a transmon and considering how it could house a single photon. In such a scenario, when the transmon is empty, it is a simple matter to add a photon by pushing with a microwave generated electric field, but doing so could also remove any photon that is already housed. Instead, the researchers suggest adding a reservoir and pushing photons into the transmon as pairs—any extra photon would move naturally into the reservoir. In the case that there is already a photon in the transmon, it would remain in place rather than move to the reservoir. Next, the researchers imagined extending the scheme by adding more transmons to form a chain. An added photon would make its way down the chain, and if no locations were empty, it would wind up in the reservoir. Eventually, the system reaches a point at which all the locations in the chain are filled with single photons—this would represent a Mott insulator state. The researchers note that such a scheme would be flexible and thus could be applied to systems with different shapes, sizes and couplings. They note also that the scheme could be used to prepare any gapped phase of matter. They point out that for such a scheme to be practical, two new advances are still needed: a way to extend it to a larger system and a means of improving the quality of preparation. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Physicochemical properties of nanoparticles may depend on their size and shape and are traditionally assessed in ensemble-level experiments, which accordingly may be plagued by averaging effects. These effects can be eliminated in single-nanoparticle experiments. Using plasmonic nanospectroscopy, we present a comprehensive study of hydride formation thermodynamics in individual Pd nanocrystals of different size and shape, and find corresponding enthalpies and entropies to be nearly size- and shape-independent. The hysteresis observed is significantly wider than in bulk, with details depending on the specifics of individual nanoparticles. Generally, the absorption branch of the hysteresis loop is size-dependent in the sub-30 nm regime, whereas desorption is size- and shape-independent. The former is consistent with a coherent phase transition during hydride formation, influenced kinetically by the specifics of nucleation, whereas the latter implies that hydride decomposition either occurs incoherently or via different kinetic pathways. Main Palladium (Pd) constitutes the most important model system for fundamental studies of metal–hydrogen interaction, which is central in areas such as hydrogen storage 1 , heat storage 2 , metal hydride batteries 3 , hydrogen sensors 4 , smart windows 5 and switchable mirrors 6 . Hydrogen forms a stable hydride with Pd, basically without activation barriers 7 . During absorption, H 2 dissociates on the Pd surface and subsequently occupies surface, subsurface and interstitial lattice sites according to their specific energetics 8 . In the bulk, at low hydrogen partial pressures, the hydrogen atoms form a solid solution (α-phase). At each temperature below the critical temperature, there is a pressure at which the chemical potentials of hydrogen in the gas phase, α-phase and hydride (β-phase) are equal, and the first-order transition to the β-phase is initiated and manifested as a ‘plateau’ in a pressure–composition ( p – C ) isotherm. In addition, hysteresis occurs between hydride formation and decomposition, induced by the appearance of a macroscopic energy barrier for the transformation between the two phases due to lattice strain 9 imposed by an increase of the lattice parameter of about 3.5% in the hydride 7 . At the same time, a change of the complex permittivity of Pd takes place 10 . In the related fields it is essential to gain deeper understanding of the role of nanosizing because nanomaterial engineering provides a powerful means to optimize material performance 11 , 12 . A summary of the corresponding findings for traditionally studied ensembles of Pd nanoparticles includes: lowering of the critical temperature for separation of the α- and β-phases with decreasing particle size 13 , narrowing of the two-phase region 14 , decreasing absorption–desorption hysteresis and increasing slope of the plateau of the corresponding loop 15 , 16 , 17 , 18 , and apparent compensation for the influence of surface tension by absorption at subsurface sites 19 . The influence of the particle size/shape distribution on these findings is, however, not fully clear 20 . Other frequent complicating factors are different types of surfactants, polymeric stabilizers or strong interactions with the support/host matrix that may affect lattice strain and its relaxation during hydrogenation 21 . With the development of nanoplasmonic sensing, it recently became possible to advance from studies of confinement effects in Pd thin films and arrays/ensembles of Pd nanoparticles to the investigation of hydrogen sorption at the single-nanoparticle level, eliminating ensemble-averaging artefacts 4 , 22 , 23 , 24 , 25 . However, these initial single-particle studies did not provide deeper insight into the corresponding physics. The first detailed single-particle experiments were performed by Baldi et al. with individual Pd nanocubes at low pressure and temperature by means of electron energy loss spectroscopy 26 . Instead of a slope in the plateau region observed earlier at the ensemble level for Pd nanocubes by Bardhan et al. 27 , they found a sharp phase transition and a size-dependent absorption plateau pressure (the thermodynamics was not quantified). This was explained by a model assuming phase coherence and tensile strain in the particle core, induced by a thin 1 nm subsurface hydride layer, which mediates the phase transition 26 . In contrast, the treatment by Bardhan et al. invoked a thermal-fluctuation-mediated phase transition to explain the observed size-dependent thermodynamic parameters 27 . Herein, we apply non-invasive single-particle plasmonic nanospectroscopy for the first comprehensive experimental assessment of both hydrogenation thermodynamics and hysteresis in individual, surfactant-free, Pd nanocrystals over an unprecedented size (from 17 nm to over 100 nm) and shape range (single-crystalline nanocubes, nanooctahedra and twinned nanorods), to address the above contradictory findings in detail. We rely on wet-chemically synthesized Pd–Au heterodimers, created by electrostatic self-assembly of plasmonic Au nanoantennas and shape-selected Pd nanocrystals we have introduced earlier 28 (see also Methods ). Hydrogen sorption is tracked by measuring the spectral shifts of the plasmonic scattering peak of individual dimers, which is proportional to the hydrogen concentration in a Pd particle 29 , 30 , as here also confirmed specifically by finite-difference time-domain (FDTD) simulations for the three investigated Pd nanoparticle shapes. Single-particle plasmonic nanospectroscopy At nanoscopic length scales, metallic nanoparticles exhibit localized surface plasmon resonance (LSPR; ref. 31 ). We rely on the fact that the LSPR spectral position of a Au nanoantenna placed adjacent to a Pd nanoparticle is sensitive to the changes in permittivity and volume expansion induced in Pd on hydrogen sorption ( Fig. 1 ) 32 . At the same time the plasmonic antenna serves as a strong light scattering unit, which makes it ‘visible’ in a dark-field optical microscope. This is important because small Pd nanoparticles (as well as many other metals) on their own have poor light scattering properties due to strong absorption 33 . Thus, the Au nanoantenna acts both as a local nanoprobe for the hydrogen sorption in the adjacent Pd particle, and as an efficient signal transducer for dark-field scattering spectroscopy (DFSS). Figure 1: Heterodimer arrangement of a plasmonic Au nanoantenna combined with a shape-selected Pd nanoparticle. a , Artist’s view: As H 2 molecules (red) dissociate and are absorbed into the Pd cube, the process can be", "role": "user" }, { "content": "Scientists at Chalmers University of Technology have developed a new way to study nanoparticles one at a time, and have discovered that individual particles that may seem identical in fact can have very different properties. The results, which may prove to be important when developing new materials or applications such as hydrogen sensors for fuel cell cars, will be published in Nature Materials. \"We were able to show that you gain deeper insights into the physics of how nanomaterials interact with molecules in their environment by looking at the individual nanoparticle as opposed to looking at many of them at the same time, which is what is usually done,\" says Associate Professor Christoph Langhammer, who led the project. By applying a new experimental approach called plasmonic nanospectroscopy, the group studied hydrogen absorption into single palladium nanoparticles. They found that particles with exactly the same shape and size may exhibit differences as great as 40 millibars in the pressure at which hydrogen is absorbed. The development of sensors that can detect hydrogen leaks in fuel cell powered cars is one example of where this new understanding could become valuable in the future. \"One main challenge when working on hydrogen sensors is to design materials whose response to hydrogen is as linear and reversible as possible. In that way, the gained fundamental understanding of the reasons underlying the differences between seemingly identical individual particles and how this makes the response irreversible in a certain hydrogen concentration range can be helpful,\" says Christoph Langhammer. Others have looked at single nanoparticles one at a time, but the new approach introduced by the Chalmers team uses visible light with low intensity to study the particles. This means that the method is non-invasive and does not disturb the system it is investigating by, for example, heating it up. \"When studying individual nanoparticles you have to send some kind of probe to ask the particle 'what are you doing?'. This usually means focusing a beam of high-energy electrons or photons or a mechanical probe onto a very tiny volume. You then quickly get very high energy densities, which might perturb the process you want to look at. This effect is minimized in our new approach, which is also compatible with ambient conditions, meaning that we can study nanoparticles one at a time in as close to a realistic environment as possible\", says Christoph Langhammer. Even though they have now reached the level where their results are ready to be published, Christoph Langhammer believes they have just scratched the surface of what their discovery and developed experimental methodology will lead to in relation to further research. He hopes that they have helped to establish a new experimental paradigm, where looking at nanoparticles individually will become standard in the scientific world. \"It is not good enough to look at, and thus obtain an average of, hundreds or millions of particles if you want to understand the details of how nanoparticles behave in different environments and applications. You have to look at individual ones, and we have found a new way to do that.\" \"My own long-term vision is to apply our method to more complex processes and materials, and to push the limits in terms of how small nanoparticles can be for us to be able to measure them. Hopefully, along the way, we will gain even deeper insights into the fascinating world of nanomaterials.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Physicochemical properties of nanoparticles may depend on their size and shape and are traditionally assessed in ensemble-level experiments, which accordingly may be plagued by averaging effects. These effects can be eliminated in single-nanoparticle experiments. Using plasmonic nanospectroscopy, we present a comprehensive study of hydride formation thermodynamics in individual Pd nanocrystals of different size and shape, and find corresponding enthalpies and entropies to be nearly size- and shape-independent. The hysteresis observed is significantly wider than in bulk, with details depending on the specifics of individual nanoparticles. Generally, the absorption branch of the hysteresis loop is size-dependent in the sub-30 nm regime, whereas desorption is size- and shape-independent. The former is consistent with a coherent phase transition during hydride formation, influenced kinetically by the specifics of nucleation, whereas the latter implies that hydride decomposition either occurs incoherently or via different kinetic pathways. Main Palladium (Pd) constitutes the most important model system for fundamental studies of metal–hydrogen interaction, which is central in areas such as hydrogen storage 1 , heat storage 2 , metal hydride batteries 3 , hydrogen sensors 4 , smart windows 5 and switchable mirrors 6 . Hydrogen forms a stable hydride with Pd, basically without activation barriers 7 . During absorption, H 2 dissociates on the Pd surface and subsequently occupies surface, subsurface and interstitial lattice sites according to their specific energetics 8 . In the bulk, at low hydrogen partial pressures, the hydrogen atoms form a solid solution (α-phase). At each temperature below the critical temperature, there is a pressure at which the chemical potentials of hydrogen in the gas phase, α-phase and hydride (β-phase) are equal, and the first-order transition to the β-phase is initiated and manifested as a ‘plateau’ in a pressure–composition ( p – C ) isotherm. In addition, hysteresis occurs between hydride formation and decomposition, induced by the appearance of a macroscopic energy barrier for the transformation between the two phases due to lattice strain 9 imposed by an increase of the lattice parameter of about 3.5% in the hydride 7 . At the same time, a change of the complex permittivity of Pd takes place 10 . In the related fields it is essential to gain deeper understanding of the role of nanosizing because nanomaterial engineering provides a powerful means to optimize material performance 11 , 12 . A summary of the corresponding findings for traditionally studied ensembles of Pd nanoparticles includes: lowering of the critical temperature for separation of the α- and β-phases with decreasing particle size 13 , narrowing of the two-phase region 14 , decreasing absorption–desorption hysteresis and increasing slope of the plateau of the corresponding loop 15 , 16 , 17 , 18 , and apparent compensation for the influence of surface tension by absorption at subsurface sites 19 . The influence of the particle size/shape distribution on these findings is, however, not fully clear 20 . Other frequent complicating factors are different types of surfactants, polymeric stabilizers or strong interactions with the support/host matrix that may affect lattice strain and its relaxation during hydrogenation 21 . With the development of nanoplasmonic sensing, it recently became possible to advance from studies of confinement effects in Pd thin films and arrays/ensembles of Pd nanoparticles to the investigation of hydrogen sorption at the single-nanoparticle level, eliminating ensemble-averaging artefacts 4 , 22 , 23 , 24 , 25 . However, these initial single-particle studies did not provide deeper insight into the corresponding physics. The first detailed single-particle experiments were performed by Baldi et al. with individual Pd nanocubes at low pressure and temperature by means of electron energy loss spectroscopy 26 . Instead of a slope in the plateau region observed earlier at the ensemble level for Pd nanocubes by Bardhan et al. 27 , they found a sharp phase transition and a size-dependent absorption plateau pressure (the thermodynamics was not quantified). This was explained by a model assuming phase coherence and tensile strain in the particle core, induced by a thin 1 nm subsurface hydride layer, which mediates the phase transition 26 . In contrast, the treatment by Bardhan et al. invoked a thermal-fluctuation-mediated phase transition to explain the observed size-dependent thermodynamic parameters 27 . Herein, we apply non-invasive single-particle plasmonic nanospectroscopy for the first comprehensive experimental assessment of both hydrogenation thermodynamics and hysteresis in individual, surfactant-free, Pd nanocrystals over an unprecedented size (from 17 nm to over 100 nm) and shape range (single-crystalline nanocubes, nanooctahedra and twinned nanorods), to address the above contradictory findings in detail. We rely on wet-chemically synthesized Pd–Au heterodimers, created by electrostatic self-assembly of plasmonic Au nanoantennas and shape-selected Pd nanocrystals we have introduced earlier 28 (see also Methods ). Hydrogen sorption is tracked by measuring the spectral shifts of the plasmonic scattering peak of individual dimers, which is proportional to the hydrogen concentration in a Pd particle 29 , 30 , as here also confirmed specifically by finite-difference time-domain (FDTD) simulations for the three investigated Pd nanoparticle shapes. Single-particle plasmonic nanospectroscopy At nanoscopic length scales, metallic nanoparticles exhibit localized surface plasmon resonance (LSPR; ref. 31 ). We rely on the fact that the LSPR spectral position of a Au nanoantenna placed adjacent to a Pd nanoparticle is sensitive to the changes in permittivity and volume expansion induced in Pd on hydrogen sorption ( Fig. 1 ) 32 . At the same time the plasmonic antenna serves as a strong light scattering unit, which makes it ‘visible’ in a dark-field optical microscope. This is important because small Pd nanoparticles (as well as many other metals) on their own have poor light scattering properties due to strong absorption 33 . Thus, the Au nanoantenna acts both as a local nanoprobe for the hydrogen sorption in the adjacent Pd particle, and as an efficient signal transducer for dark-field scattering spectroscopy (DFSS). Figure 1: Heterodimer arrangement of a plasmonic Au nanoantenna combined with a shape-selected Pd nanoparticle. a , Artist’s view: As H 2 molecules (red) dissociate and are absorbed into the Pd cube, the process can be<|im_end|> <|im_start|>assistant Scientists at Chalmers University of Technology have developed a new way to study nanoparticles one at a time, and have discovered that individual particles that may seem identical in fact can have very different properties. The results, which may prove to be important when developing new materials or applications such as hydrogen sensors for fuel cell cars, will be published in Nature Materials. "We were able to show that you gain deeper insights into the physics of how nanomaterials interact with molecules in their environment by looking at the individual nanoparticle as opposed to looking at many of them at the same time, which is what is usually done," says Associate Professor Christoph Langhammer, who led the project. By applying a new experimental approach called plasmonic nanospectroscopy, the group studied hydrogen absorption into single palladium nanoparticles. They found that particles with exactly the same shape and size may exhibit differences as great as 40 millibars in the pressure at which hydrogen is absorbed. The development of sensors that can detect hydrogen leaks in fuel cell powered cars is one example of where this new understanding could become valuable in the future. "One main challenge when working on hydrogen sensors is to design materials whose response to hydrogen is as linear and reversible as possible. In that way, the gained fundamental understanding of the reasons underlying the differences between seemingly identical individual particles and how this makes the response irreversible in a certain hydrogen concentration range can be helpful," says Christoph Langhammer. Others have looked at single nanoparticles one at a time, but the new approach introduced by the Chalmers team uses visible light with low intensity to study the particles. This means that the method is non-invasive and does not disturb the system it is investigating by, for example, heating it up. "When studying individual nanoparticles you have to send some kind of probe to ask the particle 'what are you doing?'. This usually means focusing a beam of high-energy electrons or photons or a mechanical probe onto a very tiny volume. You then quickly get very high energy densities, which might perturb the process you want to look at. This effect is minimized in our new approach, which is also compatible with ambient conditions, meaning that we can study nanoparticles one at a time in as close to a realistic environment as possible", says Christoph Langhammer. Even though they have now reached the level where their results are ready to be published, Christoph Langhammer believes they have just scratched the surface of what their discovery and developed experimental methodology will lead to in relation to further research. He hopes that they have helped to establish a new experimental paradigm, where looking at nanoparticles individually will become standard in the scientific world. "It is not good enough to look at, and thus obtain an average of, hundreds or millions of particles if you want to understand the details of how nanoparticles behave in different environments and applications. You have to look at individual ones, and we have found a new way to do that." "My own long-term vision is to apply our method to more complex processes and materials, and to push the limits in terms of how small nanoparticles can be for us to be able to measure them. Hopefully, along the way, we will gain even deeper insights into the fascinating world of nanomaterials." <|im_end|>

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2,098

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Topological states of matter exhibit fascinating physics combined with an intrinsic stability. A key challenge is the fast creation of topological phases, which requires massive reorientation of charge or spin degrees of freedom. Here we report the picosecond emergence of an extended topological phase that comprises many magnetic skyrmions. The nucleation of this phase, followed in real time via single-shot soft X-ray scattering after infrared laser excitation, is mediated by a transient topological fluctuation state. This state is enabled by the presence of a time-reversal symmetry-breaking perpendicular magnetic field and exists for less than 300 ps. Atomistic simulations indicate that the fluctuation state largely reduces the topological energy barrier and thereby enables the observed rapid and homogeneous nucleation of the skyrmion phase. These observations provide fundamental insights into the nature of topological phase transitions, and suggest a path towards ultrafast topological switching in a wide variety of materials through intermediate fluctuating states. Main Femtosecond laser pulses can induce phase transitions and unexpected transient states of matter on ultrafast timescales. Examples range from crystallographic phase transitions 1 over charge ordering 2 , 3 to transitions into hidden quantum phases 4 . If the transitions involve spontaneous symmetry breaking and, moreover, proceed faster than the characteristic quasiparticles can propagate across the transition volume, causality requires the formation of grain-boundary-type topological defects. In non-topological materials, the final-state density of such defects is well understood. For example, the formation of vortices in superfluids and superconductors is described by the Kibble–Zurek mechanism (KZM) 5 , which links the defect density to a power law of the cooling rate through the second-order phase transition. Moreover, phase transitions exist between bound and free topological states, as formulated in the Berezinskii–Kosterlitz–Thouless theory 6 , which, however, preserve the topological invariants. Phase transitions that involve net topological switching, here referred to as global topological phase transitions 7 , are conceptually different and much less understood. In particular, although the annihilation dynamics of a topological state was recently reported 8 , the formation of topological phases has been observed only under quasi-static conditions 9 , 10 , 11 , 12 , 13 , which leaves the mechanism and speed of such phase transitions largely unexplored. Perpendicular magnetic thin-film ferromagnets are ideal candidates to investigate the dynamics of global topological phase transitions. First, these materials respond strongly to femtosecond laser pulses by ultrafast demagnetization 14 , 15 and all-optical switching 16 , even though the mechanism of the latter process is still under debate. Second, many perpendicular magnetic ferromagnets exhibit a topological skyrmion ground state in a finite range of externally applied fields 17 , 18 , 19 , 20 , 21 , 22 . The intrinsic stability of such a skyrmion phase arises at room temperature primarily from non-local stray-field interactions and the Dzyaloshinskii–Moriya interaction (DMI) can additionally enforce this stability and determine the skyrmion chirality. The skyrmion phase is topologically protected and therefore often hidden during adiabatic field cycling 17 , 20 (Fig. 1a ). Instead, it can be accessed by spatially inhomogeneous or dynamical excitations 20 , 23 , 24 , which include femtosecond laser pulses 12 , 13 . Owing to the large topological energy barriers, which often exceed 100 times the thermal energy at room temperature 25 , it is expected that the transition into the topological phase is governed by rare, heterogeneous switching events followed by domain wall motion dynamics on a nanosecond timescale or slower 12 , 17 . Fig. 1: Topological magnetic phase transition mediated by a transient fluctuation state. a , Typical room-temperature phases of a ferromagnetic thin-film skyrmion material as a function of a perpendicular magnetic field. Field-accessible magnetic phases are indicated by pictographs along the solid black hysteresis curve (homogeneous black or white, uniform down or up, respectively; stripes, stripe domains; circles, skyrmions). The laser-accessible skyrmion phase is located between the hysteresis branches. The dashed red line schematically indicates the average out-of-plane magnetization of the lowest-energy skyrmion texture. Wavy red arrows illustrate phase transitions induced by laser pulses. Inset: the evolution of sample temperature and magnetic states from a uniform state (1) via a fluctuation state (2) to a skyrmion texture (3). b , Schematic of the time-resolved detection process. The sample comprises a magnetic multilayer on an X-ray transparent membrane in an out-of-plane magnetic field H z . The sample is exposed to a train of three X-ray pulses and one infrared laser pulse, which has a well-defined delay with respect to the second X-ray pulse. The coherent diffraction of the X-ray pulses is recorded by a camera with a submicrosecond readout speed. The scattering pattern shown here corresponds to a skyrmion state. Full size image Here we performed single-shot infrared pump–X-ray probe measurements to follow the topological switching dynamics from a uniform field-polarized state into a dense skyrmion phase in real time (Fig. 1b ). The experiment was conducted at the soft X-ray beamline SCS of the European X-ray free-electron laser (XFEL) source, which provides exceptional sensitivity to the process in combination with temporal and reciprocal-space resolution. We discovered that the topological phase transition is essentially completed within 300 ps, much faster even than the simple reorientation of existing stripe domains under similar conditions 26 . The unexpected speed of this transition is enabled by evolution through a transient topological fluctuation state—a state that can be distinguished from non-topological fluctuations 27 by its evolution into stable, homotopological texture. The high speed is additionally attributed to the homogeneous nucleation of skyrmions, analogous to the freezing of supercooled water and the condensation of magnons 27 . We show that the fluctuation state and the skyrmion formation dynamics are in excellent agreement with atomistic spin dynamics simulations, which leads to a detailed microscopic understanding of all-optical topological switching. Demonstration of net topological switching Our study of laser-induced topological phase transitions was based on two related perpendicular magnetic multilayer materials: Ta(3.6 nm)/Pt(3.7 nm)/[Pt(2.7 nm)/Co 60 Fe 20 B 20 (0.9 nm)/MgO(1.5 nm)] 15 /Pt(2.7 nm) and Ta(3 nm)/[Co(0.6 nm)/Pt(0.8 nm)] 15", "role": "user" }, { "content": "Physicists have discovered a much faster approach to create a pattern of spins in a magnet. This shortcut opens a new chapter in topology research. This discovery also offers an additional method to achieve more efficient magnetic data storage. The research will be published on 5 October in Nature Materials. Physicists previously demonstrated that laser light can create a pattern of magnetic spins. Now they have discovered a new route that enables this to be done much more quickly, in less than 300 picoseconds (a picosecond is one millionth of a millionth of a second). This is much faster than was previously thought possible. Useful for data storage: skyrmions Magnets consist of many small magnets, which are called spins. Normally, all the spins point in the same direction, which determines the north and south poles of the magnet. But the directions of the spins together sometimes form vortex-like configurations known as skyrmions. \"These skyrmions in magnets could be used as a new type of data storage,\" explains Johan Mentink, physicist at Radboud University. For a number of years, Radboud scientists have been looking for optimal ways to control magnetism with laser light and ultimately use it for more efficient data storage. In this technique, very short pulses of light are fired at a magnetic material. This reverses the magnetic spins in the material, which changes a bit from a 0 to a 1. \"Once the magnetic spins take the vortex-like shape of a skyrmion, this configuration is hard to erase,\" says Mentink. \"Moreover, these skyrmions are only a few nanometers (one billionth of a meter) in size, so you can store a lot of data on a very small piece of material.\" Shortcut The phase transition between these two states in a magnet—all the spins pointing in one direction to a skyrmion—is comparable to a road over a high mountain. The researchers have discovered that you can take a shortcut through the mountain by heating the material very quickly with a laser pulse. Thereby, the threshold for the phase transition becomes lower for a very short time. A remarkable aspect of this new approach is that the material is first brought into a very chaotic state, in which the topology—which can be seen as the number of skyrmions in the material—fluctuates strongly. The researchers discovered this approach by combining X-rays generated by the European free electron laser in Hamburg with extremely advanced electron microscopy and spin dynamics simulations. \"This research therefore involved an enormous team effort,\" Mentink says. New possibilities This fundamental discovery has opened a new chapter in topology research. Mentink expects that many more scientists will now start to look for similar ways to 'take a shortcut through the mountain' in other materials. This discovery also enables new approaches to create faster and more efficient data storage. There is an increasing need for this, for example due to the gigantic, energy-guzzling data centers that are required for massive data storage in the cloud. Magnetic skyrmions can provide a solution to this problem. Because they are very small and can be created very quickly with light, a lot of information can potentially be stored very quickly and efficiently on a small area. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Topological states of matter exhibit fascinating physics combined with an intrinsic stability. A key challenge is the fast creation of topological phases, which requires massive reorientation of charge or spin degrees of freedom. Here we report the picosecond emergence of an extended topological phase that comprises many magnetic skyrmions. The nucleation of this phase, followed in real time via single-shot soft X-ray scattering after infrared laser excitation, is mediated by a transient topological fluctuation state. This state is enabled by the presence of a time-reversal symmetry-breaking perpendicular magnetic field and exists for less than 300 ps. Atomistic simulations indicate that the fluctuation state largely reduces the topological energy barrier and thereby enables the observed rapid and homogeneous nucleation of the skyrmion phase. These observations provide fundamental insights into the nature of topological phase transitions, and suggest a path towards ultrafast topological switching in a wide variety of materials through intermediate fluctuating states. Main Femtosecond laser pulses can induce phase transitions and unexpected transient states of matter on ultrafast timescales. Examples range from crystallographic phase transitions 1 over charge ordering 2 , 3 to transitions into hidden quantum phases 4 . If the transitions involve spontaneous symmetry breaking and, moreover, proceed faster than the characteristic quasiparticles can propagate across the transition volume, causality requires the formation of grain-boundary-type topological defects. In non-topological materials, the final-state density of such defects is well understood. For example, the formation of vortices in superfluids and superconductors is described by the Kibble–Zurek mechanism (KZM) 5 , which links the defect density to a power law of the cooling rate through the second-order phase transition. Moreover, phase transitions exist between bound and free topological states, as formulated in the Berezinskii–Kosterlitz–Thouless theory 6 , which, however, preserve the topological invariants. Phase transitions that involve net topological switching, here referred to as global topological phase transitions 7 , are conceptually different and much less understood. In particular, although the annihilation dynamics of a topological state was recently reported 8 , the formation of topological phases has been observed only under quasi-static conditions 9 , 10 , 11 , 12 , 13 , which leaves the mechanism and speed of such phase transitions largely unexplored. Perpendicular magnetic thin-film ferromagnets are ideal candidates to investigate the dynamics of global topological phase transitions. First, these materials respond strongly to femtosecond laser pulses by ultrafast demagnetization 14 , 15 and all-optical switching 16 , even though the mechanism of the latter process is still under debate. Second, many perpendicular magnetic ferromagnets exhibit a topological skyrmion ground state in a finite range of externally applied fields 17 , 18 , 19 , 20 , 21 , 22 . The intrinsic stability of such a skyrmion phase arises at room temperature primarily from non-local stray-field interactions and the Dzyaloshinskii–Moriya interaction (DMI) can additionally enforce this stability and determine the skyrmion chirality. The skyrmion phase is topologically protected and therefore often hidden during adiabatic field cycling 17 , 20 (Fig. 1a ). Instead, it can be accessed by spatially inhomogeneous or dynamical excitations 20 , 23 , 24 , which include femtosecond laser pulses 12 , 13 . Owing to the large topological energy barriers, which often exceed 100 times the thermal energy at room temperature 25 , it is expected that the transition into the topological phase is governed by rare, heterogeneous switching events followed by domain wall motion dynamics on a nanosecond timescale or slower 12 , 17 . Fig. 1: Topological magnetic phase transition mediated by a transient fluctuation state. a , Typical room-temperature phases of a ferromagnetic thin-film skyrmion material as a function of a perpendicular magnetic field. Field-accessible magnetic phases are indicated by pictographs along the solid black hysteresis curve (homogeneous black or white, uniform down or up, respectively; stripes, stripe domains; circles, skyrmions). The laser-accessible skyrmion phase is located between the hysteresis branches. The dashed red line schematically indicates the average out-of-plane magnetization of the lowest-energy skyrmion texture. Wavy red arrows illustrate phase transitions induced by laser pulses. Inset: the evolution of sample temperature and magnetic states from a uniform state (1) via a fluctuation state (2) to a skyrmion texture (3). b , Schematic of the time-resolved detection process. The sample comprises a magnetic multilayer on an X-ray transparent membrane in an out-of-plane magnetic field H z . The sample is exposed to a train of three X-ray pulses and one infrared laser pulse, which has a well-defined delay with respect to the second X-ray pulse. The coherent diffraction of the X-ray pulses is recorded by a camera with a submicrosecond readout speed. The scattering pattern shown here corresponds to a skyrmion state. Full size image Here we performed single-shot infrared pump–X-ray probe measurements to follow the topological switching dynamics from a uniform field-polarized state into a dense skyrmion phase in real time (Fig. 1b ). The experiment was conducted at the soft X-ray beamline SCS of the European X-ray free-electron laser (XFEL) source, which provides exceptional sensitivity to the process in combination with temporal and reciprocal-space resolution. We discovered that the topological phase transition is essentially completed within 300 ps, much faster even than the simple reorientation of existing stripe domains under similar conditions 26 . The unexpected speed of this transition is enabled by evolution through a transient topological fluctuation state—a state that can be distinguished from non-topological fluctuations 27 by its evolution into stable, homotopological texture. The high speed is additionally attributed to the homogeneous nucleation of skyrmions, analogous to the freezing of supercooled water and the condensation of magnons 27 . We show that the fluctuation state and the skyrmion formation dynamics are in excellent agreement with atomistic spin dynamics simulations, which leads to a detailed microscopic understanding of all-optical topological switching. Demonstration of net topological switching Our study of laser-induced topological phase transitions was based on two related perpendicular magnetic multilayer materials: Ta(3.6 nm)/Pt(3.7 nm)/[Pt(2.7 nm)/Co 60 Fe 20 B 20 (0.9 nm)/MgO(1.5 nm)] 15 /Pt(2.7 nm) and Ta(3 nm)/[Co(0.6 nm)/Pt(0.8 nm)] 15<|im_end|> <|im_start|>assistant Physicists have discovered a much faster approach to create a pattern of spins in a magnet. This shortcut opens a new chapter in topology research. This discovery also offers an additional method to achieve more efficient magnetic data storage. The research will be published on 5 October in Nature Materials. Physicists previously demonstrated that laser light can create a pattern of magnetic spins. Now they have discovered a new route that enables this to be done much more quickly, in less than 300 picoseconds (a picosecond is one millionth of a millionth of a second). This is much faster than was previously thought possible. Useful for data storage: skyrmions Magnets consist of many small magnets, which are called spins. Normally, all the spins point in the same direction, which determines the north and south poles of the magnet. But the directions of the spins together sometimes form vortex-like configurations known as skyrmions. "These skyrmions in magnets could be used as a new type of data storage," explains Johan Mentink, physicist at Radboud University. For a number of years, Radboud scientists have been looking for optimal ways to control magnetism with laser light and ultimately use it for more efficient data storage. In this technique, very short pulses of light are fired at a magnetic material. This reverses the magnetic spins in the material, which changes a bit from a 0 to a 1. "Once the magnetic spins take the vortex-like shape of a skyrmion, this configuration is hard to erase," says Mentink. "Moreover, these skyrmions are only a few nanometers (one billionth of a meter) in size, so you can store a lot of data on a very small piece of material." Shortcut The phase transition between these two states in a magnet—all the spins pointing in one direction to a skyrmion—is comparable to a road over a high mountain. The researchers have discovered that you can take a shortcut through the mountain by heating the material very quickly with a laser pulse. Thereby, the threshold for the phase transition becomes lower for a very short time. A remarkable aspect of this new approach is that the material is first brought into a very chaotic state, in which the topology—which can be seen as the number of skyrmions in the material—fluctuates strongly. The researchers discovered this approach by combining X-rays generated by the European free electron laser in Hamburg with extremely advanced electron microscopy and spin dynamics simulations. "This research therefore involved an enormous team effort," Mentink says. New possibilities This fundamental discovery has opened a new chapter in topology research. Mentink expects that many more scientists will now start to look for similar ways to 'take a shortcut through the mountain' in other materials. This discovery also enables new approaches to create faster and more efficient data storage. There is an increasing need for this, for example due to the gigantic, energy-guzzling data centers that are required for massive data storage in the cloud. Magnetic skyrmions can provide a solution to this problem. Because they are very small and can be created very quickly with light, a lot of information can potentially be stored very quickly and efficiently on a small area. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Zika virus (ZIKV) infection of pregnant women can cause fetal microcephaly and other neurologic defects. We describe the development of a non-human primate model to better understand fetal pathogenesis. To reliably induce fetal infection at defined times, four pregnant rhesus macaques are inoculated intravenously and intraamniotically with ZIKV at gestational day (GD) 41, 50, 64, or 90, corresponding to first and second trimester of gestation. The GD41-inoculated animal, experiencing fetal death 7 days later, has high virus levels in fetal and placental tissues, implicating ZIKV as cause of death. The other three fetuses are carried to near term and euthanized; while none display gross microcephaly, all show ZIKV RNA in many tissues, especially in the brain, which exhibits calcifications and reduced neural precursor cells. Given that this model consistently recapitulates neurologic defects of human congenital Zika syndrome, it is highly relevant to unravel determinants of fetal neuropathogenesis and to explore interventions. Introduction Fetuses from pregnant women infected with Zika virus (ZIKV) sometimes display reduced growth, arthrogryposis, ocular calcifications, skeletal and sensory disorders, and central nervous system (CNS) malformations including calcifications and aberrant neural cell development 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , manifestations that are together termed congenital Zika syndrome 9 , 10 , 11 . Animal models of human ZIKV infection in pregnancy are essential for determining pathogenesis and long-term effects on the infant brain, as well as treatments or vaccines to control or prevent infection and teratogenic effects in pregnant women. Although ZIKV-infected mice show fetal growth restriction, brain infection, and in some systems, CNS lesions similar to those seen in humans 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , significant differences in CNS development between mice and humans remain as limitation of murine models. In contrast, due to more similar placentation, immunology, fetal organogenesis, and neurologic development, macaques are an emerging model for understanding ZIKV infection and disease 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , and testing candidate vaccines 30 , 31 , 32 . To date, there are few reports of ZIKV infection of pregnant non-human primates (NHP). Fetuses of 4/5 pigtail macaques whose mothers were delivered repeated subcutaneous high-dose inoculation in second or third trimester showed ZIKV-associated brain lesions, similar to those seen in human fetuses 8 , including ependymal injury in the posterior lateral ventricles and periventricular gliosis 25 , 33 . In four pregnant rhesus macaques, subcutaneously ZIKV inoculated at gestational periods equivalent to mid-first to early third trimester, maternal–fetal transmission as evidenced by ZIKV RNA and pathology in some tissues, but not fetal CNS, was observed 23 . In this exploratory study, we artificially bypassed maternal–fetal transmission by direct intra amniotic (IA) inoculation, similar to the established NHP models of other fetal infections (e.g., cytomegalovirus; simian immunodeficiency virus 34 , 35 ), and a recent intrauterine mouse model of ZIKV that resulted in viral antigen in the fetal brain 16 . We previously demonstrated that lipopolysaccharide administered IA induced neuropathology in preterm fetal rhesus macaques, similar to brain injury reported in preterm infants exposed to chorioamnionitis 36 . Furthermore, ZIKV persists in the amniotic fluid of humans for prolonged periods 37 . In addition to IA infection of the fetus, we also intravenously (IV) inoculated the mother. The purpose of combined IA and IV inoculations was to ensure fetal infection at defined times using a minimal number of animals, since at the time these studies were initiated in early 2016, the frequency and timing of spontaneous maternal–fetal transmission in ZIKV-infected pregnant humans or rhesus macaques was unknown. We used the same 2015 Brazilian ZIKV isolate we previously employed to characterize viral kinetics and tissue distribution during acute infection of non-pregnant macaques 20 . Four pregnant females ranging from gestational day (GD) 41 to GD90 at the time of inoculation were selected because the gestation of rhesus macaques is ~165 ± 10 days, and IA inoculation is feasible starting at GD40. Three GD-matched control mothers were sham-inoculated and subjected to the same anesthesia and sampling schedule as the ZIKV-inoculated mothers to ensure that adverse outcomes did not result from experimental manipulations. Here we show that ZIKV infection resulted in fetal death in the earliest inoculated animal, GD41. Fetuses inoculated later in gestation in the late first and second trimesters survived to near term, but all exhibited CNS lesions including calcification and loss of neural progenitor cells that paralleled ZIKV RNA detection in CNS tissues. Because the combined maternal and fetal ZIKV inoculation approach reproduced fetal CNS lesions observed in humans, further development and optimization of this NHP model of ZIKV infection in pregnancy is relevant to further study the determinants of fetal ZIKV neuropathogenesis and to explore therapeutic intervention strategies. Results Experimental design and pregnancy outcomes Four pregnant macaques were each IV and IA inoculated once in the first or second trimester with 5 log 10 PFU per route with a 2015 Brazilian strain of ZIKV, followed by frequent sample collection and monitoring (Fig. 1 ). Three pregnant GD-matched control mothers were sham-inoculated and sampled on the same schedule. Although we intended to monitor pregnancies to GD155 and then terminate for detailed tissue collection, the GD41-inoculated fetus (GD41 fetus) was observed to be dead on GD48, 7 days post inoculation (dpi). The mother was therefore euthanized 7 dpi for detailed analysis of fetal and maternal tissues. The pregnant animal inoculated at GD64 (GD64 mother) had intermittent placental bleeding detected by ultrasound and bloody amniotic fluid with bloody vaginal discharge starting 39 dpi, and spontaneously vaginally delivered a small but viable neonate at GD151, at which time both were euthanized. The pregnant GD50 and GD90 mothers and three control animals were all monitored to the planned experimental end point of GD155 when fetectomy was performed, followed by necropsy. The fetal head sizes for the GD50 and GD90 fetuses were within the California National", "role": "user" }, { "content": "Rhesus macaque monkeys infected in utero with Zika virus develop similar brain pathology to human infants, according to a report by researchers at the California National Primate Research Center and School of Veterinary Medicine at the University of California, Davis, published June 20 in Nature Communications. Rhesus macaques may be a suitable model system to study how Zika virus infection during pregnancy affects the fetus and to find ways to prevent, diagnose, mitigate or treat it, said Koen Van Rompay, research virologist at the CNPRC. \"This could be a useful model to test therapies for congenital Zika virus syndrome,\" Van Rompay said. \"The direct administration of Zika virus into the amniotic fluid caused brain disease in all fetuses, unlike other related studies. Since all fetuses are affected, therapies can be tested using fewer animals,\" said Lark Coffey, assistant professor in the School of Veterinary Medicine who led the study with Van Rompay. Babies born to women who were exposed to Zika virus during pregnancy can display \"congenital Zika syndrome,\" including microcephaly (unusually small head size), calcification of brain tissues and other signs of abnormal brain and eye development. It's thought that Zika virus-related brain damage may affect a larger number of children than those born with abnormally small heads. Mice infected with Zika virus can show some similar effects, but both pregnancy and brain development are quite different in rodents and humans. Rhesus macaques are more similar to humans in physiology and in how their brain and central nervous system develops. Brain lesions mimic those in Zika-affected babies Van Rompay, Coffey and colleagues infected four macaque fetuses by introducing Zika virus directly into the amniotic sac. One fetus infected early in pregnancy died; three others infected later survived to term. The animals born at term did not have microcephaly, but they did have calcification of brain tissues and other brain damage. These findings contrasted with those from 3 age-matched fetuses that were not Zika inoculated and whose brains showed no signs of damage. The brain lesions in animals mimic those in human newborns with congenital Zika syndrome, Van Rompay said. The researchers found large amounts of Zika virus in brain tissues from infected animals, but not in cord blood. That is significant because it means that infection likely cannot be diagnosed in humans just by looking at easily accessible cord blood. \"Blood samples could be negative for virus, but there may still be virus in the brain,\" Van Rompay said. \"We have learned so much from this study,\" Coffey said. \"This has helped us to better design new experiments, some of which are currently ongoing, to gain a better understanding of the effects of Zika infection on the fetus, and to test proof-of-concept of novel interventions, with the ultimate aim that these results can guide human clinical trials.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Zika virus (ZIKV) infection of pregnant women can cause fetal microcephaly and other neurologic defects. We describe the development of a non-human primate model to better understand fetal pathogenesis. To reliably induce fetal infection at defined times, four pregnant rhesus macaques are inoculated intravenously and intraamniotically with ZIKV at gestational day (GD) 41, 50, 64, or 90, corresponding to first and second trimester of gestation. The GD41-inoculated animal, experiencing fetal death 7 days later, has high virus levels in fetal and placental tissues, implicating ZIKV as cause of death. The other three fetuses are carried to near term and euthanized; while none display gross microcephaly, all show ZIKV RNA in many tissues, especially in the brain, which exhibits calcifications and reduced neural precursor cells. Given that this model consistently recapitulates neurologic defects of human congenital Zika syndrome, it is highly relevant to unravel determinants of fetal neuropathogenesis and to explore interventions. Introduction Fetuses from pregnant women infected with Zika virus (ZIKV) sometimes display reduced growth, arthrogryposis, ocular calcifications, skeletal and sensory disorders, and central nervous system (CNS) malformations including calcifications and aberrant neural cell development 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , manifestations that are together termed congenital Zika syndrome 9 , 10 , 11 . Animal models of human ZIKV infection in pregnancy are essential for determining pathogenesis and long-term effects on the infant brain, as well as treatments or vaccines to control or prevent infection and teratogenic effects in pregnant women. Although ZIKV-infected mice show fetal growth restriction, brain infection, and in some systems, CNS lesions similar to those seen in humans 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , significant differences in CNS development between mice and humans remain as limitation of murine models. In contrast, due to more similar placentation, immunology, fetal organogenesis, and neurologic development, macaques are an emerging model for understanding ZIKV infection and disease 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , and testing candidate vaccines 30 , 31 , 32 . To date, there are few reports of ZIKV infection of pregnant non-human primates (NHP). Fetuses of 4/5 pigtail macaques whose mothers were delivered repeated subcutaneous high-dose inoculation in second or third trimester showed ZIKV-associated brain lesions, similar to those seen in human fetuses 8 , including ependymal injury in the posterior lateral ventricles and periventricular gliosis 25 , 33 . In four pregnant rhesus macaques, subcutaneously ZIKV inoculated at gestational periods equivalent to mid-first to early third trimester, maternal–fetal transmission as evidenced by ZIKV RNA and pathology in some tissues, but not fetal CNS, was observed 23 . In this exploratory study, we artificially bypassed maternal–fetal transmission by direct intra amniotic (IA) inoculation, similar to the established NHP models of other fetal infections (e.g., cytomegalovirus; simian immunodeficiency virus 34 , 35 ), and a recent intrauterine mouse model of ZIKV that resulted in viral antigen in the fetal brain 16 . We previously demonstrated that lipopolysaccharide administered IA induced neuropathology in preterm fetal rhesus macaques, similar to brain injury reported in preterm infants exposed to chorioamnionitis 36 . Furthermore, ZIKV persists in the amniotic fluid of humans for prolonged periods 37 . In addition to IA infection of the fetus, we also intravenously (IV) inoculated the mother. The purpose of combined IA and IV inoculations was to ensure fetal infection at defined times using a minimal number of animals, since at the time these studies were initiated in early 2016, the frequency and timing of spontaneous maternal–fetal transmission in ZIKV-infected pregnant humans or rhesus macaques was unknown. We used the same 2015 Brazilian ZIKV isolate we previously employed to characterize viral kinetics and tissue distribution during acute infection of non-pregnant macaques 20 . Four pregnant females ranging from gestational day (GD) 41 to GD90 at the time of inoculation were selected because the gestation of rhesus macaques is ~165 ± 10 days, and IA inoculation is feasible starting at GD40. Three GD-matched control mothers were sham-inoculated and subjected to the same anesthesia and sampling schedule as the ZIKV-inoculated mothers to ensure that adverse outcomes did not result from experimental manipulations. Here we show that ZIKV infection resulted in fetal death in the earliest inoculated animal, GD41. Fetuses inoculated later in gestation in the late first and second trimesters survived to near term, but all exhibited CNS lesions including calcification and loss of neural progenitor cells that paralleled ZIKV RNA detection in CNS tissues. Because the combined maternal and fetal ZIKV inoculation approach reproduced fetal CNS lesions observed in humans, further development and optimization of this NHP model of ZIKV infection in pregnancy is relevant to further study the determinants of fetal ZIKV neuropathogenesis and to explore therapeutic intervention strategies. Results Experimental design and pregnancy outcomes Four pregnant macaques were each IV and IA inoculated once in the first or second trimester with 5 log 10 PFU per route with a 2015 Brazilian strain of ZIKV, followed by frequent sample collection and monitoring (Fig. 1 ). Three pregnant GD-matched control mothers were sham-inoculated and sampled on the same schedule. Although we intended to monitor pregnancies to GD155 and then terminate for detailed tissue collection, the GD41-inoculated fetus (GD41 fetus) was observed to be dead on GD48, 7 days post inoculation (dpi). The mother was therefore euthanized 7 dpi for detailed analysis of fetal and maternal tissues. The pregnant animal inoculated at GD64 (GD64 mother) had intermittent placental bleeding detected by ultrasound and bloody amniotic fluid with bloody vaginal discharge starting 39 dpi, and spontaneously vaginally delivered a small but viable neonate at GD151, at which time both were euthanized. The pregnant GD50 and GD90 mothers and three control animals were all monitored to the planned experimental end point of GD155 when fetectomy was performed, followed by necropsy. The fetal head sizes for the GD50 and GD90 fetuses were within the California National<|im_end|> <|im_start|>assistant Rhesus macaque monkeys infected in utero with Zika virus develop similar brain pathology to human infants, according to a report by researchers at the California National Primate Research Center and School of Veterinary Medicine at the University of California, Davis, published June 20 in Nature Communications. Rhesus macaques may be a suitable model system to study how Zika virus infection during pregnancy affects the fetus and to find ways to prevent, diagnose, mitigate or treat it, said Koen Van Rompay, research virologist at the CNPRC. "This could be a useful model to test therapies for congenital Zika virus syndrome," Van Rompay said. "The direct administration of Zika virus into the amniotic fluid caused brain disease in all fetuses, unlike other related studies. Since all fetuses are affected, therapies can be tested using fewer animals," said Lark Coffey, assistant professor in the School of Veterinary Medicine who led the study with Van Rompay. Babies born to women who were exposed to Zika virus during pregnancy can display "congenital Zika syndrome," including microcephaly (unusually small head size), calcification of brain tissues and other signs of abnormal brain and eye development. It's thought that Zika virus-related brain damage may affect a larger number of children than those born with abnormally small heads. Mice infected with Zika virus can show some similar effects, but both pregnancy and brain development are quite different in rodents and humans. Rhesus macaques are more similar to humans in physiology and in how their brain and central nervous system develops. Brain lesions mimic those in Zika-affected babies Van Rompay, Coffey and colleagues infected four macaque fetuses by introducing Zika virus directly into the amniotic sac. One fetus infected early in pregnancy died; three others infected later survived to term. The animals born at term did not have microcephaly, but they did have calcification of brain tissues and other brain damage. These findings contrasted with those from 3 age-matched fetuses that were not Zika inoculated and whose brains showed no signs of damage. The brain lesions in animals mimic those in human newborns with congenital Zika syndrome, Van Rompay said. The researchers found large amounts of Zika virus in brain tissues from infected animals, but not in cord blood. That is significant because it means that infection likely cannot be diagnosed in humans just by looking at easily accessible cord blood. "Blood samples could be negative for virus, but there may still be virus in the brain," Van Rompay said. "We have learned so much from this study," Coffey said. "This has helped us to better design new experiments, some of which are currently ongoing, to gain a better understanding of the effects of Zika infection on the fetus, and to test proof-of-concept of novel interventions, with the ultimate aim that these results can guide human clinical trials." <|im_end|>

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2,068

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The ability of climate models to simulate 20th century global mean sea level (GMSL) and regional sea-level change has been demonstrated. However, the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5) and Special Report on the Ocean and Cryosphere in a Changing Climate (SROCC) sea-level projections have not been rigorously evaluated with observed GMSL and coastal sea level from a global network of tide gauges as the short overlapping period (2007–2018) and natural variability make the detection of trends and accelerations challenging. Here, we critically evaluate these projections with satellite and tide-gauge observations. The observed trends from GMSL and the regional weighted mean at tide-gauge stations confirm the projections under three Representative Concentration Pathway (RCP) scenarios within 90% confidence level during 2007–2018. The central values of the observed GMSL (1993–2018) and regional weighted mean (1970–2018) accelerations are larger than projections for RCP2.6 and lie between (or even above) those for RCP4.5 and RCP8.5 over 2007–2032, but are not yet statistically different from any scenario. While the confirmation of the projection trends gives us confidence in current understanding of near future sea-level change, it leaves open questions concerning late 21 st century non-linear accelerations from ice-sheet contributions. Introduction As an essential indicator of global climate change and ocean variability, sea level has been simulated by models during both historical and future periods. Reliable sea-level projections are also vital for coastal communities. The IPCC AR5 1 and SROCC 2 provide global and regional sea-level projections, including estimates of contributions from oceans, glaciers, ice sheets, and land water from 2007 to 2100. The regional projections also include an allowance for relative sea level induced by glacial isostatic adjustment (GIA). Critically evaluating sea-level projections by comparing them with observations is important in enhancing our understanding of confidence in sea-level changes in the 21st century, identifying potential limitations in current projections, which helps to further calibrate and reduce uncertainties in the projections. Previous studies have demonstrated the improved ability of models in simulating 20th century sea-level changes at both global and regional scales 3 , 4 , 5 . After 1950 and particularly for the satellite era since 1993, the model simulations accounted for essentially all the observed GMSL rise, with GMSL rise since 1970 dominated by anthropogenic climate change 6 . However, critically evaluating the sea-level projections by comparison with recent observations is challenging on both global and regional scales because (i) there is considerable natural variability and the overlapping period is short (2007–2018), and (ii) regional tide-gauge records are highly influenced by local factors, such as the vertical land motion (VLM) 7 and sea-level extreme events (like storm surges). The natural variability in sea-level change (e.g. the El Niño—Southern Oscillation (ENSO) 8 ) and especially decadal (multidecadal) variations make the detection of trends and accelerations more difficult, even in long sea-level records 9 . Here, we show the trends of the IPCC AR5 and SROCC sea-level projections under three RCP scenarios from both GMSL and regional weighted mean at 177 tide-gauges stations agree well with satellite and tide-gauge observations over the common peiod 2007–2018 within 90% confidence level (90% CL), after considering the impacts of natural climate variability and correcting local residual VLM. Because of natural variability, we extend the period of observations and projections for a robust derivation of acceleration. We find the central values of observed GMSL (satellite altimeter over 1993–2018; sea-level reconstruction over 1970–2018) and regional weighted mean at tide-gauge stations (1970–2018) show larger accelerations than that from projections under RCP2.6 and lie between projected accelerations under RCP4.5 and RCP8.5, while not yet statistically different from any scenario. In the real word, the sea-level acceleration need to be reduced to be consistent with the lower and falling RCP2.6 mitigation emission scenario and the Paris targets in the late 21st century. Results Outline For GMSL, we utilise satellite altimeter observation time series over 1993–2018 from the Australian Commonwealth Scientific and Industrial Research Organization (CSIRO) and the U.S. National Aeronautics and Space Administration (NASA) Goddard Space Flight Centre (GSFC; Fig. 1a ). Both groups attempted to correct instrumental drifts during the earlier altimeter period, by either using tide-gauge records with VLM estimated based on GIA or Global Positioning System (GPS) for CSIRO 10 or turning off the on-board calibration mode for GSFC 11 . We also use the long-term GMSL reconstructions based on tide-gauge records from Church & White 2011 12 and Dangendorf 2019 13 (hereafter referred to as CW2011 and D2019, respectively) over 1970–2018. Other GMSL reconstructions are not included here, as their differences from the above two reconstructions are generally small after 1970 14 , e.g. GMSL from ref. 15 closely resemble D2019 (Supplementary Fig. 1 ). For regional sea-level observations, 177 tide gauges around the world (Fig. 2 ) since 1970 are used. Fig. 1: The global-mean sea level (GMSL) from observations compared with projections. a Monthly satellite altimeter observations (1993–2018) with instrumental drifts corrected are from the Australian Commonwealth Scientific and Industrial Research Organization (CSIRO) based on glacial isostatic adjustment (GIA-adjust; yellow) and Global Positioning System (GPS-adjust; orange), as well as from the National Aeronautics and Space Administration Goddard Space Flight Centre (NASA/GSFC; red). The GMSL reconstructions (1970–2018) from ref. 13 (D2019; light purple) and ref. 12 (CW2011; purple) are smoothed with a 5-month running-mean filter. The annual multimodel averaged GMSL projections from the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5; from light green to dark green) and Special Report on the Ocean and Cryosphere in a Changing Climate (SROCC; from light blue to dark dark blue) under three Representative Concentration Pathway (RCP) scenarios respectively (2007–2032). GMSL trends including both linear and quadratic terms are also shown offset by −50 mm. The blue shaded area indicates the overlapping period between observations and projections (2007–2018). Box plots of b GMSL trends [mm yr −1 ] over 2007–2018 and c GMSL acceleration [mm yr −2 ] over the whole period of each dataset. Error bars indicate 90% confidence level. Full size image Fig. 2:", "role": "user" }, { "content": "Projections of rising sea levels this century are on the money when tested against satellite and tide-gauge observations, scientists find. Climate model projections of sea-level rises in the early 21st century are in good agreement with sea level data recorded in the corresponding period, a recent analysis has found. And the scientists who crunched the numbers say the finding does not bode well for sea level impacts over coming decades if greenhouse gas emissions are not reined in. In an article published recently in Nature Communications, the scientists from Chinese and Australian institutions including UNSW Sydney examined the global and regional sea level projections of two reports by the Intergovernmental Panel on Climate Change: the Fifth Assessment Report (AR5) and Special Report on the Ocean and Cryosphere in a Changing Climate (SROCC). They compared the reports' projections with the observed global and coastal sea level data gathered from satellites and a network of 177 tide-gauges from the start of the projections in 2007 up to to 2018. The scientists found that the trends of the AR5 and SROCC sea level projections under three different scenarios of greenhouse gas emissions \"agree well with satellite and tide-gauge observations over the common period 2007–2018, within the 90 percent confidence level.\" Study co-author and leading sea-level expert, Professor John Church, says while he thought the projections from modelling would be accurate at the global level, he was pleasantly surprised that they were as accurate at the regional and local level. \"Our analysis implies that the models are close to observations and builds confidence in the current projections for the next several decades,\" says Prof. Church, who is part of UNSW's Climate Change Research Centre. But he adds a caveat that because the available comparison period is short, at just 11 years, he would be hesitant to extend the same degree of confidence over the longer term—from the end of this century and beyond—where acceleration of ice-sheet contribution to sea-level rise is less understood and could lead to larger rises. \"There remains a potential for larger sea level rises, particularly beyond 2100 for high emission scenarios. Therefore, it is urgent that we still try to meet the commitments of the Paris Agreement by significantly reducing emissions,\" Prof. Church says. Study co-author Dr. Xuebin Zhang, from CSIRO's Oceans and Atmosphere Division says this is the first study to compare projections of sea level rises at both a global and regional level with observations over their overlapping periods—no mean feat given the natural variability of climate and vertical land movement from region to region. \"We carefully removed the impacts from natural climate variability, for example El Niño– Southern Oscillation, and corrected vertical land movement, which led to much improved agreement.\" The analysis looked at the three different emissions scenarios in the IPCC's reports that corresponded to three different climate futures depending on what greenhouse gas mitigation strategies were adopted—known as Representative Concentration Pathway (RCP) scenarios. The lowest scenario (RCP2.6) examined is for strong mitigation of greenhouse gas emissions, about in line with 2oC of global warming by 2100 but still larger than what is required to meet the Paris Agreement of well below 2oC. The middle scenario (RCP4.5) requires stabilization of radiative forcing in the latter half of this century and results in warming well above the Paris Target. And the highest scenario (RCP8.5) is for large greenhouse gas emissions resulting in ongoing rapid warming and implies a commitment to large sea level rises. \"The analysis of the recent sea level data indicate the world is tracking between RCP4.5 and the worst case scenario of RCP8.5,\" Professor Church says. \"If we continue with large ongoing emissions as we are at present, we will commit the world to meters of sea level rise over coming centuries.\" Next the group will attempt to gain a greater understanding of the processes determining regional sea level rise. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The ability of climate models to simulate 20th century global mean sea level (GMSL) and regional sea-level change has been demonstrated. However, the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5) and Special Report on the Ocean and Cryosphere in a Changing Climate (SROCC) sea-level projections have not been rigorously evaluated with observed GMSL and coastal sea level from a global network of tide gauges as the short overlapping period (2007–2018) and natural variability make the detection of trends and accelerations challenging. Here, we critically evaluate these projections with satellite and tide-gauge observations. The observed trends from GMSL and the regional weighted mean at tide-gauge stations confirm the projections under three Representative Concentration Pathway (RCP) scenarios within 90% confidence level during 2007–2018. The central values of the observed GMSL (1993–2018) and regional weighted mean (1970–2018) accelerations are larger than projections for RCP2.6 and lie between (or even above) those for RCP4.5 and RCP8.5 over 2007–2032, but are not yet statistically different from any scenario. While the confirmation of the projection trends gives us confidence in current understanding of near future sea-level change, it leaves open questions concerning late 21 st century non-linear accelerations from ice-sheet contributions. Introduction As an essential indicator of global climate change and ocean variability, sea level has been simulated by models during both historical and future periods. Reliable sea-level projections are also vital for coastal communities. The IPCC AR5 1 and SROCC 2 provide global and regional sea-level projections, including estimates of contributions from oceans, glaciers, ice sheets, and land water from 2007 to 2100. The regional projections also include an allowance for relative sea level induced by glacial isostatic adjustment (GIA). Critically evaluating sea-level projections by comparing them with observations is important in enhancing our understanding of confidence in sea-level changes in the 21st century, identifying potential limitations in current projections, which helps to further calibrate and reduce uncertainties in the projections. Previous studies have demonstrated the improved ability of models in simulating 20th century sea-level changes at both global and regional scales 3 , 4 , 5 . After 1950 and particularly for the satellite era since 1993, the model simulations accounted for essentially all the observed GMSL rise, with GMSL rise since 1970 dominated by anthropogenic climate change 6 . However, critically evaluating the sea-level projections by comparison with recent observations is challenging on both global and regional scales because (i) there is considerable natural variability and the overlapping period is short (2007–2018), and (ii) regional tide-gauge records are highly influenced by local factors, such as the vertical land motion (VLM) 7 and sea-level extreme events (like storm surges). The natural variability in sea-level change (e.g. the El Niño—Southern Oscillation (ENSO) 8 ) and especially decadal (multidecadal) variations make the detection of trends and accelerations more difficult, even in long sea-level records 9 . Here, we show the trends of the IPCC AR5 and SROCC sea-level projections under three RCP scenarios from both GMSL and regional weighted mean at 177 tide-gauges stations agree well with satellite and tide-gauge observations over the common peiod 2007–2018 within 90% confidence level (90% CL), after considering the impacts of natural climate variability and correcting local residual VLM. Because of natural variability, we extend the period of observations and projections for a robust derivation of acceleration. We find the central values of observed GMSL (satellite altimeter over 1993–2018; sea-level reconstruction over 1970–2018) and regional weighted mean at tide-gauge stations (1970–2018) show larger accelerations than that from projections under RCP2.6 and lie between projected accelerations under RCP4.5 and RCP8.5, while not yet statistically different from any scenario. In the real word, the sea-level acceleration need to be reduced to be consistent with the lower and falling RCP2.6 mitigation emission scenario and the Paris targets in the late 21st century. Results Outline For GMSL, we utilise satellite altimeter observation time series over 1993–2018 from the Australian Commonwealth Scientific and Industrial Research Organization (CSIRO) and the U.S. National Aeronautics and Space Administration (NASA) Goddard Space Flight Centre (GSFC; Fig. 1a ). Both groups attempted to correct instrumental drifts during the earlier altimeter period, by either using tide-gauge records with VLM estimated based on GIA or Global Positioning System (GPS) for CSIRO 10 or turning off the on-board calibration mode for GSFC 11 . We also use the long-term GMSL reconstructions based on tide-gauge records from Church & White 2011 12 and Dangendorf 2019 13 (hereafter referred to as CW2011 and D2019, respectively) over 1970–2018. Other GMSL reconstructions are not included here, as their differences from the above two reconstructions are generally small after 1970 14 , e.g. GMSL from ref. 15 closely resemble D2019 (Supplementary Fig. 1 ). For regional sea-level observations, 177 tide gauges around the world (Fig. 2 ) since 1970 are used. Fig. 1: The global-mean sea level (GMSL) from observations compared with projections. a Monthly satellite altimeter observations (1993–2018) with instrumental drifts corrected are from the Australian Commonwealth Scientific and Industrial Research Organization (CSIRO) based on glacial isostatic adjustment (GIA-adjust; yellow) and Global Positioning System (GPS-adjust; orange), as well as from the National Aeronautics and Space Administration Goddard Space Flight Centre (NASA/GSFC; red). The GMSL reconstructions (1970–2018) from ref. 13 (D2019; light purple) and ref. 12 (CW2011; purple) are smoothed with a 5-month running-mean filter. The annual multimodel averaged GMSL projections from the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5; from light green to dark green) and Special Report on the Ocean and Cryosphere in a Changing Climate (SROCC; from light blue to dark dark blue) under three Representative Concentration Pathway (RCP) scenarios respectively (2007–2032). GMSL trends including both linear and quadratic terms are also shown offset by −50 mm. The blue shaded area indicates the overlapping period between observations and projections (2007–2018). Box plots of b GMSL trends [mm yr −1 ] over 2007–2018 and c GMSL acceleration [mm yr −2 ] over the whole period of each dataset. Error bars indicate 90% confidence level. Full size image Fig. 2:<|im_end|> <|im_start|>assistant Projections of rising sea levels this century are on the money when tested against satellite and tide-gauge observations, scientists find. Climate model projections of sea-level rises in the early 21st century are in good agreement with sea level data recorded in the corresponding period, a recent analysis has found. And the scientists who crunched the numbers say the finding does not bode well for sea level impacts over coming decades if greenhouse gas emissions are not reined in. In an article published recently in Nature Communications, the scientists from Chinese and Australian institutions including UNSW Sydney examined the global and regional sea level projections of two reports by the Intergovernmental Panel on Climate Change: the Fifth Assessment Report (AR5) and Special Report on the Ocean and Cryosphere in a Changing Climate (SROCC). They compared the reports' projections with the observed global and coastal sea level data gathered from satellites and a network of 177 tide-gauges from the start of the projections in 2007 up to to 2018. The scientists found that the trends of the AR5 and SROCC sea level projections under three different scenarios of greenhouse gas emissions "agree well with satellite and tide-gauge observations over the common period 2007–2018, within the 90 percent confidence level." Study co-author and leading sea-level expert, Professor John Church, says while he thought the projections from modelling would be accurate at the global level, he was pleasantly surprised that they were as accurate at the regional and local level. "Our analysis implies that the models are close to observations and builds confidence in the current projections for the next several decades," says Prof. Church, who is part of UNSW's Climate Change Research Centre. But he adds a caveat that because the available comparison period is short, at just 11 years, he would be hesitant to extend the same degree of confidence over the longer term—from the end of this century and beyond—where acceleration of ice-sheet contribution to sea-level rise is less understood and could lead to larger rises. "There remains a potential for larger sea level rises, particularly beyond 2100 for high emission scenarios. Therefore, it is urgent that we still try to meet the commitments of the Paris Agreement by significantly reducing emissions," Prof. Church says. Study co-author Dr. Xuebin Zhang, from CSIRO's Oceans and Atmosphere Division says this is the first study to compare projections of sea level rises at both a global and regional level with observations over their overlapping periods—no mean feat given the natural variability of climate and vertical land movement from region to region. "We carefully removed the impacts from natural climate variability, for example El Niño– Southern Oscillation, and corrected vertical land movement, which led to much improved agreement." The analysis looked at the three different emissions scenarios in the IPCC's reports that corresponded to three different climate futures depending on what greenhouse gas mitigation strategies were adopted—known as Representative Concentration Pathway (RCP) scenarios. The lowest scenario (RCP2.6) examined is for strong mitigation of greenhouse gas emissions, about in line with 2oC of global warming by 2100 but still larger than what is required to meet the Paris Agreement of well below 2oC. The middle scenario (RCP4.5) requires stabilization of radiative forcing in the latter half of this century and results in warming well above the Paris Target. And the highest scenario (RCP8.5) is for large greenhouse gas emissions resulting in ongoing rapid warming and implies a commitment to large sea level rises. "The analysis of the recent sea level data indicate the world is tracking between RCP4.5 and the worst case scenario of RCP8.5," Professor Church says. "If we continue with large ongoing emissions as we are at present, we will commit the world to meters of sea level rise over coming centuries." Next the group will attempt to gain a greater understanding of the processes determining regional sea level rise. <|im_end|>

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2,358

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background High levels of standing genomic variation in wide-ranging marine species may enhance prospects for their long-term persistence. Patterns of connectivity and adaptation in such species are often thought to be influenced by spatial factors, environmental heterogeneity, and oceanographic and geomorphological features. Population-level studies that analytically integrate genome-wide data with environmental information (i.e., seascape genomics) have the potential to inform the spatial distribution of adaptive diversity in wide-ranging marine species, such as many marine mammals. We assessed genotype-environment associations (GEAs) in 214 common dolphins ( Delphinus delphis ) along > 3000 km of the southern coast of Australia. Results We identified 747 candidate adaptive SNPs out of a filtered panel of 17,327 SNPs, and five putatively locally-adapted populations with high levels of standing genomic variation were disclosed along environmentally heterogeneous coasts. Current velocity, sea surface temperature, salinity, and primary productivity were the key environmental variables associated with genomic variation. These environmental variables are in turn related to three main oceanographic phenomena that are likely affecting the dispersal of common dolphins: (1) regional oceanographic circulation, (2) localised and seasonal upwellings, and (3) seasonal on-shelf circulation in protected coastal habitats. Signals of selection at exonic gene regions suggest that adaptive divergence is related to important metabolic traits. Conclusion To the best of our knowledge, this represents the first seascape genomics study for common dolphins (genus Delphinus ). Information from the associations between populations and their environment can assist population management in forecasting the adaptive capacity of common dolphins to climate change and other anthropogenic impacts. Peer Review reports Background Microevolutionary processes influenced by environmental heterogeneity can create adaptive divergence among populations [ 1 , 2 , 3 ]. Marine ecosystems are environmentally heterogeneous, with coastal and pelagic species impacted by contrasting selective pressures that can lead to local adaptation (e.g., [ 3 , 4 , 5 ]). Local adaptation occurs when an individual or group of individuals display higher fitness in a distinct spatial and temporal environment due to specific genetic variants [ 6 , 7 , 8 ]. Natural selection acts on both new mutations and standing genetic variation, with most adaptations involving multiple loci and genomic regions [ 9 , 10 ]. In marine environments, understanding the influence of geomorphological and oceanographic features, as well as anthropogenic pressures on genomic variation, enhances our ability to refine knowledge about population structure and rapid evolution [ 11 , 12 ], including for widespread species with high dispersal potential. Genomic data has improved our understanding of macro- and microevolutionary processes, providing greater power and accuracy to detect large scale molecular adaptations, as well as population structure, gene flow and adaptive divergence between populations [ 13 , 14 , 15 ]. In toothed whales (Odontoceti), most studies of adaptations using genomic markers have focused on a macroevolutionary perspective, while studies investigating ecological specialisation on a microevolutionary level have been documented only for a few species. This includes ecotype adaptations of killer whales ( Orcinus orca [ 16 ]), spinner dolphins ( Stenella longirostris [ 17 ]), finless porpoises ( Neophocaena phocaenoides [ 18 , 19 ]), and bottlenose dolphins ( Tursiops aduncus [ 20 ], and T. truncatus [ 21 ]). Despite these examples, population-level studies of microevolutionary processes remain highly under documented in Odontocetes, specifically in small cetaceans. In particular, little is known about the adaptive resilience of small cetaceans to local or regional environmental changes and to future climatic scenarios. The lack of such studies constrains our capacity to provide information for conservation and management, as well as clarifying important aspects of a species’ biology. The common dolphin ( Delphinus delphis ) is a widespread small cetacean that inhabits temperate, subtropical and some tropical waters around the world [ 22 , 23 , 24 ]. Their broad distribution suggests that several habitats are suitable for this species (e.g., [ 25 , 26 ]). In Australia, common dolphins range from embayments and gulf waters to coastal, shelf and pelagic waters [ 26 , 27 , 28 ]. From a neutral genomic perspective, the species in Australasia displays a hierarchical metapopulation structure and fine-scale population sub-structuring [ 29 ]. Although common dolphins exhibit high potential for dispersal, prey distribution has been suggested as a main driver for their movements [ 27 , 30 , 31 ]. In Australasian waters, they mainly hunt and feed upon schooling fish such as jack mackerel ( Trachurus declivis, T. s. murphyi and T. novaezelandiae ), blue mackerel ( Scomber australasicus ), sardines ( Sardina sagax ) and anchovies ( Engraulis australis ) [ 32 , 33 ]. The ranges of common dolphin populations seem to be influenced by the distribution and abundance of their prey, and often coincide with oceanographic circulation, areas of high primary productivity, and regions of high salinity and low sea surface temperature interfaces [ 27 , 31 , 34 ]. This suggests that oceanographic features and oceanic circulation patterns could be shaping dispersal of common dolphins, as described for other Australian marine taxa (e.g., [ 35 , 36 , 37 ]). However, associations between environmental variables and genetic populations of common dolphin have only been described at broad geographical scales between different oceans [ 34 ], and the impact of regional oceanographic features is yet to be revealed. Common dolphins in southern Australia are subject to various anthropogenic stressors, such as interactions and mortalities in fisheries (e.g., [ 28 , 38 , 39 ]), and climatic change (e.g., [ 40 , 41 ]), both of which can lead to negative health outcomes and potential declines of populations (e.g., [ 42 , 43 ]). The widespread distribution of common dolphins in southern Australia, where marine environmental gradients and discontinuities are observed, provides an excellent opportunity to investigate microevolutionary processes and adaptive divergence in a highly-mobile marine species. The temperate waters of southern Australia harbour productive habitats for common dolphins (e.g., [ 31 , 38 , 44 ]). Australia’s southern zonal coastal boundary stretches for > 3000 km, with high species endemism [ 45 ].", "role": "user" }, { "content": "The first widespread census of the genetic diversity of common dolphin (Delphinus delphis) populations living along 3000km of Australia's southern coastline has raised key pointers for future conservation efforts. The comprehensive Flinders University study calls for more conservation and policy efforts to preserve adaptive DNA diversity and assist connectivity between these dolphin groups. This will support long-term gene flow and adaptation during ongoing habitat changes—including oceanic conditions affected by climate change and human enterprises. Flinders University researcher Dr. Andrea Barceló—first author in the study just published in BMC Ecology and Evolution—says high levels of genomic variation can play an important part in the long-term survival of these wide-ranging marine mammals and other species. \"Information about how the environment affects DNA diversity of marine populations can assist with the population management and in forecasting how they may cope with climate change and other anthropogenic impacts,\" says Dr. Barceló. Five populations of common dolphin (Delphinus delphis) were studied by Flinders University marine biologists. Credit: CEBEL, Flinders University As well, Flinders and Macquarie University researchers say maintaining connectivity can promote long-term genomic variation, which in turn will enhance population viability under anthropogenic impacts, including unfavorable climatic events. \"While so many breeding and feeding conditions are still unknown, it's important for managers of our coastal environments to consider the importance of DNA diversity, particularly in the event of changes in key environmental conditions such as water temperatures, salinity, and food sources,\" adds co-author marine biologist Associate Professor Luciana Möller, from at Flinders University's College of Science and Engineering. The adaptive divergence from more than 200 dolphins showed five dolphin populations from Western Australia to Victoria and compared this with the key environmental conditions and available fish food supplies fuelled by oceanic upwellings and local seasonal circulations. Genomic variation in dolphins of the southern coast of Western Australia was associated to local currents, while genomic differentiation of common dolphins from sites along the continental shelf break was impacted by fluctuations of primary productivity and sea surface temperatures. I contrast, genomic differentiation of common dolphins from protected coastal habitats and more enclosed embayment areas was associated mainly with fluctuations in salinity and local environment temperatures. Such seascape genomic assessment identified candidate genes for future comparative studies of common dolphins and potentially other delphinid species that share similar dynamic environments around the world. The article—\"Seascape genomics of common dolphins (Delphinus delphis) reveals adaptive diversity linked to regional and local oceanography\" (2022) by Andrea Barceló, Jonathan Sandoval‑Castillo, Chris Brauer, Kerstin Bilgmann, Guido J Parra, Luciano B Beheregary and Luciana M Möller—has been published in the journal BMC Ecology and Evolution . ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background High levels of standing genomic variation in wide-ranging marine species may enhance prospects for their long-term persistence. Patterns of connectivity and adaptation in such species are often thought to be influenced by spatial factors, environmental heterogeneity, and oceanographic and geomorphological features. Population-level studies that analytically integrate genome-wide data with environmental information (i.e., seascape genomics) have the potential to inform the spatial distribution of adaptive diversity in wide-ranging marine species, such as many marine mammals. We assessed genotype-environment associations (GEAs) in 214 common dolphins ( Delphinus delphis ) along > 3000 km of the southern coast of Australia. Results We identified 747 candidate adaptive SNPs out of a filtered panel of 17,327 SNPs, and five putatively locally-adapted populations with high levels of standing genomic variation were disclosed along environmentally heterogeneous coasts. Current velocity, sea surface temperature, salinity, and primary productivity were the key environmental variables associated with genomic variation. These environmental variables are in turn related to three main oceanographic phenomena that are likely affecting the dispersal of common dolphins: (1) regional oceanographic circulation, (2) localised and seasonal upwellings, and (3) seasonal on-shelf circulation in protected coastal habitats. Signals of selection at exonic gene regions suggest that adaptive divergence is related to important metabolic traits. Conclusion To the best of our knowledge, this represents the first seascape genomics study for common dolphins (genus Delphinus ). Information from the associations between populations and their environment can assist population management in forecasting the adaptive capacity of common dolphins to climate change and other anthropogenic impacts. Peer Review reports Background Microevolutionary processes influenced by environmental heterogeneity can create adaptive divergence among populations [ 1 , 2 , 3 ]. Marine ecosystems are environmentally heterogeneous, with coastal and pelagic species impacted by contrasting selective pressures that can lead to local adaptation (e.g., [ 3 , 4 , 5 ]). Local adaptation occurs when an individual or group of individuals display higher fitness in a distinct spatial and temporal environment due to specific genetic variants [ 6 , 7 , 8 ]. Natural selection acts on both new mutations and standing genetic variation, with most adaptations involving multiple loci and genomic regions [ 9 , 10 ]. In marine environments, understanding the influence of geomorphological and oceanographic features, as well as anthropogenic pressures on genomic variation, enhances our ability to refine knowledge about population structure and rapid evolution [ 11 , 12 ], including for widespread species with high dispersal potential. Genomic data has improved our understanding of macro- and microevolutionary processes, providing greater power and accuracy to detect large scale molecular adaptations, as well as population structure, gene flow and adaptive divergence between populations [ 13 , 14 , 15 ]. In toothed whales (Odontoceti), most studies of adaptations using genomic markers have focused on a macroevolutionary perspective, while studies investigating ecological specialisation on a microevolutionary level have been documented only for a few species. This includes ecotype adaptations of killer whales ( Orcinus orca [ 16 ]), spinner dolphins ( Stenella longirostris [ 17 ]), finless porpoises ( Neophocaena phocaenoides [ 18 , 19 ]), and bottlenose dolphins ( Tursiops aduncus [ 20 ], and T. truncatus [ 21 ]). Despite these examples, population-level studies of microevolutionary processes remain highly under documented in Odontocetes, specifically in small cetaceans. In particular, little is known about the adaptive resilience of small cetaceans to local or regional environmental changes and to future climatic scenarios. The lack of such studies constrains our capacity to provide information for conservation and management, as well as clarifying important aspects of a species’ biology. The common dolphin ( Delphinus delphis ) is a widespread small cetacean that inhabits temperate, subtropical and some tropical waters around the world [ 22 , 23 , 24 ]. Their broad distribution suggests that several habitats are suitable for this species (e.g., [ 25 , 26 ]). In Australia, common dolphins range from embayments and gulf waters to coastal, shelf and pelagic waters [ 26 , 27 , 28 ]. From a neutral genomic perspective, the species in Australasia displays a hierarchical metapopulation structure and fine-scale population sub-structuring [ 29 ]. Although common dolphins exhibit high potential for dispersal, prey distribution has been suggested as a main driver for their movements [ 27 , 30 , 31 ]. In Australasian waters, they mainly hunt and feed upon schooling fish such as jack mackerel ( Trachurus declivis, T. s. murphyi and T. novaezelandiae ), blue mackerel ( Scomber australasicus ), sardines ( Sardina sagax ) and anchovies ( Engraulis australis ) [ 32 , 33 ]. The ranges of common dolphin populations seem to be influenced by the distribution and abundance of their prey, and often coincide with oceanographic circulation, areas of high primary productivity, and regions of high salinity and low sea surface temperature interfaces [ 27 , 31 , 34 ]. This suggests that oceanographic features and oceanic circulation patterns could be shaping dispersal of common dolphins, as described for other Australian marine taxa (e.g., [ 35 , 36 , 37 ]). However, associations between environmental variables and genetic populations of common dolphin have only been described at broad geographical scales between different oceans [ 34 ], and the impact of regional oceanographic features is yet to be revealed. Common dolphins in southern Australia are subject to various anthropogenic stressors, such as interactions and mortalities in fisheries (e.g., [ 28 , 38 , 39 ]), and climatic change (e.g., [ 40 , 41 ]), both of which can lead to negative health outcomes and potential declines of populations (e.g., [ 42 , 43 ]). The widespread distribution of common dolphins in southern Australia, where marine environmental gradients and discontinuities are observed, provides an excellent opportunity to investigate microevolutionary processes and adaptive divergence in a highly-mobile marine species. The temperate waters of southern Australia harbour productive habitats for common dolphins (e.g., [ 31 , 38 , 44 ]). Australia’s southern zonal coastal boundary stretches for > 3000 km, with high species endemism [ 45 ].<|im_end|> <|im_start|>assistant The first widespread census of the genetic diversity of common dolphin (Delphinus delphis) populations living along 3000km of Australia's southern coastline has raised key pointers for future conservation efforts. The comprehensive Flinders University study calls for more conservation and policy efforts to preserve adaptive DNA diversity and assist connectivity between these dolphin groups. This will support long-term gene flow and adaptation during ongoing habitat changes—including oceanic conditions affected by climate change and human enterprises. Flinders University researcher Dr. Andrea Barceló—first author in the study just published in BMC Ecology and Evolution—says high levels of genomic variation can play an important part in the long-term survival of these wide-ranging marine mammals and other species. "Information about how the environment affects DNA diversity of marine populations can assist with the population management and in forecasting how they may cope with climate change and other anthropogenic impacts," says Dr. Barceló. Five populations of common dolphin (Delphinus delphis) were studied by Flinders University marine biologists. Credit: CEBEL, Flinders University As well, Flinders and Macquarie University researchers say maintaining connectivity can promote long-term genomic variation, which in turn will enhance population viability under anthropogenic impacts, including unfavorable climatic events. "While so many breeding and feeding conditions are still unknown, it's important for managers of our coastal environments to consider the importance of DNA diversity, particularly in the event of changes in key environmental conditions such as water temperatures, salinity, and food sources," adds co-author marine biologist Associate Professor Luciana Möller, from at Flinders University's College of Science and Engineering. The adaptive divergence from more than 200 dolphins showed five dolphin populations from Western Australia to Victoria and compared this with the key environmental conditions and available fish food supplies fuelled by oceanic upwellings and local seasonal circulations. Genomic variation in dolphins of the southern coast of Western Australia was associated to local currents, while genomic differentiation of common dolphins from sites along the continental shelf break was impacted by fluctuations of primary productivity and sea surface temperatures. I contrast, genomic differentiation of common dolphins from protected coastal habitats and more enclosed embayment areas was associated mainly with fluctuations in salinity and local environment temperatures. Such seascape genomic assessment identified candidate genes for future comparative studies of common dolphins and potentially other delphinid species that share similar dynamic environments around the world. The article—"Seascape genomics of common dolphins (Delphinus delphis) reveals adaptive diversity linked to regional and local oceanography" (2022) by Andrea Barceló, Jonathan Sandoval‑Castillo, Chris Brauer, Kerstin Bilgmann, Guido J Parra, Luciano B Beheregary and Luciana M Möller—has been published in the journal BMC Ecology and Evolution . <|im_end|>

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220, 1313, 1174, 220, 1419, 1174, 220, 1187, 21087, 11205, 7353, 8141, 13533, 430, 3892, 71699, 527, 14791, 369, 420, 9606, 320, 68, 1326, 2637, 510, 220, 914, 1174, 220, 1627, 97811, 763, 8494, 11, 4279, 83506, 2134, 505, 8126, 352, 1392, 323, 342, 14643, 21160, 311, 35335, 11, 28745, 323, 12077, 13070, 21160, 510, 220, 1627, 1174, 220, 1544, 1174, 220, 1591, 21087, 5659, 264, 21277, 81064, 13356, 11, 279, 9606, 304, 6126, 36259, 19207, 264, 70994, 2322, 391, 454, 2987, 6070, 323, 7060, 13230, 7187, 1207, 12, 63272, 510, 220, 1682, 21087, 10541, 4279, 83506, 31324, 1579, 4754, 369, 79835, 278, 11, 37693, 8141, 706, 1027, 12090, 439, 264, 1925, 5696, 369, 872, 19567, 510, 220, 1544, 1174, 220, 966, 1174, 220, 2148, 21087, 763, 6126, 300, 1122, 21160, 11, 814, 14918, 19614, 323, 5510, 5304, 68721, 7795, 1778, 439, 26128, 296, 9881, 301, 320, 1183, 613, 56266, 4051, 344, 285, 11, 350, 13, 274, 13, 8309, 12989, 72, 323, 350, 13, 6747, 6043, 89, 18615, 73078, 7026, 6437, 296, 9881, 301, 320, 328, 884, 655, 264, 5523, 6099, 355, 7026, 274, 569, 1572, 320, 328, 569, 2259, 30811, 710, 883, 323, 34330, 12831, 320, 2998, 911, 5049, 285, 264, 5523, 285, 883, 510, 220, 843, 1174, 220, 1644, 21087, 578, 21986, 315, 4279, 99269, 22673, 2873, 311, 387, 28160, 555, 279, 8141, 323, 37492, 315, 872, 37693, 11, 323, 3629, 72359, 449, 18435, 12968, 35855, 11, 5789, 315, 1579, 6156, 26206, 11, 323, 13918, 315, 1579, 4371, 13797, 323, 3428, 9581, 7479, 9499, 25066, 510, 220, 1544, 1174, 220, 2148, 1174, 220, 1958, 21087, 1115, 13533, 430, 18435, 12968, 4519, 323, 18435, 292, 35855, 12912, 1436, 387, 46620, 79835, 278, 315, 4279, 83506, 11, 439, 7633, 369, 1023, 13673, 29691, 77314, 320, 68, 1326, 2637, 510, 220, 1758, 1174, 220, 1927, 1174, 220, 1806, 97811, 4452, 11, 30257, 1990, 12434, 7482, 323, 19465, 22673, 315, 4279, 99269, 617, 1193, 1027, 7633, 520, 7353, 54001, 29505, 1990, 2204, 54280, 510, 220, 1958, 10881, 323, 279, 5536, 315, 15481, 18435, 12968, 4519, 374, 3686, 311, 387, 10675, 13, 7874, 83506, 304, 18561, 8494, 527, 3917, 311, 5370, 41416, 29569, 8631, 1105, 11, 1778, 439, 22639, 323, 49972, 1385, 304, 82596, 320, 68, 1326, 2637, 510, 220, 1591, 1174, 220, 1987, 1174, 220, 2137, 2331, 705, 323, 11323, 780, 2349, 320, 68, 1326, 2637, 510, 220, 1272, 1174, 220, 3174, 2331, 705, 2225, 315, 902, 649, 3063, 311, 8389, 2890, 20124, 323, 4754, 58054, 315, 22673, 320, 68, 1326, 2637, 510, 220, 2983, 1174, 220, 3391, 97811, 578, 24716, 8141, 315, 4279, 83506, 304, 18561, 8494, 11, 1405, 29691, 12434, 53249, 323, 45980, 84, 1385, 527, 13468, 11, 5825, 459, 9250, 6776, 311, 19874, 8162, 5230, 3294, 661, 11618, 323, 48232, 82258, 304, 264, 7701, 42179, 29691, 9606, 13, 578, 6940, 349, 21160, 315, 18561, 8494, 75742, 27331, 71699, 369, 4279, 83506, 320, 68, 1326, 2637, 510, 220, 2148, 1174, 220, 1987, 1174, 220, 2096, 97811, 8494, 753, 18561, 1167, 25180, 35335, 19254, 50699, 369, 871, 220, 3101, 15, 13437, 11, 449, 1579, 9606, 842, 336, 2191, 510, 220, 1774, 21087, 128257, 198, 128256, 78191, 198, 791, 1176, 24716, 44702, 315, 279, 19465, 20057, 315, 4279, 99269, 320, 16939, 55853, 355, 1624, 37889, 8, 22673, 5496, 3235, 220, 3101, 15, 16400, 315, 8494, 596, 18561, 80944, 706, 9408, 1401, 28554, 369, 3938, 29711, 9045, 13, 578, 16195, 3061, 32551, 3907, 4007, 6880, 369, 810, 29711, 323, 4947, 9045, 311, 21813, 48232, 15922, 20057, 323, 7945, 31357, 1990, 1521, 99269, 5315, 13, 1115, 690, 1862, 1317, 9860, 15207, 6530, 323, 34185, 2391, 14529, 39646, 4442, 76070, 18435, 292, 4787, 11754, 555, 10182, 2349, 323, 3823, 40919, 13, 3061, 32551, 3907, 32185, 2999, 13, 41184, 4821, 3757, 1832, 2345, 3983, 3229, 304, 279, 4007, 1120, 4756, 304, 82806, 78375, 323, 38321, 2345, 98036, 1579, 5990, 315, 81064, 23851, 649, 1514, 459, 3062, 961, 304, 279, 1317, 9860, 20237, 315, 1521, 7029, 82105, 29691, 56669, 323, 1023, 9606, 13, 330, 15218, 922, 1268, 279, 4676, 22223, 15922, 20057, 315, 29691, 22673, 649, 7945, 449, 279, 7187, 6373, 323, 304, 79482, 1268, 814, 1253, 37586, 449, 10182, 2349, 323, 1023, 41416, 29569, 25949, 1359, 2795, 2999, 13, 4821, 3757, 1832, 13, 21594, 22673, 315, 4279, 99269, 320, 16939, 55853, 355, 1624, 37889, 8, 1051, 20041, 555, 3061, 32551, 3907, 29691, 6160, 22012, 13, 16666, 25, 356, 8428, 2818, 11, 3061, 32551, 3907, 1666, 1664, 11, 3061, 32551, 323, 7553, 447, 67545, 3907, 12074, 2019, 20958, 31357, 649, 12192, 1317, 9860, 81064, 23851, 11, 902, 304, 2543, 690, 18885, 7187, 68507, 1234, 41416, 29569, 25949, 11, 2737, 93071, 11323, 780, 4455, 13, 330, 8142, 779, 1690, 40308, 323, 26040, 4787, 527, 2103, 9987, 11, 433, 596, 3062, 369, 20258, 315, 1057, 35335, 22484, 311, 2980, 279, 12939, 315, 15922, 20057, 11, 8104, 304, 279, 1567, 315, 4442, 304, 1401, 12434, 4787, 1778, 439, 3090, 20472, 11, 4371, 13797, 11, 323, 3691, 8336, 1359, 11621, 1080, 43802, 29691, 88704, 33468, 17054, 14103, 12699, 49782, 56056, 11, 505, 520, 3061, 32551, 3907, 596, 9304, 315, 10170, 323, 17005, 13, 578, 48232, 82258, 505, 810, 1109, 220, 1049, 83506, 8710, 4330, 99269, 22673, 505, 11104, 8494, 311, 23225, 323, 7863, 420, 449, 279, 1401, 12434, 4787, 323, 2561, 7795, 3691, 17135, 10633, 839, 555, 18435, 292, 709, 9336, 826, 323, 2254, 36899, 4319, 7607, 13, 9500, 3151, 23851, 304, 83506, 315, 279, 18561, 13962, 315, 11104, 8494, 574, 5938, 311, 2254, 60701, 11, 1418, 81064, 60038, 315, 4279, 83506, 505, 6732, 3235, 279, 58636, 28745, 1464, 574, 40028, 555, 65649, 315, 6156, 26206, 323, 9581, 7479, 20472, 13, 358, 13168, 11, 81064, 60038, 315, 4279, 83506, 505, 2682, 35335, 71699, 323, 810, 44910, 8126, 6202, 5789, 574, 5938, 14918, 449, 65649, 304, 4371, 13797, 323, 2254, 4676, 20472, 13, 15483, 52840, 5443, 81064, 15813, 11054, 9322, 21389, 369, 3938, 55394, 7978, 315, 4279, 83506, 323, 13893, 1023, 1624, 55853, 307, 9606, 430, 4430, 4528, 8915, 22484, 2212, 279, 1917, 13, 578, 4652, 93830, 1542, 300, 5443, 4173, 24203, 315, 4279, 83506, 320, 16939, 55853, 355, 1624, 37889, 8, 21667, 48232, 20057, 10815, 311, 15481, 323, 2254, 18435, 5814, 1, 320, 2366, 17, 8, 555, 41184, 4821, 3757, 1832, 11, 24150, 328, 4988, 838, 57064, 19235, 22532, 11, 11517, 26531, 8977, 11, 36258, 48561, 118682, 18022, 11, 12433, 78, 622, 4366, 969, 11, 14103, 13389, 426, 14954, 486, 34588, 323, 14103, 12699, 386, 49782, 56056, 2345, 4752, 1027, 4756, 304, 279, 8486, 82806, 78375, 323, 38321, 662, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cas9-mediated gene editing is a powerful tool for addressing research questions in arthropods. Current approaches rely upon delivering Cas9 ribonucleoprotein (RNP) complex by embryonic microinjection, which is challenging, is limited to a small number of species, and is inefficient even in optimized taxa. Here we develop a technology termed Receptor-Mediated Ovary Transduction of Cargo (ReMOT Control) to deliver Cas9 RNP to the arthropod germline by injection into adult female mosquitoes. We identify a peptide (P2C) that mediates transduction of Cas9 RNP from the female hemolymph to the developing mosquito oocytes, resulting in heritable gene editing of the offspring with efficiency as high as 0.3 mutants per injected mosquito. We demonstrate that P2C functions in six mosquito species. Identification of taxa-specific ovary-specific ligand–receptor pairs may further extend the use of ReMOT Control for gene editing in novel species. Introduction Since the first application of the Clustered Regularly Interspaced Short Palindromic Repeats and its associated endonuclease 9 (CRISPR-Cas9 system) for site-specific genome editing, the technology has been used in a variety of arthropod species 1 , 2 . Successful application of CRISPR-Cas9 to edit the germline of arthropods relies on injection of gene-editing materials into pre-blastoderm embryos (embryonic microinjection) 3 , 4 , 5 , 6 . This dependence is a significant barrier to the successful general application of transformation technologies, particularly for non-specialist laboratories, as it requires expensive equipment and training to implement 4 . In addition, many non-model species are recalcitrant to the technique because their eggs are damaged during the injection procedure, because they cannot be induced to lay large amounts of synchronous eggs, or because they give live birth rather than lay eggs (as in the case of viviparous species such as tsetse flies and aphids). These restrictions dramatically limit the use of CRISPR-Cas9 technology across diverse systems. Most female oviparous animals deliver protein material to their developing ovaries through a conserved process of ovary and egg maturation called vitellogenesis. In insects and other arthropods, yolk protein precursors (YPPs) are synthesized in the fat body, secreted into the hemolymph, and are taken up into the ovaries by receptor-mediated endocytosis (RME) 7 , 8 , 9 . During vitellogenesis, multiple receptors in the oocyte membrane are available and bind YPP ligands that are internalized, accumulated in endosomal vesicles, and sorted into yolk granules for nutrient storage for the developing embryo 10 , 11 , 12 . The use of specific ligands to deliver material into mammalian cells by receptor-mediated endocytosis has been explored for drug delivery since the 1980s 13 , 14 , 15 . For example, when the protein transferrin was used as a ligand and chemically conjugated to molecular cargo such as toxins 16 , liposomes 17 , 18 proteins 13 , or DNA 19 , these molecules were internalized into the cell via the transferrin receptor and released into the cell cytoplasm in vitro and in vivo 20 , 21 , 22 . Delivery efficacy depends on successful release of cargo from the endosomes and lysosomes 13 , 17 , 18 , 19 , 20 , 23 , 24 , often by chemical membrane destabilizers such as ammonium chloride, amines, chloroquine, or monensin 13 , 15 , 25 , 26 . We hypothesized that a ligand derived from arthropod YPPs could be fused or bound to molecular cargo such as the Cas9 ribonucleoprotein (RNP) complex (Cas9 complexed with a single-guide RNA (sgRNA)) and, when injected in the hemolymph of vitellogenic females, be delivered into the oocyte at levels necessary to achieve genome editing in the embryo, bypassing the requirement for embryonic microinjection. We term this strategy Receptor-Mediated Ovary Transduction of Cargo (ReMOT Control) (Supplementary Fig. 1 ). Mosquitoes are excellent models for development and testing of this technology because synchronous egg development can be induced by blood feeding, and significant literature exists on vitellogenesis and receptor-mediated internalization of mosquito yolk proteins 7 , 27 , 28 , 29 , 30 . Here we report the successful delivery of Cas9 RNP to mosquito ovaries and subsequent targeted gene editing of the disease vector mosquito Aedes aegypti at efficiencies comparable to traditional embryo microinjection. Results Delivery of protein cargo into mosquito oocytes using P2C Drosophila melanogaster Yolk proteins (DmYP) 1, 2, and 3 are small (50 kD) YPPs that are recognized by receptors belonging to the protein superfamily of low-density lipoprotein receptors. This family includes vitellogenin receptors, lipophorin receptors, and yolk protein receptors that are present in oocytes of diverse oviparous animal species and that can recognize related YPP ligands 31 . A previous study 32 used immunohistochemistry to demonstrate that the 439 amino acid (aa) D. melanogaster Yolk Protein 1 (DmYP1) was internalized by the oocytes of the mosquito Anopheles gambiae when recombinant DmYP1 was injected in the hemolymph of vitellogenic females. To test whether DmYP1 (or derivatives thereof) might act as suitable ligands to deliver protein cargo into mosquito oocytes, a DmYP1 fusion protein containing the enhanced green fluorescent protein (EGFP) was expressed using D. melanogaster S2 cells transfected with the plasmid pAc5-DmYPss-DmYP1-EGFP (see Methods). The protein was injected into the thorax of A. gambiae females 12 and 24 h post-blood feeding (PBF) (Supplementary Fig. 2 ). Recombinant EGFP lacking a targeting ligand was injected as a negative control. Ovaries dissected at 24, 36, 48, 60, and 72 h PBF were examined for visible EGFP fluorescence. EGFP was visualized in >98% of primary oocytes regardless of the timing of the injection (Supplementary Table 1 ) and at all stages of oocyte development including in fully developed eggs ready to be oviposited (Supplementary Fig. 3 ). For easier downstream construct design and expression, we used deletion analysis to identify a smaller region of DmYP1 sufficient for uptake into mosquito ovaries (Fig. 1a ). Fragments containing the 120 aa N-terminal portion of the protein (“P2”) could be taken up into ovaries (Fig. 1b ). Further deletion analysis of the P2 fragment identified that a 41 aa fragment, termed P2C (NLQQQRQHGKNGNQDYQDQSNEQRKNQRTSSEEDYSEEVKN), was fully sufficient to deliver EGFP to", "role": "user" }, { "content": "A technology designed to improve CRISPR-Cas9 gene editing in mosquitoes and other arthropods succeeds with a high degree of efficiency, while eliminating the need for difficult microinjection of genetic material, according to researchers. These results could pave the way for scientists examining a wide range of arthropods—and even some vertebrates—to more easily manipulate gene expression for fundamental research and practical applications such as control of vector-borne diseases like Zika virus and malaria, elimination of agricultural insect pests, and potentially gene therapy for human and animal health. CRISPR—Clustered Regularly Interspaced Short Palindromic Repeats—is a relatively new and revolutionary way to modify an organism's genome by precisely delivering a DNA-cutting enzyme, Cas9, to a targeted region of DNA. The resulting mutation can delete or replace specific DNA pieces, thereby promoting or disabling certain traits. Current approaches in arthropods rely on delivering the gene-editing Cas9 directly to eggs by embryonic microinjection, a difficult and inefficient process that works in only a small number of species, noted Jason Rasgon, professor of entomology and disease epidemiology, Penn State College of Agricultural Sciences. \"In addition, microinjection can damage the eggs, and it requires expensive equipment and training to implement,\" he said. \"These restrictions dramatically limit the use of CRISPR-Cas9 technology across diverse species.\" To address these limitations, Rasgon's lab developed ReMOT Control—Receptor-Mediated Ovary Transduction of Cargo—a method the researchers say can deliver Cas9 cargo to a targeted portion of the genome by easy injection into the blood of female arthropods, where it can be introduced into the developing eggs via receptors in the ovary. Rasgon explained that during ovary and egg maturation, mosquitoes and other arthropods synthesize yolk proteins, which are secreted into the blood and taken up into the ovaries. The team hypothesized that molecules derived from these yolk proteins could be fused to Cas9 cargo and delivered into the egg at levels necessary to achieve genome editing in the embryo, bypassing the need for embryonic microinjection. In the process of testing this hypothesis in Aedes aegypti, a mosquito that can spread pathogens such as dengue, chikungunya, Zika, and yellow fever viruses, the team identified a peptide known as P2C, a ligand that is recognized by ovarian receptors and functions in five other mosquito species as well. To visually show that P2C could achieve uptake in the ovary, the researchers injected the peptide, infused with green fluorescent protein, into mosquitoes. They subsequently found fluorescence in more than 98 percent of primary oocytes. For gene-editing experiments, the scientists targeted a gene that, when knocked out, results in white eye color rather than dark, providing a visible phenotype to aid in screening. They found that P2C, when bonded with the Cas9 enzyme, was able to deliver the gene-editing cargo to the ovary, where the desired mutation was achieved at a high rate of efficiency, resulting in genetically modified offspring. The results of the study, published recently in Nature Communications, show that compared to embryo injection, gene editing by ReMOT Control is efficient and technically much easier to accomplish, according to Rasgon. \"Whereas the microinjection apparatus can cost thousands of dollars and require extensive training to use, the equipment for ReMOT Control injections costs approximately $2, and the technique can be learned in less than an hour,\" he said. \"The lower cost and ease of adult injections makes this method a substantial improvement over existing embryo-injection techniques, putting gene-editing capability into the reach of nonspecialist laboratories and potentially revolutionizing the broad application of functional arthropod genetics.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cas9-mediated gene editing is a powerful tool for addressing research questions in arthropods. Current approaches rely upon delivering Cas9 ribonucleoprotein (RNP) complex by embryonic microinjection, which is challenging, is limited to a small number of species, and is inefficient even in optimized taxa. Here we develop a technology termed Receptor-Mediated Ovary Transduction of Cargo (ReMOT Control) to deliver Cas9 RNP to the arthropod germline by injection into adult female mosquitoes. We identify a peptide (P2C) that mediates transduction of Cas9 RNP from the female hemolymph to the developing mosquito oocytes, resulting in heritable gene editing of the offspring with efficiency as high as 0.3 mutants per injected mosquito. We demonstrate that P2C functions in six mosquito species. Identification of taxa-specific ovary-specific ligand–receptor pairs may further extend the use of ReMOT Control for gene editing in novel species. Introduction Since the first application of the Clustered Regularly Interspaced Short Palindromic Repeats and its associated endonuclease 9 (CRISPR-Cas9 system) for site-specific genome editing, the technology has been used in a variety of arthropod species 1 , 2 . Successful application of CRISPR-Cas9 to edit the germline of arthropods relies on injection of gene-editing materials into pre-blastoderm embryos (embryonic microinjection) 3 , 4 , 5 , 6 . This dependence is a significant barrier to the successful general application of transformation technologies, particularly for non-specialist laboratories, as it requires expensive equipment and training to implement 4 . In addition, many non-model species are recalcitrant to the technique because their eggs are damaged during the injection procedure, because they cannot be induced to lay large amounts of synchronous eggs, or because they give live birth rather than lay eggs (as in the case of viviparous species such as tsetse flies and aphids). These restrictions dramatically limit the use of CRISPR-Cas9 technology across diverse systems. Most female oviparous animals deliver protein material to their developing ovaries through a conserved process of ovary and egg maturation called vitellogenesis. In insects and other arthropods, yolk protein precursors (YPPs) are synthesized in the fat body, secreted into the hemolymph, and are taken up into the ovaries by receptor-mediated endocytosis (RME) 7 , 8 , 9 . During vitellogenesis, multiple receptors in the oocyte membrane are available and bind YPP ligands that are internalized, accumulated in endosomal vesicles, and sorted into yolk granules for nutrient storage for the developing embryo 10 , 11 , 12 . The use of specific ligands to deliver material into mammalian cells by receptor-mediated endocytosis has been explored for drug delivery since the 1980s 13 , 14 , 15 . For example, when the protein transferrin was used as a ligand and chemically conjugated to molecular cargo such as toxins 16 , liposomes 17 , 18 proteins 13 , or DNA 19 , these molecules were internalized into the cell via the transferrin receptor and released into the cell cytoplasm in vitro and in vivo 20 , 21 , 22 . Delivery efficacy depends on successful release of cargo from the endosomes and lysosomes 13 , 17 , 18 , 19 , 20 , 23 , 24 , often by chemical membrane destabilizers such as ammonium chloride, amines, chloroquine, or monensin 13 , 15 , 25 , 26 . We hypothesized that a ligand derived from arthropod YPPs could be fused or bound to molecular cargo such as the Cas9 ribonucleoprotein (RNP) complex (Cas9 complexed with a single-guide RNA (sgRNA)) and, when injected in the hemolymph of vitellogenic females, be delivered into the oocyte at levels necessary to achieve genome editing in the embryo, bypassing the requirement for embryonic microinjection. We term this strategy Receptor-Mediated Ovary Transduction of Cargo (ReMOT Control) (Supplementary Fig. 1 ). Mosquitoes are excellent models for development and testing of this technology because synchronous egg development can be induced by blood feeding, and significant literature exists on vitellogenesis and receptor-mediated internalization of mosquito yolk proteins 7 , 27 , 28 , 29 , 30 . Here we report the successful delivery of Cas9 RNP to mosquito ovaries and subsequent targeted gene editing of the disease vector mosquito Aedes aegypti at efficiencies comparable to traditional embryo microinjection. Results Delivery of protein cargo into mosquito oocytes using P2C Drosophila melanogaster Yolk proteins (DmYP) 1, 2, and 3 are small (50 kD) YPPs that are recognized by receptors belonging to the protein superfamily of low-density lipoprotein receptors. This family includes vitellogenin receptors, lipophorin receptors, and yolk protein receptors that are present in oocytes of diverse oviparous animal species and that can recognize related YPP ligands 31 . A previous study 32 used immunohistochemistry to demonstrate that the 439 amino acid (aa) D. melanogaster Yolk Protein 1 (DmYP1) was internalized by the oocytes of the mosquito Anopheles gambiae when recombinant DmYP1 was injected in the hemolymph of vitellogenic females. To test whether DmYP1 (or derivatives thereof) might act as suitable ligands to deliver protein cargo into mosquito oocytes, a DmYP1 fusion protein containing the enhanced green fluorescent protein (EGFP) was expressed using D. melanogaster S2 cells transfected with the plasmid pAc5-DmYPss-DmYP1-EGFP (see Methods). The protein was injected into the thorax of A. gambiae females 12 and 24 h post-blood feeding (PBF) (Supplementary Fig. 2 ). Recombinant EGFP lacking a targeting ligand was injected as a negative control. Ovaries dissected at 24, 36, 48, 60, and 72 h PBF were examined for visible EGFP fluorescence. EGFP was visualized in >98% of primary oocytes regardless of the timing of the injection (Supplementary Table 1 ) and at all stages of oocyte development including in fully developed eggs ready to be oviposited (Supplementary Fig. 3 ). For easier downstream construct design and expression, we used deletion analysis to identify a smaller region of DmYP1 sufficient for uptake into mosquito ovaries (Fig. 1a ). Fragments containing the 120 aa N-terminal portion of the protein (“P2”) could be taken up into ovaries (Fig. 1b ). Further deletion analysis of the P2 fragment identified that a 41 aa fragment, termed P2C (NLQQQRQHGKNGNQDYQDQSNEQRKNQRTSSEEDYSEEVKN), was fully sufficient to deliver EGFP to<|im_end|> <|im_start|>assistant A technology designed to improve CRISPR-Cas9 gene editing in mosquitoes and other arthropods succeeds with a high degree of efficiency, while eliminating the need for difficult microinjection of genetic material, according to researchers. These results could pave the way for scientists examining a wide range of arthropods—and even some vertebrates—to more easily manipulate gene expression for fundamental research and practical applications such as control of vector-borne diseases like Zika virus and malaria, elimination of agricultural insect pests, and potentially gene therapy for human and animal health. CRISPR—Clustered Regularly Interspaced Short Palindromic Repeats—is a relatively new and revolutionary way to modify an organism's genome by precisely delivering a DNA-cutting enzyme, Cas9, to a targeted region of DNA. The resulting mutation can delete or replace specific DNA pieces, thereby promoting or disabling certain traits. Current approaches in arthropods rely on delivering the gene-editing Cas9 directly to eggs by embryonic microinjection, a difficult and inefficient process that works in only a small number of species, noted Jason Rasgon, professor of entomology and disease epidemiology, Penn State College of Agricultural Sciences. "In addition, microinjection can damage the eggs, and it requires expensive equipment and training to implement," he said. "These restrictions dramatically limit the use of CRISPR-Cas9 technology across diverse species." To address these limitations, Rasgon's lab developed ReMOT Control—Receptor-Mediated Ovary Transduction of Cargo—a method the researchers say can deliver Cas9 cargo to a targeted portion of the genome by easy injection into the blood of female arthropods, where it can be introduced into the developing eggs via receptors in the ovary. Rasgon explained that during ovary and egg maturation, mosquitoes and other arthropods synthesize yolk proteins, which are secreted into the blood and taken up into the ovaries. The team hypothesized that molecules derived from these yolk proteins could be fused to Cas9 cargo and delivered into the egg at levels necessary to achieve genome editing in the embryo, bypassing the need for embryonic microinjection. In the process of testing this hypothesis in Aedes aegypti, a mosquito that can spread pathogens such as dengue, chikungunya, Zika, and yellow fever viruses, the team identified a peptide known as P2C, a ligand that is recognized by ovarian receptors and functions in five other mosquito species as well. To visually show that P2C could achieve uptake in the ovary, the researchers injected the peptide, infused with green fluorescent protein, into mosquitoes. They subsequently found fluorescence in more than 98 percent of primary oocytes. For gene-editing experiments, the scientists targeted a gene that, when knocked out, results in white eye color rather than dark, providing a visible phenotype to aid in screening. They found that P2C, when bonded with the Cas9 enzyme, was able to deliver the gene-editing cargo to the ovary, where the desired mutation was achieved at a high rate of efficiency, resulting in genetically modified offspring. The results of the study, published recently in Nature Communications, show that compared to embryo injection, gene editing by ReMOT Control is efficient and technically much easier to accomplish, according to Rasgon. "Whereas the microinjection apparatus can cost thousands of dollars and require extensive training to use, the equipment for ReMOT Control injections costs approximately $2, and the technique can be learned in less than an hour," he said. "The lower cost and ease of adult injections makes this method a substantial improvement over existing embryo-injection techniques, putting gene-editing capability into the reach of nonspecialist laboratories and potentially revolutionizing the broad application of functional arthropod genetics." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Oncolytic virotherapy is an effective immunotherapeutic approach for cancer treatment via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines and promotion of antitumor T cell responses. Solid tumors limit the effectiveness of immunotherapeutics in diverse ways such as secretion of immunosuppressive cytokines and expression of immune inhibitory ligands to inhibit antitumor T cell function. Blocking programmed cell death protein (PD)-1 signaling, which mediates T cell suppression via engagement of its inhibitory ligands, PD-L1 or PD-L2, is of particular interest due to recent successes in many types of cancer. In syngeneic murine rhabdomyosarcoma models, we found that M3-9-M (MHC I high) but not 76-9 (MHC I low) tumors respond to oncolytic herpes simplex virus-1 (oHSV-1) and PD-1 blockade combination therapy. In addition, the therapeutic outcomes in M3-9-M tumor models correlated with the increased incidence of CD4 + and CD8 + T cells but not with the CD4 + CD25 + Foxp3 + regulatory T cell populations in the tumor. Overall, our data suggest the combination of PD-1 blockade and oHSV-1 may be an effective treatment strategy for childhood soft tissue sarcoma. Introduction Oncolytic viruses were originally envisaged to be a therapeutic platform for cancer by virtue of their ability to preferentially kill tumor cells directly. The major barrier to their implementation was thought to be antiviral immunity, which would limit the spread and duration of the infection. There is now ample evidence suggesting that the immune response to oncolytic viruses can be therapeutic both via changes in the tumor microenvironment and the induction of antitumor T cell immunity 1 . Such effects, however, are likely subject to immunoevasive mechanisms characteristic of many cancers. Solid tumors evade antitumor immunity by a variety of mechanisms including secretion of immunosuppressive cytokines, recruitment of suppressive immune cells and expression of T cell inhibitory ligands. The T cell exhaustion marker, PD-1, has emerged as an effective cancer therapeutic target, particularly for tumors that express its ligands PD-L1 and/or PD-L2 2 . Inhibitors of this axis are most effective in patients with cancers harboring high numbers of nonsynonymous genetic mutations and therefore expressing high levels of neoantigens 3 , 4 . Whether antitumor T cells elicited in the context of intratumoral herpes simplex virus infection are subjected to the same suppressive effects, and thus might be enhanced by the same strategies, remains to be elucidated. In addition, the microenvironmental conditions that influence the outcome of viroimmunotherapy are poorly understood. We recently exploited two explantable syngeneic mouse rhabdomyosarcoma tumor models to study herpes virus-induced T cell-mediated antitumor effects 5 . The first model, 76-9, is a methylcholanthrene-induced embryonal mRMS that was originally derived from a female C57BL/6 mouse 6 . The second model, M3-9-M, was derived from a male C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53 7 . We found that both models show significant response to oHSV virotherapy in C57BL/6 hosts, despite poor tumor susceptibility to oncolytic human HSV-1 infection and replication 5 . The effect was lost when these studies were conducted in athymic nude mice, which suggests this efficacy is dependent on an antitumor T cell response and thus might benefit from PD-1 inhibition. Phenotypic analysis revealed that indeed both mRMS cell lines expressed high levels of PD-L1 8 . We also found that while each displayed MHC class I, surface expression of this protein was considerably higher in M3-9-M than in 76-9 5 , 8 . These models thus provide an ideal setting for investigating the response to T cell checkpoint inhibitors in combination with oncolytic herpes simplex virotherapy. Results Combining HSV1716 with anti-PD-1 antibody significantly prolongs survival in mice bearing M3-9-M tumors We implanted male C57BL/6 mice with 5 × 10 6 M3-9-M cells subcutaneously and allowed the tumors to reach a size of ~350 mm 3 before initiating treatment (Fig. 1a ). We then injected the tumors directly with the oncolytic virus HSV1716 (which was derived from an HSV-1 clinical isolate and is deleted for RL1 , encoding ICP34.5 9 ) or a vehicle control. Subsets of these mice were also regularly given intraperitoneal injections of PD-1 blocking antibody or an isotype control. Control animals displayed rapid tumor growth, reaching our endpoint criteria within 3 weeks (Fig. 1b and c , black line). Conversely, animals that were treated with PD-1 blocking antibody (Fig. 1b and c , green line) or intratumorally with HSV1716 (Fig. 1b and c , blue line) showed delayed tumor growth and enhanced overall survival. While the antitumor efficacy of these monotherapies was significant compared to the vehicle control, we found no statistical significance between the two. In contrast, their combination resulted in even greater antitumor efficacy and substantially prolonged overall survival compared to PD-1 blockade or HSV1716 treatments alone (Fig. 1b and c , red line). Figure 1 Combination of HSV1716 with anti-PD-1 antibody significantly prolongs survival in the male M3-9-M tumor model. ( a ) Schematic illustrates the dosing regimens for mice bearing subcutaneous M3-9-M tumors. Male C57BL/6 mice were implanted with 5 × 10 6 M3-9-M cells subcutaneously and treated with three intratumoral (i.tu.) injections of 10 8 pfu HSV1716 followed by intraperitoneal (i.p.) injections of anti-PD-1 antibody. ( b ) Tumor volumes of mice treated with anti-PD-1 (green lines; n = 6), HSV1716 (blue lines; n = 6) and combined therapy (red lines; n = 7) were measured twice a week and plotted individually against tumor volumes recorded for control mice (black lines; n = 7). ( c ) Kaplan-Meier survival curves for each treatment group demonstrate the improved efficacy of combining PD-1 blockade with HSV1716 virotherapy. Survival data were evaluated for statistical significance with Log-rank Mantel-Cox test. Full size image We performed similar efficacy and survival studies in female C57BL/6 mice transplanted with 76-9 tumors, which express low levels of MHC class I compared to M3-9-M 5 . In contrast to our M3-9-M studies, the combination of anti-PD-1 and HSV1716 failed to significantly impact tumor growth and animal survival (Fig. S1 ).", "role": "user" }, { "content": "Rhabdomyosarcoma, a cancer made up of cells that normally develop into skeletal muscles, is the most common soft tissue cancer in children. If it is detected early and localized in certain areas, rhabdomyosarcoma is usually curable with traditional therapies like surgery, radiation and chemotherapy. However, these treatments are fraught with side effects, especially for children. A recent study points to a new treatment strategy that takes advantage of the body's own immune response. Over the past decade, immunotherapy has become an important part of treating some cancers effectively and with fewer side effects than traditional therapies. One immunotherapeutic approach is oncolytic virotherapy, in which a virus is used to target cancer cells specifically. Oncolytic viruses infect and kill malignant, but not normal, cells. In the new study, researchers from Nationwide Children's Hospital used a combination of immunotherapies in a mouse model of rhabdomyosarcoma. In addition to oncolytic virotherapy, the team also blocked the signaling of programmed cell death protein (PD)-1, which mediates the suppression of T-cells. \"Other researchers have recognized that if we can block the PD-1 checkpoint and unleash the T-cells a bit more, they might fight cancer better,\" says Timothy Cripe, MD, PhD, chief of Hematology, Oncology and Blood and Marrow Transplantation at Nationwide Children's and senior author of the study. \"We thought that if a virus infection brings in more T-cells, and the PD-1 blockade allows those cells to fight cancer cells, then maybe the two therapies will work better together.\" Combining the two immunotherapies delayed tumor growth and enhanced overall survival in a mouse model of rhabdomyosarcoma, says the study's first author, Chun-Yu Chen, PhD, research scientist in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children's. \"We used a mouse model to demonstrate that when we combine oncolytic therapy with PD-1 blockade, we see a better therapeutic outcome compared to either of the therapies individually,\" says Dr. Chen. The researchers say the combination therapy is so effective because it marshals more of the T-cells that attack infections and tumors to the site of the cancer without increasing the counterbalancing, regulatory T-cells that suppress immune attacks. Both oncolytic virotherapy and PD-1 blockade are FDA-approved for treating cancer; this new study provides preclinical data to support combining them in pediatric cancer patients. Dr. Cripe, also a principal investigator at in the Center for Childhood Cancer and Blood Diseases at The Research Institute, says his team is working with a company to determine whether they will move forward with clinical trials. They are also interested in figuring out how differences in immunogenicity might affect the success of the combination treatment. \"Our paper gives us some clues as to predictive biomarkers of who might respond best to this type of treatment,\" says Dr. Cripe, also a professor of Pediatrics at The Ohio State University College of Medicine. \"If we can identify patients who have a tumor that is recognized by the immune system better, we can individually select patients in which this combination treatment will work best. \"It has been shown that immunotherapy works for some adult cancers; the question is, what impact will it have on childhood cancers?\" says Dr. Cripe. \"We are fortunate to be at an institution that has all the resources that allow us to study this in the lab and in the clinical setting and find out its full potential.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Oncolytic virotherapy is an effective immunotherapeutic approach for cancer treatment via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines and promotion of antitumor T cell responses. Solid tumors limit the effectiveness of immunotherapeutics in diverse ways such as secretion of immunosuppressive cytokines and expression of immune inhibitory ligands to inhibit antitumor T cell function. Blocking programmed cell death protein (PD)-1 signaling, which mediates T cell suppression via engagement of its inhibitory ligands, PD-L1 or PD-L2, is of particular interest due to recent successes in many types of cancer. In syngeneic murine rhabdomyosarcoma models, we found that M3-9-M (MHC I high) but not 76-9 (MHC I low) tumors respond to oncolytic herpes simplex virus-1 (oHSV-1) and PD-1 blockade combination therapy. In addition, the therapeutic outcomes in M3-9-M tumor models correlated with the increased incidence of CD4 + and CD8 + T cells but not with the CD4 + CD25 + Foxp3 + regulatory T cell populations in the tumor. Overall, our data suggest the combination of PD-1 blockade and oHSV-1 may be an effective treatment strategy for childhood soft tissue sarcoma. Introduction Oncolytic viruses were originally envisaged to be a therapeutic platform for cancer by virtue of their ability to preferentially kill tumor cells directly. The major barrier to their implementation was thought to be antiviral immunity, which would limit the spread and duration of the infection. There is now ample evidence suggesting that the immune response to oncolytic viruses can be therapeutic both via changes in the tumor microenvironment and the induction of antitumor T cell immunity 1 . Such effects, however, are likely subject to immunoevasive mechanisms characteristic of many cancers. Solid tumors evade antitumor immunity by a variety of mechanisms including secretion of immunosuppressive cytokines, recruitment of suppressive immune cells and expression of T cell inhibitory ligands. The T cell exhaustion marker, PD-1, has emerged as an effective cancer therapeutic target, particularly for tumors that express its ligands PD-L1 and/or PD-L2 2 . Inhibitors of this axis are most effective in patients with cancers harboring high numbers of nonsynonymous genetic mutations and therefore expressing high levels of neoantigens 3 , 4 . Whether antitumor T cells elicited in the context of intratumoral herpes simplex virus infection are subjected to the same suppressive effects, and thus might be enhanced by the same strategies, remains to be elucidated. In addition, the microenvironmental conditions that influence the outcome of viroimmunotherapy are poorly understood. We recently exploited two explantable syngeneic mouse rhabdomyosarcoma tumor models to study herpes virus-induced T cell-mediated antitumor effects 5 . The first model, 76-9, is a methylcholanthrene-induced embryonal mRMS that was originally derived from a female C57BL/6 mouse 6 . The second model, M3-9-M, was derived from a male C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53 7 . We found that both models show significant response to oHSV virotherapy in C57BL/6 hosts, despite poor tumor susceptibility to oncolytic human HSV-1 infection and replication 5 . The effect was lost when these studies were conducted in athymic nude mice, which suggests this efficacy is dependent on an antitumor T cell response and thus might benefit from PD-1 inhibition. Phenotypic analysis revealed that indeed both mRMS cell lines expressed high levels of PD-L1 8 . We also found that while each displayed MHC class I, surface expression of this protein was considerably higher in M3-9-M than in 76-9 5 , 8 . These models thus provide an ideal setting for investigating the response to T cell checkpoint inhibitors in combination with oncolytic herpes simplex virotherapy. Results Combining HSV1716 with anti-PD-1 antibody significantly prolongs survival in mice bearing M3-9-M tumors We implanted male C57BL/6 mice with 5 × 10 6 M3-9-M cells subcutaneously and allowed the tumors to reach a size of ~350 mm 3 before initiating treatment (Fig. 1a ). We then injected the tumors directly with the oncolytic virus HSV1716 (which was derived from an HSV-1 clinical isolate and is deleted for RL1 , encoding ICP34.5 9 ) or a vehicle control. Subsets of these mice were also regularly given intraperitoneal injections of PD-1 blocking antibody or an isotype control. Control animals displayed rapid tumor growth, reaching our endpoint criteria within 3 weeks (Fig. 1b and c , black line). Conversely, animals that were treated with PD-1 blocking antibody (Fig. 1b and c , green line) or intratumorally with HSV1716 (Fig. 1b and c , blue line) showed delayed tumor growth and enhanced overall survival. While the antitumor efficacy of these monotherapies was significant compared to the vehicle control, we found no statistical significance between the two. In contrast, their combination resulted in even greater antitumor efficacy and substantially prolonged overall survival compared to PD-1 blockade or HSV1716 treatments alone (Fig. 1b and c , red line). Figure 1 Combination of HSV1716 with anti-PD-1 antibody significantly prolongs survival in the male M3-9-M tumor model. ( a ) Schematic illustrates the dosing regimens for mice bearing subcutaneous M3-9-M tumors. Male C57BL/6 mice were implanted with 5 × 10 6 M3-9-M cells subcutaneously and treated with three intratumoral (i.tu.) injections of 10 8 pfu HSV1716 followed by intraperitoneal (i.p.) injections of anti-PD-1 antibody. ( b ) Tumor volumes of mice treated with anti-PD-1 (green lines; n = 6), HSV1716 (blue lines; n = 6) and combined therapy (red lines; n = 7) were measured twice a week and plotted individually against tumor volumes recorded for control mice (black lines; n = 7). ( c ) Kaplan-Meier survival curves for each treatment group demonstrate the improved efficacy of combining PD-1 blockade with HSV1716 virotherapy. Survival data were evaluated for statistical significance with Log-rank Mantel-Cox test. Full size image We performed similar efficacy and survival studies in female C57BL/6 mice transplanted with 76-9 tumors, which express low levels of MHC class I compared to M3-9-M 5 . In contrast to our M3-9-M studies, the combination of anti-PD-1 and HSV1716 failed to significantly impact tumor growth and animal survival (Fig. S1 ).<|im_end|> <|im_start|>assistant Rhabdomyosarcoma, a cancer made up of cells that normally develop into skeletal muscles, is the most common soft tissue cancer in children. If it is detected early and localized in certain areas, rhabdomyosarcoma is usually curable with traditional therapies like surgery, radiation and chemotherapy. However, these treatments are fraught with side effects, especially for children. A recent study points to a new treatment strategy that takes advantage of the body's own immune response. Over the past decade, immunotherapy has become an important part of treating some cancers effectively and with fewer side effects than traditional therapies. One immunotherapeutic approach is oncolytic virotherapy, in which a virus is used to target cancer cells specifically. Oncolytic viruses infect and kill malignant, but not normal, cells. In the new study, researchers from Nationwide Children's Hospital used a combination of immunotherapies in a mouse model of rhabdomyosarcoma. In addition to oncolytic virotherapy, the team also blocked the signaling of programmed cell death protein (PD)-1, which mediates the suppression of T-cells. "Other researchers have recognized that if we can block the PD-1 checkpoint and unleash the T-cells a bit more, they might fight cancer better," says Timothy Cripe, MD, PhD, chief of Hematology, Oncology and Blood and Marrow Transplantation at Nationwide Children's and senior author of the study. "We thought that if a virus infection brings in more T-cells, and the PD-1 blockade allows those cells to fight cancer cells, then maybe the two therapies will work better together." Combining the two immunotherapies delayed tumor growth and enhanced overall survival in a mouse model of rhabdomyosarcoma, says the study's first author, Chun-Yu Chen, PhD, research scientist in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children's. "We used a mouse model to demonstrate that when we combine oncolytic therapy with PD-1 blockade, we see a better therapeutic outcome compared to either of the therapies individually," says Dr. Chen. The researchers say the combination therapy is so effective because it marshals more of the T-cells that attack infections and tumors to the site of the cancer without increasing the counterbalancing, regulatory T-cells that suppress immune attacks. Both oncolytic virotherapy and PD-1 blockade are FDA-approved for treating cancer; this new study provides preclinical data to support combining them in pediatric cancer patients. Dr. Cripe, also a principal investigator at in the Center for Childhood Cancer and Blood Diseases at The Research Institute, says his team is working with a company to determine whether they will move forward with clinical trials. They are also interested in figuring out how differences in immunogenicity might affect the success of the combination treatment. "Our paper gives us some clues as to predictive biomarkers of who might respond best to this type of treatment," says Dr. Cripe, also a professor of Pediatrics at The Ohio State University College of Medicine. "If we can identify patients who have a tumor that is recognized by the immune system better, we can individually select patients in which this combination treatment will work best. "It has been shown that immunotherapy works for some adult cancers; the question is, what impact will it have on childhood cancers?" says Dr. Cripe. "We are fortunate to be at an institution that has all the resources that allow us to study this in the lab and in the clinical setting and find out its full potential." <|im_end|>

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2,261

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Gelatinous zooplankton are increasingly acknowledged to contribute significantly to the carbon cycle worldwide, yet many taxa within this diverse group remain poorly studied. Here, we investigate the pelagic tunicate Pyrosoma atlanticum in the waters surrounding the Cabo Verde Archipelago. By using a combination of pelagic and benthic in situ observations, sampling, and molecular genetic analyses (barcoding, eDNA), we reveal that: P. atlanticum abundance is most likely driven by local island-induced productivity, that it substantially contributes to the organic carbon export flux and is part of a diverse range of biological interactions. Downward migrating pyrosomes actively transported an estimated 13% of their fecal pellets below the mixed layer, equaling a carbon flux of 1.96–64.55 mg C m −2 day −1 . We show that analysis of eDNA can detect pyrosome material beyond their migration range, suggesting that pyrosomes have ecological impacts below the upper water column. Moribund P. atlanticum colonies contributed an average of 15.09 ± 17.89 (s.d.) mg C m −2 to the carbon flux reaching the island benthic slopes. Our pelagic in situ observations further show that P. atlanticum formed an abundant substrate in the water column (reaching up to 0.28 m 2 substrate area per m 2 ), with animals using pyrosomes for settlement, as a shelter and/or a food source. In total, twelve taxa from four phyla were observed to interact with pyrosomes in the midwater and on the benthos. Introduction Although gelatinous zooplankton are among the most abundant inhabitants of the open ocean 1 , 2 , their roles in marine ecosystems have traditionally been underestimated 3 . Gelatinous zooplankton refers to a polyphyletic group of marine organisms, characterized by high water content of their tissues (~ 95%) and a planktonic existence (carried by the currents). This group includes taxa such as ctenophores, medusae, siphonophores and pelagic tunicates (i.e. salps, pyrosomes, doliolids and larvaceans) 1 , 3 , 4 . Since many of these animals possess delicate bodies that are easily damaged by net collections, it was not until the advent of underwater technologies such as blue-water SCUBA and submersibles that their ability to seasonally dominate pelagic midwater communities was noted 1 , 3 , 4 . With this discovery, a more complex picture of their roles in marine ecosystems soon emerged. Gelatinous zooplankton are now increasingly recognized as important players in the global carbon cycle, accumulating and transporting organic carbon to the seabed 5 , 6 , 7 . Nevertheless, at present day, only a small fraction of our ocean has been explored and gelatinous zooplankton remain poorly studied, particularly in deep pelagic ecosystems 2 , 8 . Pyrosomes are abundant gelatinous zooplankton in open ocean environments and continental shelf slopes, but relatively little is known about their general biology 9 , 10 , 11 , 12 . Most studies on the role of pyrosomes in ocean ecosystems focus on Pyrosoma atlanticum Peron, 1804, a species common throughout the Pacific, Atlantic and Indian Oceans 13 . Pyrosoma atlanticum has been shown to markedly redirect primary production with clearance rates measured up to 35 L h −1 for a single colony 12 . Additionally, dense shoals were estimated to clear up to 53% of the phytoplankton stock 14 . Since P. atlanticum possesses one of the highest carbon contents measured among gelatinous zooplankton (35% of dry weight) 15 , sinking moribund or dead colonies can transport substantial amounts of organic matter to the deep 15 , 16 , 17 . Mass mortality of pyrosome blooms, for instance, can result in so called ‘jelly-falls’, providing abundant food for a variety of benthic fauna 15 , 17 . Together with living pyrosomes, decrepit colonies were shown to be consumed by echinoderms, actinarians, crustaceans 15 , 17 , fishes, turtles 18 , marine birds 19 , 20 and even marine mammals 21 , 22 . Few of these studies, however, have addressed the ecology of P. atlanticum in the water column, and rarely via in situ observations 15 , 16 , 17 , 23 . In addition to being a food source, living pyrosome colonies further add to the downward flux of carbon by the fast production of fecal pellets, which may have as much as 22% carbon per unit dry weight 14 . The rate of this downward carbon flux may be further enhanced through P. atlanticum ’s diel vertical migrations, by which they can actively transport fecal material below the mixed layer 10 . The extent of this transport, however, has only been estimated theoretically 10 , 14 and it remains unknown whether the fecal material reaches greater depths in practice. To our knowledge, pyrosome fecal pellets have not been reported from sediment traps, even though the sedimentation of salp fecal material has been well documented (e.g. 24 , 25 and references therein). A novel molecular method that may provide an effective tool to confirm this transport is the detection and barcoding of environmental DNA (eDNA) 26 . eDNA is defined as the genetic material that organisms shed in the form of dead tissue cells, feces or mucous, which can be extracted from their environment as it usually remains in the water for a period of time without direct presence of the animal. Although eDNA analyses are becoming increasingly popular to document biodiversity of marine communities 26 , 27 , the technique has never been implemented to detect pyrosome DNA (from colonies or fecal pellets) at depth. During two research cruises to the Cabo Verde region of the eastern tropical North Atlantic (ETNA), we encountered large aggregations of P. atlanticum, which allowed us to investigate its ecological role in this system. Even though the open ocean surrounding the Cabo Verde archipelago is oligotrophic, geographic features such as seamounts and islands induce local upwelling and therefore enhance biological productivity 28 , 29 . In addition, northeasterly trade winds force eddy formation in the wake of the islands and enhance upwelling depending on season 30 , 31 . The region features a weak mesopelagic oxygen minimum zone (OMZ),", "role": "user" }, { "content": "Pyrosomes, named after the Greek words for 'fire bodies' due their bright bioluminescence, are pelagic tunicates that spend their entire lives swimming in the open ocean. They are made up of many smaller animals, known as zooids, that sit together in a tubular matrix, known as tunic (hence the name pelagic tunicates). Because they live in the open ocean, they generally go unnoticed. In spite of this, increasing research points to their importance in marine environments, as they can form dense blooms that impact food web dynamics and contribute to the movement and transformation of organic carbon. The study conducted with GEOMAR research vessel POSEIDON in 2018 and 2019 in the vicinity of the Cabo Verde Islands, of which the results have now been published in the international journal Scientific Reports, addressed important research gaps; observations on the interactions between pyrosomes and their environment have rarely been made in the water column. Most studies that investigated pyrosomes with submersibles looked at moribund colonies on the seabed or used net catches that generally disrupt species interactions. Furthermore, the aim was to estimate the contribution of these organisms to the local marine carbon cycle. For the eastern Atlantic such information was still largely unknown. \"Because we combined underwater observations, sampling and genetic analyses, we were able to gain several new insights into pyrosome ecology,\" says lead author Vanessa Stenvers, from GEOMAR. During the expedition, the organisms were observed directly with the research submersible JAGO, and also studied via a pelagic towed camera system, PELAGIOS, as well as by net and water sampling. \"Our study shows that pyrosomes form an important biological substrate in the water column that other animals use for settlement, shelter and/or as a food source,\" explains Vanessa Stenvers. \"We have estimated that Pyrosoma atlanticum provides up to 0.28 m2 of substrate area per square meter of total area during a bloom period. This is a huge number if you consider that there are little physical features in the water column besides the animals that live there,\" says the marine biologist. Pyrosome in the water column. Credit: PELAGIOS, GEOMAR. Thanks to the underwater observations, the team also discovered several new species interactions, including the jellyfish Drymonema gorgo, which fed on pyrosomes, and a yet undescribed oxycephalid amphipod that was frequently observed on pyrosomes. Upon closer inspection, these amphipods had removed individual zooids to create a cavity in the colony into which they retreated upon disturbance. Pyrosome blooms were found to be related to high values of chlorophyll. Since the filter-feeding organisms directly consume microalgae, they profit from upwelling conditions that are found both on the lee side of the islands as well as in mid-ocean eddies. The latter are circular currents that can move cold nutrient-rich water from deeper depths up to the surface. \"Furthermore, we found that Pyrosoma atlanticum plays an important role in how about the vertical transport of organic carbon in the waters around the Cabo Verde Islands,\" explains Dr. Henk-Jan Hoving, who leads the Deep Sea Biology research group at GEOMAR and is senior co-author of the study. Pyrosomes migrate up and down the water column daily to feed in the productive upper marine layers at night. At dusk, they migrate back to deeper water layers. During this migration, they actively transport their feces to these depths, while also releasing carbon through respiration. \"In addition to observations and theoretical estimates, we have been able to show with the detection of environmental DNA from water samples that pyrosome material can also be detected below their migration range, i.e. sinking into the deep ocean,\" explains Dr. Hoving. Another way for pyrosomes to contribute to the carbon cycle is by deposition of dead and dying colonies to the seafloor, where they act as food for organisms living there. \"From the submersible JAGO, I observed that pyrosomes were consumed on the seafloor by decapods, such as large crabs, shrimps and hermit crabs, illustrating their important role as food for seabed scavengers,\" says marine biologist and co-author Rui Freitas of the Marine Institute at the Universidade Técnica do Atlântico, Mindelo, Cabo Verde. \"Thus, the present results illustrate the important and versatile ecological role of Pyrosoma atlanticum in the ocean around the Cabo Verde Islands, affecting both pelagic and benthic ecosystems,\" Henk-Jan Hoving concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Gelatinous zooplankton are increasingly acknowledged to contribute significantly to the carbon cycle worldwide, yet many taxa within this diverse group remain poorly studied. Here, we investigate the pelagic tunicate Pyrosoma atlanticum in the waters surrounding the Cabo Verde Archipelago. By using a combination of pelagic and benthic in situ observations, sampling, and molecular genetic analyses (barcoding, eDNA), we reveal that: P. atlanticum abundance is most likely driven by local island-induced productivity, that it substantially contributes to the organic carbon export flux and is part of a diverse range of biological interactions. Downward migrating pyrosomes actively transported an estimated 13% of their fecal pellets below the mixed layer, equaling a carbon flux of 1.96–64.55 mg C m −2 day −1 . We show that analysis of eDNA can detect pyrosome material beyond their migration range, suggesting that pyrosomes have ecological impacts below the upper water column. Moribund P. atlanticum colonies contributed an average of 15.09 ± 17.89 (s.d.) mg C m −2 to the carbon flux reaching the island benthic slopes. Our pelagic in situ observations further show that P. atlanticum formed an abundant substrate in the water column (reaching up to 0.28 m 2 substrate area per m 2 ), with animals using pyrosomes for settlement, as a shelter and/or a food source. In total, twelve taxa from four phyla were observed to interact with pyrosomes in the midwater and on the benthos. Introduction Although gelatinous zooplankton are among the most abundant inhabitants of the open ocean 1 , 2 , their roles in marine ecosystems have traditionally been underestimated 3 . Gelatinous zooplankton refers to a polyphyletic group of marine organisms, characterized by high water content of their tissues (~ 95%) and a planktonic existence (carried by the currents). This group includes taxa such as ctenophores, medusae, siphonophores and pelagic tunicates (i.e. salps, pyrosomes, doliolids and larvaceans) 1 , 3 , 4 . Since many of these animals possess delicate bodies that are easily damaged by net collections, it was not until the advent of underwater technologies such as blue-water SCUBA and submersibles that their ability to seasonally dominate pelagic midwater communities was noted 1 , 3 , 4 . With this discovery, a more complex picture of their roles in marine ecosystems soon emerged. Gelatinous zooplankton are now increasingly recognized as important players in the global carbon cycle, accumulating and transporting organic carbon to the seabed 5 , 6 , 7 . Nevertheless, at present day, only a small fraction of our ocean has been explored and gelatinous zooplankton remain poorly studied, particularly in deep pelagic ecosystems 2 , 8 . Pyrosomes are abundant gelatinous zooplankton in open ocean environments and continental shelf slopes, but relatively little is known about their general biology 9 , 10 , 11 , 12 . Most studies on the role of pyrosomes in ocean ecosystems focus on Pyrosoma atlanticum Peron, 1804, a species common throughout the Pacific, Atlantic and Indian Oceans 13 . Pyrosoma atlanticum has been shown to markedly redirect primary production with clearance rates measured up to 35 L h −1 for a single colony 12 . Additionally, dense shoals were estimated to clear up to 53% of the phytoplankton stock 14 . Since P. atlanticum possesses one of the highest carbon contents measured among gelatinous zooplankton (35% of dry weight) 15 , sinking moribund or dead colonies can transport substantial amounts of organic matter to the deep 15 , 16 , 17 . Mass mortality of pyrosome blooms, for instance, can result in so called ‘jelly-falls’, providing abundant food for a variety of benthic fauna 15 , 17 . Together with living pyrosomes, decrepit colonies were shown to be consumed by echinoderms, actinarians, crustaceans 15 , 17 , fishes, turtles 18 , marine birds 19 , 20 and even marine mammals 21 , 22 . Few of these studies, however, have addressed the ecology of P. atlanticum in the water column, and rarely via in situ observations 15 , 16 , 17 , 23 . In addition to being a food source, living pyrosome colonies further add to the downward flux of carbon by the fast production of fecal pellets, which may have as much as 22% carbon per unit dry weight 14 . The rate of this downward carbon flux may be further enhanced through P. atlanticum ’s diel vertical migrations, by which they can actively transport fecal material below the mixed layer 10 . The extent of this transport, however, has only been estimated theoretically 10 , 14 and it remains unknown whether the fecal material reaches greater depths in practice. To our knowledge, pyrosome fecal pellets have not been reported from sediment traps, even though the sedimentation of salp fecal material has been well documented (e.g. 24 , 25 and references therein). A novel molecular method that may provide an effective tool to confirm this transport is the detection and barcoding of environmental DNA (eDNA) 26 . eDNA is defined as the genetic material that organisms shed in the form of dead tissue cells, feces or mucous, which can be extracted from their environment as it usually remains in the water for a period of time without direct presence of the animal. Although eDNA analyses are becoming increasingly popular to document biodiversity of marine communities 26 , 27 , the technique has never been implemented to detect pyrosome DNA (from colonies or fecal pellets) at depth. During two research cruises to the Cabo Verde region of the eastern tropical North Atlantic (ETNA), we encountered large aggregations of P. atlanticum, which allowed us to investigate its ecological role in this system. Even though the open ocean surrounding the Cabo Verde archipelago is oligotrophic, geographic features such as seamounts and islands induce local upwelling and therefore enhance biological productivity 28 , 29 . In addition, northeasterly trade winds force eddy formation in the wake of the islands and enhance upwelling depending on season 30 , 31 . The region features a weak mesopelagic oxygen minimum zone (OMZ),<|im_end|> <|im_start|>assistant Pyrosomes, named after the Greek words for 'fire bodies' due their bright bioluminescence, are pelagic tunicates that spend their entire lives swimming in the open ocean. They are made up of many smaller animals, known as zooids, that sit together in a tubular matrix, known as tunic (hence the name pelagic tunicates). Because they live in the open ocean, they generally go unnoticed. In spite of this, increasing research points to their importance in marine environments, as they can form dense blooms that impact food web dynamics and contribute to the movement and transformation of organic carbon. The study conducted with GEOMAR research vessel POSEIDON in 2018 and 2019 in the vicinity of the Cabo Verde Islands, of which the results have now been published in the international journal Scientific Reports, addressed important research gaps; observations on the interactions between pyrosomes and their environment have rarely been made in the water column. Most studies that investigated pyrosomes with submersibles looked at moribund colonies on the seabed or used net catches that generally disrupt species interactions. Furthermore, the aim was to estimate the contribution of these organisms to the local marine carbon cycle. For the eastern Atlantic such information was still largely unknown. "Because we combined underwater observations, sampling and genetic analyses, we were able to gain several new insights into pyrosome ecology," says lead author Vanessa Stenvers, from GEOMAR. During the expedition, the organisms were observed directly with the research submersible JAGO, and also studied via a pelagic towed camera system, PELAGIOS, as well as by net and water sampling. "Our study shows that pyrosomes form an important biological substrate in the water column that other animals use for settlement, shelter and/or as a food source," explains Vanessa Stenvers. "We have estimated that Pyrosoma atlanticum provides up to 0.28 m2 of substrate area per square meter of total area during a bloom period. This is a huge number if you consider that there are little physical features in the water column besides the animals that live there," says the marine biologist. Pyrosome in the water column. Credit: PELAGIOS, GEOMAR. Thanks to the underwater observations, the team also discovered several new species interactions, including the jellyfish Drymonema gorgo, which fed on pyrosomes, and a yet undescribed oxycephalid amphipod that was frequently observed on pyrosomes. Upon closer inspection, these amphipods had removed individual zooids to create a cavity in the colony into which they retreated upon disturbance. Pyrosome blooms were found to be related to high values of chlorophyll. Since the filter-feeding organisms directly consume microalgae, they profit from upwelling conditions that are found both on the lee side of the islands as well as in mid-ocean eddies. The latter are circular currents that can move cold nutrient-rich water from deeper depths up to the surface. "Furthermore, we found that Pyrosoma atlanticum plays an important role in how about the vertical transport of organic carbon in the waters around the Cabo Verde Islands," explains Dr. Henk-Jan Hoving, who leads the Deep Sea Biology research group at GEOMAR and is senior co-author of the study. Pyrosomes migrate up and down the water column daily to feed in the productive upper marine layers at night. At dusk, they migrate back to deeper water layers. During this migration, they actively transport their feces to these depths, while also releasing carbon through respiration. "In addition to observations and theoretical estimates, we have been able to show with the detection of environmental DNA from water samples that pyrosome material can also be detected below their migration range, i.e. sinking into the deep ocean," explains Dr. Hoving. Another way for pyrosomes to contribute to the carbon cycle is by deposition of dead and dying colonies to the seafloor, where they act as food for organisms living there. "From the submersible JAGO, I observed that pyrosomes were consumed on the seafloor by decapods, such as large crabs, shrimps and hermit crabs, illustrating their important role as food for seabed scavengers," says marine biologist and co-author Rui Freitas of the Marine Institute at the Universidade Técnica do Atlântico, Mindelo, Cabo Verde. "Thus, the present results illustrate the important and versatile ecological role of Pyrosoma atlanticum in the ocean around the Cabo Verde Islands, affecting both pelagic and benthic ecosystems," Henk-Jan Hoving concludes. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As one of the largest land mammals, the origin and evolution of the giant rhino Paraceratherium bugtiense in Pakistan have been unclear. We report a new species Paraceratherium linxiaense sp. nov. from northwestern China with an age of 26.5 Ma. Morphology and phylogeny reveal that P. linxiaense is the highly derived species of the genus Paraceratherium , and its clade with P. lepidum has a tight relationship to P. bugtiense . Based on the paleogeographical literature, P. bugtiense represents a range expansion of Paraceratherium from Central Asia via the Tibetan region. By the late Oligocene, P. lepidum and P. linxiaense were found in the north side of the Tibetan Plateau. The Tibetan region likely hosted some areas with low elevation, possibly under 2000 m during Oligocene, and the lineage of giant rhinos could have dispersed freely along the eastern coast of the Tethys Ocean and perhaps through some lowlands of this region. Introduction The giant rhino (derived genera of Paraceratheriidae, Rhinocerotoidea, Perissodactyla, such as Paraceratherium , Dzungariotherium , Aralotherium , and Turpanotherium ) has been considered as one of the largest land mammals that ever lived 1 . Its skull and legs are longer than all reported land mammals, but the metapodials are not massive in outline. Its body size was suitable for open woodlands under humid or arid climatic conditions 2 . Except for some remains found in Eastern Europe 3 , Anatolia 4 , 5 , and Caucasus 6 , giant rhinos lived mainly in Asia, especially in China, Mongolia, Kazakhstan, and Pakistan 7 . All forms of the giant rhino, including six genera, have been recorded from northwest to southwest China through the middle Eocene to the late Oligocene. Among them, Juxia from the middle Eocene is considered as the unequivocal ancestor of all giant rhinos because of a set of the primitive and primarily specialized features 7 . The genus Paraceratherium was the most widely distributed form of the giant rhino, but aside from East and Central Asia, many records from East Europe 3 and West Asia 4 , 5 , 6 comprise fragmentary specimens, and only Paraceratherium bugtiense , known from the southwestern corner of the Tibetan Plateau 8 , has ample records and undoubtable taxa identity and is key to the origin and dispersal history of Paraceratherium 9 , 10 . Here we report a completely preserved skull with an articulated mandible and atlas, representing a new species of Paraceratherium from the upper Oligocene Jiaozigou Formation of the Linxia Basin in Gansu Province, China, located at the northeastern border of the Tibetan Plateau 11 , 12 . The Jiaozigou fauna of the Linxia Basin also includes the giant rhinos Turpanotherium and Dzungariotherium , the rodent Tsaganomys , the creodont Megalopterodon , the chalicothere Schizotherium , the hyracodont Ardynia , the rhinocerotid Aprotodon , and the entelodont Paraentelodon (Supplementary Table 1 ), making it similar to the Nanpoping fauna of the Lanzhou Basin and other Tabenbulukian faunas from Inner Mongolia and Ningxia. This suggests the widespread occurrence of open woodland during the late Oligocene in northwestern China, with a mix of woodland and grassland 7 . Results Systematic paleontology Perissodactyla Owen, 1848 Paraceratheriidae Osborn, 1923 Paraceratherium Forster-Cooper, 1911 Paraceratherium linxiaense sp. nov. Type specimens A complete skull and mandible with the associated atlas (holotype, HMV 2006, Fig. 1 ), and an axis and two thoracic vertebrae of another individual (paratype, HMV 2007, Fig. 2 ), which are preserved at the Hezheng Paleozoological Museum in Hezheng County, Gansu Province, China. HMV 2006 represents a full adult individual. The specific name, linxiaense, refers to the geographical location of the discovery in the Linxia Basin (Fig. 3 ). Fig. 1: Holotype (HMV 2006) of Paraceratherium linxiaense sp. nov. Skull: a lateral view; b ventral view; c dorsal view; d anterior view; e occipital view. Mandible: f , h lateral view and medial view of left ramus, respectively; g occlusal view. Skull and mandible share the scale bar, but both anterior and nuchal views have an independent scale bar. Full size image Fig. 2: Vertebrae of Paraceratherium linxiaense . a atlas (HMV 2006); b axis (HMV 2007); c 4 th –5 th articulated thoracic vertebrae (HMV 2007). 1, right view; 2, posterior view; 3, left view; 4, dorsal view; 5, anterior view; 6, ventral view; 7, postero-ventral view. The articular facets on 4 th -5 th thoracic vertebrae are marked with the red semitransparent outline whatever it is intact or has been damaged. Full size image Fig. 3: Type locality of Paraceratherium linxiaense . Map showing the giant rhino fossil locality of the Linxia Basin in Wangjiachuan Village, Dongxiang County, Gansu Province, China. Full size image Type locality and horizon IVPP locality LX1808 (N35°35’05.16”, E103°18’51.02”; 1983 m above sea level, Fig. 4 ) is near the village of Wangjiachuan, 10.8 km southwest of the town of Dongxiang County, Linxia Hui Autonomous Prefecture, Gansu Province, China (Fig. 3 ). HMV 2006 and 2007 are from the sandstones in the lower part of the Jiaozigou Formation (Fig. 5 , Supplementary Note 1 ). Fig. 4: Type horizon of Paraceratherium linxiaense . Exposures of fluvial and lacustrine sediments of the Linxia Basin (LX 1808) at the type locality of this new species (HMV 2006, yellow square) and where the axis and thoracic vertebrae were also found in Wangjiachuan Village, Dongxiang County, Gansu Province, China. Full size image Fig. 5: Cenozoic section of the Linxia Basin. Deposits with correlation to ATNTS 2012 49 (left) for the magnetostratigraphic results 50 (middle) and the Wangjiachuan section bearing the fossils of Paraceratherium linxiaense sp. nov. (right). Full size image Age IVPP locality LX1808 is faunally and paleomagnetically dated to the middle of chron C8r with an estimated age of 26.5 million years ago (Ma) in the late Oligocene (Fig. 5 ). Diagnosis Paraceratherium linxiaense possesses features that characterize the genus, such as a giant body size, long premaxillae with anterior ends extending downward, separated parietal crests, high condyle compared to the height of nuchal surface,", "role": "user" }, { "content": "The giant rhino, Paraceratherium, is considered the largest land mammal that ever lived and was mainly found in Asia, especially China, Mongolia, Kazakhstan, and Pakistan. How this genus dispersed across Asia was long a mystery, however. A new discovery has now shed light on this process. Prof. Deng Tao from the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences and his collaborators from China and the U.S.A. recently reported a new species Paraceratherium linxiaense sp. nov., which offers important clues to the dispersal of giant rhinos across Asia. The study was published in Communications Biology on June 17. The new species' fossils comprise a completely preserved skull and mandible with their associated atlas, as well as an axis and two thoracic vertebrae from another individual. The fossils were recovered from the Late Oligocene deposits of the Linxia Basin in Gansu Province, China, which is located on the northeastern border of the Tibetan Plateau. Phylogenetic analysis yielded a single most parsimonious tree, which places P. linxiaense as a derived giant rhino, within the monophyletic clade of the Oligocene Asian Paraceratherium. Within the Paraceratherium clade, the researchers' phylogenetic analysis produced a series of progressively more-derived species—from P. grangeri, through P. huangheense, P. asiaticum, and P. bugtiense—finally terminating in P. lepidum and P. linxiaense. P. linxiaense is at a high level of specialization, similar to P. lepidum, and both are derived from P. bugtiense. Distribution and migration of Paraceratherium in the Oligocene Eurasia. Localities of the early Oligocene species were marked by the yellow color, and the red indicates the late Oligocene species. Credit: IVPP Adaptation of the atlas and axis to the large body and long neck of the giant rhino already characterized P. grangeri and P. bugtiense, and was further developed in P. linxiaense, whose atlas is elongated, indicative of a long neck and higher axis with a nearly horizontal position for its posterior articular face. These features are correlated with a more flexible neck. The giant rhino of western Pakistan is from the Oligocene strata, representing a single species, Paraceratherium bugtiense. On the other hand, the rest of the genus Paraceratherium, which is distributed across the Mongolian Plateau, northwestern China, and the area north of the Tibetan Plateau to Kazakhstan, is highly diversified. The researchers found that all six species of Paraceratherium are sisters to Aralotherium and form a monophyletic clade in which P. grangeri is the most primitive, succeeded by P. huangheense and P. asiaticum. The researchers were thus able to determine that, in the Early Oligocene, P. asiaticum dispersed westward to Kazakhstan and its descendant lineage expanded to South Asia as P. bugtiense. In the Late Oligocene, Paraceratherium returned northward, crossing the Tibetan area to produce P. lepidium to the west in Kazakhstan and P. linxiaense to the east in the Linxia Basin. Ecological reconstruction of giant rhinos and their accompanying fauna in the Linxia Basin during the Oligocene. Credit: Chen Yu The researchers noted the aridity of the Early Oligocene in Central Asia at a time when South Asia was relatively moist, with a mosaic of forested and open landscapes. \"Late Oligocene tropical conditions allowed the giant rhino to return northward to Central Asia, implying that the Tibetan region was still not uplifted as a high-elevation plateau,\" said Prof. Deng. During the Oligocene, the giant rhino could obviously disperse freely from the Mongolian Plateau to South Asia along the eastern coast of the Tethys Ocean and perhaps through Tibet. The topographical possibility that the giant rhino crossed the Tibetan area to reach the Indian-Pakistani subcontinent in the Oligocene can also be supported by other evidence. Up to the Late Oligocene, the evolution and migration from P. bugtiense to P. linxiaense and P. lepidum show that the \"Tibetan Plateau\" was not yet a barrier to the movement of the largest land mammal. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract As one of the largest land mammals, the origin and evolution of the giant rhino Paraceratherium bugtiense in Pakistan have been unclear. We report a new species Paraceratherium linxiaense sp. nov. from northwestern China with an age of 26.5 Ma. Morphology and phylogeny reveal that P. linxiaense is the highly derived species of the genus Paraceratherium , and its clade with P. lepidum has a tight relationship to P. bugtiense . Based on the paleogeographical literature, P. bugtiense represents a range expansion of Paraceratherium from Central Asia via the Tibetan region. By the late Oligocene, P. lepidum and P. linxiaense were found in the north side of the Tibetan Plateau. The Tibetan region likely hosted some areas with low elevation, possibly under 2000 m during Oligocene, and the lineage of giant rhinos could have dispersed freely along the eastern coast of the Tethys Ocean and perhaps through some lowlands of this region. Introduction The giant rhino (derived genera of Paraceratheriidae, Rhinocerotoidea, Perissodactyla, such as Paraceratherium , Dzungariotherium , Aralotherium , and Turpanotherium ) has been considered as one of the largest land mammals that ever lived 1 . Its skull and legs are longer than all reported land mammals, but the metapodials are not massive in outline. Its body size was suitable for open woodlands under humid or arid climatic conditions 2 . Except for some remains found in Eastern Europe 3 , Anatolia 4 , 5 , and Caucasus 6 , giant rhinos lived mainly in Asia, especially in China, Mongolia, Kazakhstan, and Pakistan 7 . All forms of the giant rhino, including six genera, have been recorded from northwest to southwest China through the middle Eocene to the late Oligocene. Among them, Juxia from the middle Eocene is considered as the unequivocal ancestor of all giant rhinos because of a set of the primitive and primarily specialized features 7 . The genus Paraceratherium was the most widely distributed form of the giant rhino, but aside from East and Central Asia, many records from East Europe 3 and West Asia 4 , 5 , 6 comprise fragmentary specimens, and only Paraceratherium bugtiense , known from the southwestern corner of the Tibetan Plateau 8 , has ample records and undoubtable taxa identity and is key to the origin and dispersal history of Paraceratherium 9 , 10 . Here we report a completely preserved skull with an articulated mandible and atlas, representing a new species of Paraceratherium from the upper Oligocene Jiaozigou Formation of the Linxia Basin in Gansu Province, China, located at the northeastern border of the Tibetan Plateau 11 , 12 . The Jiaozigou fauna of the Linxia Basin also includes the giant rhinos Turpanotherium and Dzungariotherium , the rodent Tsaganomys , the creodont Megalopterodon , the chalicothere Schizotherium , the hyracodont Ardynia , the rhinocerotid Aprotodon , and the entelodont Paraentelodon (Supplementary Table 1 ), making it similar to the Nanpoping fauna of the Lanzhou Basin and other Tabenbulukian faunas from Inner Mongolia and Ningxia. This suggests the widespread occurrence of open woodland during the late Oligocene in northwestern China, with a mix of woodland and grassland 7 . Results Systematic paleontology Perissodactyla Owen, 1848 Paraceratheriidae Osborn, 1923 Paraceratherium Forster-Cooper, 1911 Paraceratherium linxiaense sp. nov. Type specimens A complete skull and mandible with the associated atlas (holotype, HMV 2006, Fig. 1 ), and an axis and two thoracic vertebrae of another individual (paratype, HMV 2007, Fig. 2 ), which are preserved at the Hezheng Paleozoological Museum in Hezheng County, Gansu Province, China. HMV 2006 represents a full adult individual. The specific name, linxiaense, refers to the geographical location of the discovery in the Linxia Basin (Fig. 3 ). Fig. 1: Holotype (HMV 2006) of Paraceratherium linxiaense sp. nov. Skull: a lateral view; b ventral view; c dorsal view; d anterior view; e occipital view. Mandible: f , h lateral view and medial view of left ramus, respectively; g occlusal view. Skull and mandible share the scale bar, but both anterior and nuchal views have an independent scale bar. Full size image Fig. 2: Vertebrae of Paraceratherium linxiaense . a atlas (HMV 2006); b axis (HMV 2007); c 4 th –5 th articulated thoracic vertebrae (HMV 2007). 1, right view; 2, posterior view; 3, left view; 4, dorsal view; 5, anterior view; 6, ventral view; 7, postero-ventral view. The articular facets on 4 th -5 th thoracic vertebrae are marked with the red semitransparent outline whatever it is intact or has been damaged. Full size image Fig. 3: Type locality of Paraceratherium linxiaense . Map showing the giant rhino fossil locality of the Linxia Basin in Wangjiachuan Village, Dongxiang County, Gansu Province, China. Full size image Type locality and horizon IVPP locality LX1808 (N35°35’05.16”, E103°18’51.02”; 1983 m above sea level, Fig. 4 ) is near the village of Wangjiachuan, 10.8 km southwest of the town of Dongxiang County, Linxia Hui Autonomous Prefecture, Gansu Province, China (Fig. 3 ). HMV 2006 and 2007 are from the sandstones in the lower part of the Jiaozigou Formation (Fig. 5 , Supplementary Note 1 ). Fig. 4: Type horizon of Paraceratherium linxiaense . Exposures of fluvial and lacustrine sediments of the Linxia Basin (LX 1808) at the type locality of this new species (HMV 2006, yellow square) and where the axis and thoracic vertebrae were also found in Wangjiachuan Village, Dongxiang County, Gansu Province, China. Full size image Fig. 5: Cenozoic section of the Linxia Basin. Deposits with correlation to ATNTS 2012 49 (left) for the magnetostratigraphic results 50 (middle) and the Wangjiachuan section bearing the fossils of Paraceratherium linxiaense sp. nov. (right). Full size image Age IVPP locality LX1808 is faunally and paleomagnetically dated to the middle of chron C8r with an estimated age of 26.5 million years ago (Ma) in the late Oligocene (Fig. 5 ). Diagnosis Paraceratherium linxiaense possesses features that characterize the genus, such as a giant body size, long premaxillae with anterior ends extending downward, separated parietal crests, high condyle compared to the height of nuchal surface,<|im_end|> <|im_start|>assistant The giant rhino, Paraceratherium, is considered the largest land mammal that ever lived and was mainly found in Asia, especially China, Mongolia, Kazakhstan, and Pakistan. How this genus dispersed across Asia was long a mystery, however. A new discovery has now shed light on this process. Prof. Deng Tao from the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences and his collaborators from China and the U.S.A. recently reported a new species Paraceratherium linxiaense sp. nov., which offers important clues to the dispersal of giant rhinos across Asia. The study was published in Communications Biology on June 17. The new species' fossils comprise a completely preserved skull and mandible with their associated atlas, as well as an axis and two thoracic vertebrae from another individual. The fossils were recovered from the Late Oligocene deposits of the Linxia Basin in Gansu Province, China, which is located on the northeastern border of the Tibetan Plateau. Phylogenetic analysis yielded a single most parsimonious tree, which places P. linxiaense as a derived giant rhino, within the monophyletic clade of the Oligocene Asian Paraceratherium. Within the Paraceratherium clade, the researchers' phylogenetic analysis produced a series of progressively more-derived species—from P. grangeri, through P. huangheense, P. asiaticum, and P. bugtiense—finally terminating in P. lepidum and P. linxiaense. P. linxiaense is at a high level of specialization, similar to P. lepidum, and both are derived from P. bugtiense. Distribution and migration of Paraceratherium in the Oligocene Eurasia. Localities of the early Oligocene species were marked by the yellow color, and the red indicates the late Oligocene species. Credit: IVPP Adaptation of the atlas and axis to the large body and long neck of the giant rhino already characterized P. grangeri and P. bugtiense, and was further developed in P. linxiaense, whose atlas is elongated, indicative of a long neck and higher axis with a nearly horizontal position for its posterior articular face. These features are correlated with a more flexible neck. The giant rhino of western Pakistan is from the Oligocene strata, representing a single species, Paraceratherium bugtiense. On the other hand, the rest of the genus Paraceratherium, which is distributed across the Mongolian Plateau, northwestern China, and the area north of the Tibetan Plateau to Kazakhstan, is highly diversified. The researchers found that all six species of Paraceratherium are sisters to Aralotherium and form a monophyletic clade in which P. grangeri is the most primitive, succeeded by P. huangheense and P. asiaticum. The researchers were thus able to determine that, in the Early Oligocene, P. asiaticum dispersed westward to Kazakhstan and its descendant lineage expanded to South Asia as P. bugtiense. In the Late Oligocene, Paraceratherium returned northward, crossing the Tibetan area to produce P. lepidium to the west in Kazakhstan and P. linxiaense to the east in the Linxia Basin. Ecological reconstruction of giant rhinos and their accompanying fauna in the Linxia Basin during the Oligocene. Credit: Chen Yu The researchers noted the aridity of the Early Oligocene in Central Asia at a time when South Asia was relatively moist, with a mosaic of forested and open landscapes. "Late Oligocene tropical conditions allowed the giant rhino to return northward to Central Asia, implying that the Tibetan region was still not uplifted as a high-elevation plateau," said Prof. Deng. During the Oligocene, the giant rhino could obviously disperse freely from the Mongolian Plateau to South Asia along the eastern coast of the Tethys Ocean and perhaps through Tibet. The topographical possibility that the giant rhino crossed the Tibetan area to reach the Indian-Pakistani subcontinent in the Oligocene can also be supported by other evidence. Up to the Late Oligocene, the evolution and migration from P. bugtiense to P. linxiaense and P. lepidum show that the "Tibetan Plateau" was not yet a barrier to the movement of the largest land mammal. <|im_end|>

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507, 7864, 78782, 320, 30035, 13, 220, 20, 7609, 95452, 4366, 9779, 1894, 2411, 10006, 68294, 1137, 50326, 4519, 430, 70755, 279, 64677, 11, 1778, 439, 264, 14880, 2547, 1404, 11, 1317, 864, 2880, 484, 6043, 449, 37229, 10548, 33459, 45578, 11, 19180, 1370, 3978, 278, 1922, 37379, 11, 1579, 9955, 982, 7863, 311, 279, 2673, 315, 308, 1412, 278, 7479, 11, 128257, 198, 128256, 78191, 198, 791, 14880, 22408, 3394, 11, 4366, 9779, 1894, 2411, 11, 374, 6646, 279, 7928, 4363, 36041, 278, 430, 3596, 12439, 323, 574, 14918, 1766, 304, 13936, 11, 5423, 5734, 11, 91850, 11, 73537, 11, 323, 17076, 13, 2650, 420, 64677, 77810, 4028, 13936, 574, 1317, 264, 23347, 11, 4869, 13, 362, 502, 18841, 706, 1457, 25351, 3177, 389, 420, 1920, 13, 8626, 13, 92829, 60608, 505, 279, 10181, 315, 650, 14140, 65216, 12629, 63333, 323, 88507, 32329, 897, 2508, 320, 3166, 4505, 8, 315, 279, 8620, 16192, 315, 23199, 323, 813, 79119, 505, 5734, 323, 279, 549, 815, 885, 13, 6051, 5068, 264, 502, 9606, 4366, 9779, 1894, 2411, 10006, 68294, 1137, 993, 13, 6747, 2637, 902, 6209, 3062, 43775, 311, 279, 79835, 278, 315, 14880, 22408, 15570, 4028, 13936, 13, 578, 4007, 574, 4756, 304, 26545, 40023, 389, 5651, 220, 1114, 13, 578, 502, 9606, 6, 81473, 54350, 264, 6724, 34683, 35113, 323, 11837, 1260, 449, 872, 5938, 62032, 11, 439, 1664, 439, 459, 8183, 323, 1403, 73833, 94257, 5309, 51313, 68, 505, 2500, 3927, 13, 578, 81473, 1051, 26403, 505, 279, 36931, 507, 7864, 78782, 34751, 315, 279, 8732, 68294, 61358, 304, 480, 598, 84, 38894, 11, 5734, 11, 902, 374, 7559, 389, 279, 87244, 3973, 315, 279, 73074, 31403, 2933, 13, 93682, 86945, 5411, 6492, 58487, 264, 3254, 1455, 10364, 26490, 1245, 5021, 11, 902, 7634, 393, 13, 10006, 68294, 1137, 439, 264, 14592, 14880, 22408, 3394, 11, 2949, 279, 1647, 5237, 982, 29150, 1206, 1037, 315, 279, 507, 7864, 78782, 14875, 4366, 9779, 1894, 2411, 13, 25218, 279, 4366, 9779, 1894, 2411, 1206, 1037, 11, 279, 12074, 6, 37555, 86945, 5411, 6492, 9124, 264, 4101, 315, 72859, 810, 72286, 9606, 88958, 393, 13, 1099, 4091, 72, 11, 1555, 393, 13, 34065, 526, 383, 1137, 11, 393, 13, 47731, 780, 372, 11, 323, 393, 13, 10077, 10462, 1137, 2345, 40276, 71681, 304, 393, 13, 514, 10629, 372, 323, 393, 13, 10006, 68294, 1137, 13, 393, 13, 10006, 68294, 1137, 374, 520, 264, 1579, 2237, 315, 66979, 11, 4528, 311, 393, 13, 514, 10629, 372, 11, 323, 2225, 527, 14592, 505, 393, 13, 10077, 10462, 1137, 13, 35009, 323, 12172, 315, 4366, 9779, 1894, 2411, 304, 279, 507, 7864, 78782, 88177, 689, 13, 8949, 1385, 315, 279, 4216, 507, 7864, 78782, 9606, 1051, 13160, 555, 279, 14071, 1933, 11, 323, 279, 2579, 15151, 279, 3389, 507, 7864, 78782, 9606, 13, 16666, 25, 17244, 4505, 59531, 367, 315, 279, 62032, 323, 8183, 311, 279, 3544, 2547, 323, 1317, 13272, 315, 279, 14880, 22408, 3394, 2736, 32971, 393, 13, 1099, 4091, 72, 323, 393, 13, 10077, 10462, 1137, 11, 323, 574, 4726, 8040, 304, 393, 13, 10006, 68294, 1137, 11, 6832, 62032, 374, 74595, 660, 11, 64005, 315, 264, 1317, 13272, 323, 5190, 8183, 449, 264, 7154, 16600, 2361, 369, 1202, 46000, 1989, 24553, 3663, 13, 4314, 4519, 527, 49393, 449, 264, 810, 19303, 13272, 13, 578, 14880, 22408, 3394, 315, 19001, 17076, 374, 505, 279, 507, 7864, 78782, 610, 460, 11, 14393, 264, 3254, 9606, 11, 4366, 9779, 1894, 2411, 10077, 10462, 1137, 13, 1952, 279, 1023, 1450, 11, 279, 2800, 315, 279, 64677, 4366, 9779, 1894, 2411, 11, 902, 374, 4332, 4028, 279, 44539, 89108, 31403, 2933, 11, 10411, 31382, 5734, 11, 323, 279, 3158, 10411, 315, 279, 73074, 31403, 2933, 311, 73537, 11, 374, 7701, 85957, 13, 578, 12074, 1766, 430, 682, 4848, 9606, 315, 4366, 9779, 1894, 2411, 527, 30393, 311, 1676, 278, 1605, 2411, 323, 1376, 264, 1647, 5237, 982, 29150, 1206, 1037, 304, 902, 393, 13, 1099, 4091, 72, 374, 279, 1455, 28694, 11, 26399, 555, 393, 13, 34065, 526, 383, 1137, 323, 393, 13, 47731, 780, 372, 13, 578, 12074, 1051, 8617, 3025, 311, 8417, 430, 11, 304, 279, 23591, 507, 7864, 78782, 11, 393, 13, 47731, 780, 372, 77810, 9909, 1637, 311, 73537, 323, 1202, 76951, 65009, 17626, 311, 4987, 13936, 439, 393, 13, 10077, 10462, 1137, 13, 763, 279, 36931, 507, 7864, 78782, 11, 4366, 9779, 1894, 2411, 6052, 10411, 1637, 11, 27736, 279, 73074, 3158, 311, 8356, 393, 13, 514, 10629, 2411, 311, 279, 9909, 304, 73537, 323, 393, 13, 10006, 68294, 1137, 311, 279, 11226, 304, 279, 8732, 68294, 61358, 13, 37211, 5848, 43738, 315, 14880, 22408, 15570, 323, 872, 24442, 100014, 304, 279, 8732, 68294, 61358, 2391, 279, 507, 7864, 78782, 13, 16666, 25, 25507, 28372, 578, 12074, 10555, 279, 802, 19025, 315, 279, 23591, 507, 7864, 78782, 304, 10913, 13936, 520, 264, 892, 994, 4987, 13936, 574, 12309, 21147, 11, 449, 264, 71624, 315, 13952, 291, 323, 1825, 55890, 13, 330, 62557, 507, 7864, 78782, 35148, 4787, 5535, 279, 14880, 22408, 3394, 311, 471, 10411, 1637, 311, 10913, 13936, 11, 73967, 430, 279, 73074, 5654, 574, 2103, 539, 97547, 291, 439, 264, 1579, 5773, 44857, 65388, 1359, 1071, 8626, 13, 92829, 13, 12220, 279, 507, 7864, 78782, 11, 279, 14880, 22408, 3394, 1436, 14224, 834, 82344, 26662, 505, 279, 44539, 89108, 31403, 2933, 311, 4987, 13936, 3235, 279, 24024, 13962, 315, 279, 350, 774, 1065, 22302, 323, 8530, 1555, 45261, 13, 578, 1948, 32277, 13336, 430, 279, 14880, 22408, 3394, 28129, 279, 73074, 3158, 311, 5662, 279, 7904, 9483, 587, 40422, 1207, 75695, 304, 279, 507, 7864, 78782, 649, 1101, 387, 7396, 555, 1023, 6029, 13, 3216, 311, 279, 36931, 507, 7864, 78782, 11, 279, 15740, 323, 12172, 505, 393, 13, 10077, 10462, 1137, 311, 393, 13, 10006, 68294, 1137, 323, 393, 13, 514, 10629, 372, 1501, 430, 279, 330, 51, 581, 295, 276, 31403, 2933, 1, 574, 539, 3686, 264, 22881, 311, 279, 7351, 315, 279, 7928, 4363, 36041, 278, 13, 220, 128257, 198 ]

2,598

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The B-DNA double helix can dynamically accommodate G-C and A-T base pairs in either Watson–Crick or Hoogsteen configurations. Here, we show that G-C + (in which + indicates protonation) and A-U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result, N 1 -methyladenosine and N 1 -methylguanosine, which occur in DNA as a form of alkylation damage and in RNA as post-transcriptional modifications, have dramatically different consequences. Whereas they create G-C + and A-T Hoogsteen base pairs in duplex DNA, thereby maintaining the structural integrity of the double helix, they block base-pairing and induce local duplex melting in RNA. These observations provide a mechanism for disrupting RNA structure through post-transcriptional modifications. The different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help cells meet the opposing requirements of maintaining genome stability, on the one hand, and of dynamically modulating the structure of the epitranscriptome, on the other. Main The Watson–Crick (WC) double helix is the most common structural element in RNA and the dominant structure of genomic DNA. It provides the basis for templated replication, transcription, and translation, and it also serves as a scaffold that defines the 3D structure of DNA, RNA, and their protein complexes. The canonical double helices formed by RNA (A form) and DNA (B form) differ in several important respects ( Fig. 1a ). In B-form DNA (B-DNA), the five-membered deoxyribose ring is flexible and favors the C2′- endo sugar pucker ( Fig. 1a ). In contrast, owing to the sugar 2′-OH group, the sugar in A-RNA is more rigid and adopts an alternative C3′- endo conformation 1 , 2 ( Fig. 1a ). This conformation in turn brings the oxygen atoms (O5′ and O3′) adjoining sequential nucleotides closer, thus effectively compressing and rigidifying the A-form helix, widening its helical diameter, and displacing base pairs away from the helical axis 1 , 3 ( Fig. 1a ). In addition, B-DNA and A-RNA differ considerably with respect to their deformability, and B-DNA is generally more flexible 4 . The higher bendability of B-DNA than A-RNA is fundamentally important in many biochemical processes including the tight compaction of genome within the nucleus in higher-order organisms. Figure 1: Absence of detectable WC ⇌ HG exchange in A-RNA by NMR relaxation dispersion. ( a ) Comparison of A-form RNA (violet) and B-form (blue) DNA double helices. ( b ) WC and HG base pairs in dynamic equilibrium in B-DNA. Sites used for RD measurements are in orange. ( c ) A 6 -DNA and hp-A 6 -RNA duplexes with base pairs targeted in RD measurements highlighted. ( d ) Off-resonance RD profiles showing R 2 + R ex as a function of spin-lock offset ( Ω 2π −1 Hz, where Ω = Ω obs – ω RF ) and power ( ω SL 2π −1 Hz, in insets). Error bars, experimental uncertainty (s.d.) estimated from monoexponential fitting of n = 10 (A 6 -DNA) and n = 6 (hp-A 6 -RNA) independently measured peak intensities by using a Monte Carlo–based method (Online Methods ). The solid line represents a fit to two-state exchange 6 . Full size image Recently, NMR studies have uncovered a new dynamic property in canonical B-DNA; WC dG-dC and dA-dT base pairs exist in a dynamic equilibrium with alternative Hoogsteen (HG) base pairs 5 , 6 . An HG base pair is created by rotation of a WC purine base ∼ 180° around the glycosidic bond, so that it adopts a syn rather than anti conformation 5 ( Fig. 1b ). The two bases are also brought ∼ 2.0–2.5 Å closer, thus allowing formation of a unique set of hydrogen bonds ( Fig. 1b ). HG base pairs exist transiently (with typical lifetimes of 0.1–1 ms) and in low abundance (with populations typically <3%) in naked canonical B-DNA 6 , 7 . However, dA-dT and dG-dC + HG base pairs can become the dominant configuration (reviewed in ref. 8 ) in DNA–protein 9 and DNA–small molecule 10 complexes, in which these base pairs contribute to DNA recognition; in damaged nucleotides, in which they contribute to damage accommodation and repair 11 , 12 , 13 ; and in the active sites of translesion synthesis polymerases that use HG pairing to bypass damage during DNA replication 14 . Purine-purine HG base pairs have also been shown to play important roles in DNA replication errors and in DNA-damage accommodation and repair 15 , 16 . Here, we set out to study WC–HG dynamics in canonical A-RNA duplexes. We show that, unlike the canonical B-DNA double helix, rA-rU and rG-rC + HG base pairs are strongly disfavored in A-RNA duplexes. As a result, whereas the DNA double helix can absorb damaged nucleotides (such as N 1 -methyldeoxyadenosine (m 1 dA) and N 1 -methyldeoxyguanosine (m 1 dG)) that are incapable of forming WC base pairs by forming HG base pairs, the same methyl marks, N 1 -methyladenosine (m 1 rA) and N 1 -methylguanosine (m 1 rG), acting as a post-transcriptional modification in RNA, block base-pairing altogether. These phenomena provide a direct mechanism for potently modulating the structure of the epitranscriptome. Our results indicate that HG-dependent DNA biochemical transactions may not be as readily supported in RNA duplexes, and they identify a unique dynamic property in B-DNA that may help enhance its ability to function as the repository of genetic information. Results Absence of conformational exchange in A-RNA We used NMR spin relaxation in the rotating frame ( R 1ρ ) 17 , 18 , 19 to examine whether WC base pairs in A-RNA duplexes transiently adopt HG base pairs, as in B-DNA. A dynamic equilibrium between a dominant ground state (GS) and short-lived low-abundance 'excited state' (ES) conformation can lead to line-broadening of NMR resonances if the conformational exchange occurs on the microsecond-to-millisecond timescale. The R 1ρ experiment 17 measures this line-broadening contribution ( R ex ) to the transverse relaxation rate ( R 2 ) during a relaxation period in which", "role": "user" }, { "content": "A new study could explain why DNA and not RNA, its older chemical cousin, is the main repository of genetic information. The DNA double helix is a more forgiving molecule that can contort itself into different shapes to absorb chemical damage to the basic building blocks—A, G, C and T—of genetic code. In contrast, when RNA is in the form of a double helix it is so rigid and unyielding that rather than accommodating damaged bases, it falls apart completely. The research, published August 1, 2016 in the journal Nature Structural and Molecular Biology, underscores the dynamic nature of the DNA double helix, which is central to maintaining the stability of the genome and warding off ailments like cancer and aging. The finding will likely rewrite textbook coverage of the difference between the two purveyors of genetic information, DNA and RNA. \"There is an amazing complexity built into these simple beautiful structures, whole new layers or dimensions that we have been blinded to because we didn't have the tools to see them, until now,\" said Hashim M. Al-Hashimi, Ph.D., senior author of the study and professor of biochemistry at Duke University School of Medicine. DNA's famous double helix is often depicted as a spiral staircase, with two long strands twisted around each other and steps composed of four chemical building blocks called bases. Each of these bases contain rings of carbon, along with various configurations of nitrogen, oxygen, and hydrogen. The arrangement of these atoms allow G to pair with C and A to pair with T, like interlocking gears in an elegant machine. When Watson and Crick published their model of the DNA double helix in 1953, they predicted exactly how these pairs would fit together. Yet other researchers struggled to provide evidence of these so-called Watson-Crick base pairs. Then in 1959, a biochemist named Karst Hoogsteen took a picture of an A-T base pair that had a slightly skewed geometry, with one base rotated 180 degrees relative to the other. Since then, both Watson-Crick and Hoogsteen base pairs have been observed in still images of DNA. Five years ago, Al-Hashimi and his team showed that base pairs constantly morph back and forth between Watson-Crick and the Hoogsteen configurations in the DNA double helix. Al-Hashimi says that Hoogsteen base pairs typically show up when DNA is bound up by a protein or damaged by chemical insults. The DNA goes back to its more straightforward pairing when it is released from the protein or has repaired the damage to its bases. \"DNA seems to use these Hoogsteen base pairs to add another dimension to its structure, morphing into different shapes to achieve added functionality inside the cell,\" said Al-Hashimi. Al-Hashimi and his team wanted to know if the same phenomenon might also be occurring when RNA, the middleman between DNA and proteins, formed a double helix. Because these shifts in base pairing involve the movement of molecules at an atomic level, they are difficult to detect by conventional methods. Therefore, Al-Hashimi's graduate student Huiqing Zhou used a sophisticated imaging technique known as NMR relaxation dispersion to visualize these tiny changes. First, she designed two model double helices—one made of DNA and one made of RNA. Then, she used the NMR technique to track the flipping of individual G and A bases that make up the spiraling steps, pairing up according to Watson-Crick or Hoogsteen rules. Prior studies indicated that at any given time, one percent of the bases in the DNA double helix were morphing into Hoogsteen base pairs. But when Zhou looked at the corresponding RNA double helix, she found absolutely no detectable movement; the base pairs were all frozen in place, stuck in the Watson-Crick configuration. The researchers wondered if their model of RNA was an unusual exception or anomaly, so they designed a wide range of RNA molecules and tested them under a wide variety of conditions, but still none appeared to contort into the Hoogsteen configuration. They were concerned that the RNA might actually be forming Hoogsteen base pairs, but that they were happening so quickly that they weren't able to catch them in the act. Zhou added a chemical known as a methyl group to a specific spot on the bases to block Watson-Crick base pairing, so the RNA would be trapped in the Hoogsteen configuration. She was surprised to find that rather than connecting through Hoogsteen base pairs, the two strands of RNA came apart near the damage site. \"In DNA this modification is a form of damage, and it can readily be absorbed by flipping the base and forming a Hoogsteen base pair. In contrast, the same modification severely disrupts the double helical structure of RNA,\" said Zhou, who is lead author of the study. The team believes that RNA doesn't form Hoogsteen base pairs because its double helical structure (known as A-form) is more compressed than DNA's (B-form) structure. As a result, RNA can't flip one base without hitting another, or without moving around atoms, which would tear apart the helix. \"For something as fundamental as the double helix, it is amazing that we are discovering these basic properties so late in the game,\" said Al-Hashimi. \"We need to continue to zoom in to obtain a deeper understanding regarding these basic molecules of life.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The B-DNA double helix can dynamically accommodate G-C and A-T base pairs in either Watson–Crick or Hoogsteen configurations. Here, we show that G-C + (in which + indicates protonation) and A-U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result, N 1 -methyladenosine and N 1 -methylguanosine, which occur in DNA as a form of alkylation damage and in RNA as post-transcriptional modifications, have dramatically different consequences. Whereas they create G-C + and A-T Hoogsteen base pairs in duplex DNA, thereby maintaining the structural integrity of the double helix, they block base-pairing and induce local duplex melting in RNA. These observations provide a mechanism for disrupting RNA structure through post-transcriptional modifications. The different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help cells meet the opposing requirements of maintaining genome stability, on the one hand, and of dynamically modulating the structure of the epitranscriptome, on the other. Main The Watson–Crick (WC) double helix is the most common structural element in RNA and the dominant structure of genomic DNA. It provides the basis for templated replication, transcription, and translation, and it also serves as a scaffold that defines the 3D structure of DNA, RNA, and their protein complexes. The canonical double helices formed by RNA (A form) and DNA (B form) differ in several important respects ( Fig. 1a ). In B-form DNA (B-DNA), the five-membered deoxyribose ring is flexible and favors the C2′- endo sugar pucker ( Fig. 1a ). In contrast, owing to the sugar 2′-OH group, the sugar in A-RNA is more rigid and adopts an alternative C3′- endo conformation 1 , 2 ( Fig. 1a ). This conformation in turn brings the oxygen atoms (O5′ and O3′) adjoining sequential nucleotides closer, thus effectively compressing and rigidifying the A-form helix, widening its helical diameter, and displacing base pairs away from the helical axis 1 , 3 ( Fig. 1a ). In addition, B-DNA and A-RNA differ considerably with respect to their deformability, and B-DNA is generally more flexible 4 . The higher bendability of B-DNA than A-RNA is fundamentally important in many biochemical processes including the tight compaction of genome within the nucleus in higher-order organisms. Figure 1: Absence of detectable WC ⇌ HG exchange in A-RNA by NMR relaxation dispersion. ( a ) Comparison of A-form RNA (violet) and B-form (blue) DNA double helices. ( b ) WC and HG base pairs in dynamic equilibrium in B-DNA. Sites used for RD measurements are in orange. ( c ) A 6 -DNA and hp-A 6 -RNA duplexes with base pairs targeted in RD measurements highlighted. ( d ) Off-resonance RD profiles showing R 2 + R ex as a function of spin-lock offset ( Ω 2π −1 Hz, where Ω = Ω obs – ω RF ) and power ( ω SL 2π −1 Hz, in insets). Error bars, experimental uncertainty (s.d.) estimated from monoexponential fitting of n = 10 (A 6 -DNA) and n = 6 (hp-A 6 -RNA) independently measured peak intensities by using a Monte Carlo–based method (Online Methods ). The solid line represents a fit to two-state exchange 6 . Full size image Recently, NMR studies have uncovered a new dynamic property in canonical B-DNA; WC dG-dC and dA-dT base pairs exist in a dynamic equilibrium with alternative Hoogsteen (HG) base pairs 5 , 6 . An HG base pair is created by rotation of a WC purine base ∼ 180° around the glycosidic bond, so that it adopts a syn rather than anti conformation 5 ( Fig. 1b ). The two bases are also brought ∼ 2.0–2.5 Å closer, thus allowing formation of a unique set of hydrogen bonds ( Fig. 1b ). HG base pairs exist transiently (with typical lifetimes of 0.1–1 ms) and in low abundance (with populations typically <3%) in naked canonical B-DNA 6 , 7 . However, dA-dT and dG-dC + HG base pairs can become the dominant configuration (reviewed in ref. 8 ) in DNA–protein 9 and DNA–small molecule 10 complexes, in which these base pairs contribute to DNA recognition; in damaged nucleotides, in which they contribute to damage accommodation and repair 11 , 12 , 13 ; and in the active sites of translesion synthesis polymerases that use HG pairing to bypass damage during DNA replication 14 . Purine-purine HG base pairs have also been shown to play important roles in DNA replication errors and in DNA-damage accommodation and repair 15 , 16 . Here, we set out to study WC–HG dynamics in canonical A-RNA duplexes. We show that, unlike the canonical B-DNA double helix, rA-rU and rG-rC + HG base pairs are strongly disfavored in A-RNA duplexes. As a result, whereas the DNA double helix can absorb damaged nucleotides (such as N 1 -methyldeoxyadenosine (m 1 dA) and N 1 -methyldeoxyguanosine (m 1 dG)) that are incapable of forming WC base pairs by forming HG base pairs, the same methyl marks, N 1 -methyladenosine (m 1 rA) and N 1 -methylguanosine (m 1 rG), acting as a post-transcriptional modification in RNA, block base-pairing altogether. These phenomena provide a direct mechanism for potently modulating the structure of the epitranscriptome. Our results indicate that HG-dependent DNA biochemical transactions may not be as readily supported in RNA duplexes, and they identify a unique dynamic property in B-DNA that may help enhance its ability to function as the repository of genetic information. Results Absence of conformational exchange in A-RNA We used NMR spin relaxation in the rotating frame ( R 1ρ ) 17 , 18 , 19 to examine whether WC base pairs in A-RNA duplexes transiently adopt HG base pairs, as in B-DNA. A dynamic equilibrium between a dominant ground state (GS) and short-lived low-abundance 'excited state' (ES) conformation can lead to line-broadening of NMR resonances if the conformational exchange occurs on the microsecond-to-millisecond timescale. The R 1ρ experiment 17 measures this line-broadening contribution ( R ex ) to the transverse relaxation rate ( R 2 ) during a relaxation period in which<|im_end|> <|im_start|>assistant A new study could explain why DNA and not RNA, its older chemical cousin, is the main repository of genetic information. The DNA double helix is a more forgiving molecule that can contort itself into different shapes to absorb chemical damage to the basic building blocks—A, G, C and T—of genetic code. In contrast, when RNA is in the form of a double helix it is so rigid and unyielding that rather than accommodating damaged bases, it falls apart completely. The research, published August 1, 2016 in the journal Nature Structural and Molecular Biology, underscores the dynamic nature of the DNA double helix, which is central to maintaining the stability of the genome and warding off ailments like cancer and aging. The finding will likely rewrite textbook coverage of the difference between the two purveyors of genetic information, DNA and RNA. "There is an amazing complexity built into these simple beautiful structures, whole new layers or dimensions that we have been blinded to because we didn't have the tools to see them, until now," said Hashim M. Al-Hashimi, Ph.D., senior author of the study and professor of biochemistry at Duke University School of Medicine. DNA's famous double helix is often depicted as a spiral staircase, with two long strands twisted around each other and steps composed of four chemical building blocks called bases. Each of these bases contain rings of carbon, along with various configurations of nitrogen, oxygen, and hydrogen. The arrangement of these atoms allow G to pair with C and A to pair with T, like interlocking gears in an elegant machine. When Watson and Crick published their model of the DNA double helix in 1953, they predicted exactly how these pairs would fit together. Yet other researchers struggled to provide evidence of these so-called Watson-Crick base pairs. Then in 1959, a biochemist named Karst Hoogsteen took a picture of an A-T base pair that had a slightly skewed geometry, with one base rotated 180 degrees relative to the other. Since then, both Watson-Crick and Hoogsteen base pairs have been observed in still images of DNA. Five years ago, Al-Hashimi and his team showed that base pairs constantly morph back and forth between Watson-Crick and the Hoogsteen configurations in the DNA double helix. Al-Hashimi says that Hoogsteen base pairs typically show up when DNA is bound up by a protein or damaged by chemical insults. The DNA goes back to its more straightforward pairing when it is released from the protein or has repaired the damage to its bases. "DNA seems to use these Hoogsteen base pairs to add another dimension to its structure, morphing into different shapes to achieve added functionality inside the cell," said Al-Hashimi. Al-Hashimi and his team wanted to know if the same phenomenon might also be occurring when RNA, the middleman between DNA and proteins, formed a double helix. Because these shifts in base pairing involve the movement of molecules at an atomic level, they are difficult to detect by conventional methods. Therefore, Al-Hashimi's graduate student Huiqing Zhou used a sophisticated imaging technique known as NMR relaxation dispersion to visualize these tiny changes. First, she designed two model double helices—one made of DNA and one made of RNA. Then, she used the NMR technique to track the flipping of individual G and A bases that make up the spiraling steps, pairing up according to Watson-Crick or Hoogsteen rules. Prior studies indicated that at any given time, one percent of the bases in the DNA double helix were morphing into Hoogsteen base pairs. But when Zhou looked at the corresponding RNA double helix, she found absolutely no detectable movement; the base pairs were all frozen in place, stuck in the Watson-Crick configuration. The researchers wondered if their model of RNA was an unusual exception or anomaly, so they designed a wide range of RNA molecules and tested them under a wide variety of conditions, but still none appeared to contort into the Hoogsteen configuration. They were concerned that the RNA might actually be forming Hoogsteen base pairs, but that they were happening so quickly that they weren't able to catch them in the act. Zhou added a chemical known as a methyl group to a specific spot on the bases to block Watson-Crick base pairing, so the RNA would be trapped in the Hoogsteen configuration. She was surprised to find that rather than connecting through Hoogsteen base pairs, the two strands of RNA came apart near the damage site. "In DNA this modification is a form of damage, and it can readily be absorbed by flipping the base and forming a Hoogsteen base pair. In contrast, the same modification severely disrupts the double helical structure of RNA," said Zhou, who is lead author of the study. The team believes that RNA doesn't form Hoogsteen base pairs because its double helical structure (known as A-form) is more compressed than DNA's (B-form) structure. As a result, RNA can't flip one base without hitting another, or without moving around atoms, which would tear apart the helix. "For something as fundamental as the double helix, it is amazing that we are discovering these basic properties so late in the game," said Al-Hashimi. "We need to continue to zoom in to obtain a deeper understanding regarding these basic molecules of life." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE 2 ) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE 2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE 2 inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections. Main Therapeutic treatments to control or cure chronic viral infections such as HIV are in great need. Those capable of boosting the antigen-specific T cell response without excessive immunopathology would offer the most clinical promise. Many viruses that establish chronic infection have evolved strategies to evade immune detection. However, an equally important process is the host-driven immune suppression that attenuates antiviral immunity to limit immunopathology. This autoregulation is especially notable for activated CTLs, which by nature cause collateral damage 1 , 2 , 3 . Several negative CTL regulators have been identified in association with HCV, HBV and HIV infection in humans and lymphocytic choriomeningitis virus clone 13 (LCMV-CL13) infection in mice, including regulatory T cells (T reg cells), transforming growth factor β (TGF-β), interleukin 10 (IL-10), and the inhibitory receptors PD-1, TIM-3, CTLA-4 and LAG-3 (refs. 1 , 2 , 3 ). Although the expression of inhibitory molecules is part of the normal autoregulatory machinery observed in all activated CTLs, over time the persistence of antigen and inhibitory receptor signaling can impair the proliferation, survival and effector function of CTLs (a process commonly referred to as exhaustion) or lead to physical depletion of certain epitope-specific CTL populations 1 , 2 , 3 . In these circumstances, the ability of CTLs to produce cytokines and kill infected targets is inversely proportional to viral load 4 , 5 . Although CTL exhaustion contributes to viral persistence while limiting immunopathology during chronic infection, it also helps virus-specific CTLs persist by diminishing activation-induced T cell death 6 , 7 , 8 . Exhausted CTLs are also present in tumors 9 , 10 , 11 . The blockade of inhibitory pathways such as the PD-1, IL-10 and TGF-β pathways can boost CTL numbers and effector functions in the face of chronic infection and cancer 7 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . The discovery of additional factors that govern CTL exhaustion might lead to more efficacious treatments. Here we identify an important role for PGE 2 in suppressing CTL survival and function during chronic LCMV infection. PGE 2 is a lipid synthesized from arachidonic acid by the sequential actions of cyclooxygenases (COX-1 and/or -2) and PGE synthases (PGESs). Microsomal PGES 1 (mPGES1), encoded by Ptges , is likely the most relevant PGES during inflammation and infection in mice and is also found in humans 18 , 19 . PGE 2 has a paradoxical role in immune responses, acting as both a proinflammatory mediator 20 and a potent immunosuppressant, especially in tumors and type I immune responses to limit the functions of natural killer (NK) cells, CD4 and CTLs 19 , 21 , 22 . In tumors, PGE 2 induces IL-10, T reg cells and myeloid-derived suppressor cells 20 , 23 , 24 , 25 . In CTLs, PGE 2 suppresses proliferation, cytotoxicity and IFNγ production in vitro 19 , and the use of COX-2 inhibitors to treat mice infected with murine leukemic retrovirus RadLV-Rs restored T cell proliferative responses 26 . In this study we found that the increased expression of the PGE 2 receptors EP2 ( Ptger2 ) and EP4 ( Ptger4 ) on virus-specific CTLs contributed to functional exhaustion and viral persistence in LCMV-CL13–infected mice, and that the PGE 2 signaling pathway is a promising target of therapeutic intervention, either on its own or with PD-1 blockade. Results CTLs upregulate EP2 and EP4 during chronic infection Whole-genome expression profiling of exhausted CTLs revealed that virus-specific CTLs upregulate the expression of several inhibitory receptors, including the PGE 2 receptors EP2 and EP4, during chronic LCMV-CL13 infection 4 . Using quantitative PCR (qPCR), we confirmed that the expression of Ptger2 and Ptger4 increased over the duration of LCMV-CL13 infection relative to expression in cells from naive and LCMV-Armstrong (Arm)-infected mice ( Supplementary Fig. 1 ). CTLs expressing very high levels of PD-1 during chronic viral infection have been shown to be more functionally exhausted than those expressing intermediate levels 27 , 28 , 29 . To determine whether the amount of Ptger2 or Ptger4 expressed in the virus-specific CTLs correlated with PD-1 expression, we isolated PD-1 hi and PD-1 intermediate CTLs from LCMV-CL13–infected animals and assessed the amounts of Ptger2 and Ptger4 mRNA by qPCR. We found that PD-1 hi CTLs expressed twofold higher levels of both Ptger2 and Ptger4 mRNA than their PD-1 intermediate counterparts ( Fig. 1a ). Thus, the expression of EP2 and EP4 directly correlated with PD-1 expression and was higher on the more terminally exhausted CTL subset. Figure 1: PGE 2 signaling directly suppresses CTL function via the receptors EP2 and EP4 during LCMV infection. ( a ) Expression of Ptger2 and Ptger4 mRNA was measured using qRT-PCR in PD-1 hi CD44 hi CD8 + and PD-1 int CD44 hi CD8 + T cells from LCMV-CL13–infected mice at day 21 p.i. Data are from two independent experiments with a total of 13", "role": "user" }, { "content": "A Yale-led team has identified a promising new combination immunotherapy to enhance the body's ability to fight chronic viral infections and possibly cancer. Their study was published March 23 in Nature Medicine. Viruses that cause chronic infection, such as HIV and Hepatitis B and C, are able to persist in the body despite attack from T cells, the body's main line of defense against pathogens. They persist because, over time, our T cells weaken to the point of \"T-cell exhaustion.\" To circumvent this process, the research team—led by Susan Kaech, associate professor of immunobiology at Yale School of Medicine—investigated two pathways that cause T cell suppression. The first pathway is triggered by prostaglandin E2 (PGE2), a lipid known to suppress the immune system's response to tumors. To explore the relationship between PGE2 and T cells, the research team studied mice with viral infections and observed that PGE2 levels increased, particularly during chronic infection. The enhanced PGE2 reduced both the number of T cells that attack the infected cells and their anti-viral functions. As Kaech explained, T cells have receptors keeping them in balance by telling them to either stop or go. \"What we have discovered is that PGE2 is another type of receptor giving a stop signal,\" said Kaech, who is also a member of Yale Cancer Center. In fact, when the team studied mice lacking PGE2 receptors, or the ability to synthesize normal amounts of PGE2, T cells thrived. The researchers next tested the combined effect of systemically reducing PGE2 while simultaneously blocking another pathway known as PD-1. In previous studies, PD-1 had also been shown to inhibit T cells. The researchers treated virus-infected mice lacking normal PGE2 production with anti-PD-1 antibodies, and observed that the combined blockade of PGE2 and PD-1 resulted in even greater increased T-cell function and enhanced viral control. \"Blocking both pathways leads to an augmentation of the antiviral response that is bigger than either treatment alone,\" Kaech explained. In a final step, the researchers found they could achieve the same boost to T cells by administering celecoxib (Celebrex), a non-steroidal anti-inflammatory drug (NSAID) commonly used to manage pain. \"Since these inhibitors are already in common use, we wondered if using them to decrease PGE2 signaling would also improve T-cell responses,\" said Jonathan Chen, first author on the study and a resident in pathology at Massachusetts General Hospital. One important implication of the study is the potential use of NSAIDs as adjunct therapy to treat patients with chronic infections and cancer. \"By administering a medicine many of us take routinely, we could potentially augment the effects of PD-1 blockade, which is showing remarkable outcomes in cancer trials,\" said Kaech. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE 2 ) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE 2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE 2 inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections. Main Therapeutic treatments to control or cure chronic viral infections such as HIV are in great need. Those capable of boosting the antigen-specific T cell response without excessive immunopathology would offer the most clinical promise. Many viruses that establish chronic infection have evolved strategies to evade immune detection. However, an equally important process is the host-driven immune suppression that attenuates antiviral immunity to limit immunopathology. This autoregulation is especially notable for activated CTLs, which by nature cause collateral damage 1 , 2 , 3 . Several negative CTL regulators have been identified in association with HCV, HBV and HIV infection in humans and lymphocytic choriomeningitis virus clone 13 (LCMV-CL13) infection in mice, including regulatory T cells (T reg cells), transforming growth factor β (TGF-β), interleukin 10 (IL-10), and the inhibitory receptors PD-1, TIM-3, CTLA-4 and LAG-3 (refs. 1 , 2 , 3 ). Although the expression of inhibitory molecules is part of the normal autoregulatory machinery observed in all activated CTLs, over time the persistence of antigen and inhibitory receptor signaling can impair the proliferation, survival and effector function of CTLs (a process commonly referred to as exhaustion) or lead to physical depletion of certain epitope-specific CTL populations 1 , 2 , 3 . In these circumstances, the ability of CTLs to produce cytokines and kill infected targets is inversely proportional to viral load 4 , 5 . Although CTL exhaustion contributes to viral persistence while limiting immunopathology during chronic infection, it also helps virus-specific CTLs persist by diminishing activation-induced T cell death 6 , 7 , 8 . Exhausted CTLs are also present in tumors 9 , 10 , 11 . The blockade of inhibitory pathways such as the PD-1, IL-10 and TGF-β pathways can boost CTL numbers and effector functions in the face of chronic infection and cancer 7 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . The discovery of additional factors that govern CTL exhaustion might lead to more efficacious treatments. Here we identify an important role for PGE 2 in suppressing CTL survival and function during chronic LCMV infection. PGE 2 is a lipid synthesized from arachidonic acid by the sequential actions of cyclooxygenases (COX-1 and/or -2) and PGE synthases (PGESs). Microsomal PGES 1 (mPGES1), encoded by Ptges , is likely the most relevant PGES during inflammation and infection in mice and is also found in humans 18 , 19 . PGE 2 has a paradoxical role in immune responses, acting as both a proinflammatory mediator 20 and a potent immunosuppressant, especially in tumors and type I immune responses to limit the functions of natural killer (NK) cells, CD4 and CTLs 19 , 21 , 22 . In tumors, PGE 2 induces IL-10, T reg cells and myeloid-derived suppressor cells 20 , 23 , 24 , 25 . In CTLs, PGE 2 suppresses proliferation, cytotoxicity and IFNγ production in vitro 19 , and the use of COX-2 inhibitors to treat mice infected with murine leukemic retrovirus RadLV-Rs restored T cell proliferative responses 26 . In this study we found that the increased expression of the PGE 2 receptors EP2 ( Ptger2 ) and EP4 ( Ptger4 ) on virus-specific CTLs contributed to functional exhaustion and viral persistence in LCMV-CL13–infected mice, and that the PGE 2 signaling pathway is a promising target of therapeutic intervention, either on its own or with PD-1 blockade. Results CTLs upregulate EP2 and EP4 during chronic infection Whole-genome expression profiling of exhausted CTLs revealed that virus-specific CTLs upregulate the expression of several inhibitory receptors, including the PGE 2 receptors EP2 and EP4, during chronic LCMV-CL13 infection 4 . Using quantitative PCR (qPCR), we confirmed that the expression of Ptger2 and Ptger4 increased over the duration of LCMV-CL13 infection relative to expression in cells from naive and LCMV-Armstrong (Arm)-infected mice ( Supplementary Fig. 1 ). CTLs expressing very high levels of PD-1 during chronic viral infection have been shown to be more functionally exhausted than those expressing intermediate levels 27 , 28 , 29 . To determine whether the amount of Ptger2 or Ptger4 expressed in the virus-specific CTLs correlated with PD-1 expression, we isolated PD-1 hi and PD-1 intermediate CTLs from LCMV-CL13–infected animals and assessed the amounts of Ptger2 and Ptger4 mRNA by qPCR. We found that PD-1 hi CTLs expressed twofold higher levels of both Ptger2 and Ptger4 mRNA than their PD-1 intermediate counterparts ( Fig. 1a ). Thus, the expression of EP2 and EP4 directly correlated with PD-1 expression and was higher on the more terminally exhausted CTL subset. Figure 1: PGE 2 signaling directly suppresses CTL function via the receptors EP2 and EP4 during LCMV infection. ( a ) Expression of Ptger2 and Ptger4 mRNA was measured using qRT-PCR in PD-1 hi CD44 hi CD8 + and PD-1 int CD44 hi CD8 + T cells from LCMV-CL13–infected mice at day 21 p.i. Data are from two independent experiments with a total of 13<|im_end|> <|im_start|>assistant A Yale-led team has identified a promising new combination immunotherapy to enhance the body's ability to fight chronic viral infections and possibly cancer. Their study was published March 23 in Nature Medicine. Viruses that cause chronic infection, such as HIV and Hepatitis B and C, are able to persist in the body despite attack from T cells, the body's main line of defense against pathogens. They persist because, over time, our T cells weaken to the point of "T-cell exhaustion." To circumvent this process, the research team—led by Susan Kaech, associate professor of immunobiology at Yale School of Medicine—investigated two pathways that cause T cell suppression. The first pathway is triggered by prostaglandin E2 (PGE2), a lipid known to suppress the immune system's response to tumors. To explore the relationship between PGE2 and T cells, the research team studied mice with viral infections and observed that PGE2 levels increased, particularly during chronic infection. The enhanced PGE2 reduced both the number of T cells that attack the infected cells and their anti-viral functions. As Kaech explained, T cells have receptors keeping them in balance by telling them to either stop or go. "What we have discovered is that PGE2 is another type of receptor giving a stop signal," said Kaech, who is also a member of Yale Cancer Center. In fact, when the team studied mice lacking PGE2 receptors, or the ability to synthesize normal amounts of PGE2, T cells thrived. The researchers next tested the combined effect of systemically reducing PGE2 while simultaneously blocking another pathway known as PD-1. In previous studies, PD-1 had also been shown to inhibit T cells. The researchers treated virus-infected mice lacking normal PGE2 production with anti-PD-1 antibodies, and observed that the combined blockade of PGE2 and PD-1 resulted in even greater increased T-cell function and enhanced viral control. "Blocking both pathways leads to an augmentation of the antiviral response that is bigger than either treatment alone," Kaech explained. In a final step, the researchers found they could achieve the same boost to T cells by administering celecoxib (Celebrex), a non-steroidal anti-inflammatory drug (NSAID) commonly used to manage pain. "Since these inhibitors are already in common use, we wondered if using them to decrease PGE2 signaling would also improve T-cell responses," said Jonathan Chen, first author on the study and a resident in pathology at Massachusetts General Hospital. One important implication of the study is the potential use of NSAIDs as adjunct therapy to treat patients with chronic infections and cancer. "By administering a medicine many of us take routinely, we could potentially augment the effects of PD-1 blockade, which is showing remarkable outcomes in cancer trials," said Kaech. <|im_end|>

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2,084

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Aims/hypothesis Sex differences in macrovascular disease, especially in stroke, are observed across studies of epidemiology. We studied a large sample of patients with type 2 diabetes to better understand the relationship between glycaemic control and stroke risk. Methods We prospectively investigated the sex-specific association between different levels of HbA 1c and incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes. Results During a mean follow-up of 6.7 years, 2,949 incident cases of stroke were identified. The multivariable-adjusted HRs of stroke associated with different levels of HbA 1c at baseline (HbA 1c <6.0% [<42 mmol/mol], 6.0–6.9% [42–52 mmol/mol] [reference group], 7.0–7.9% [53–63 mmol/mol], 8.0–8.9% [64–74 mmol/mol], 9.0–9.9% [75–85 mmol/mol] and ≥10.0% [≥86 mmol/mol]) were 0.96 (95% CI 0.80, 1.14), 1.00, 1.04 (0.85, 1.28), 1.11 (0.89, 1.39), 1.10 (0.86, 1.41) and 1.22 (0.92, 1.35) ( p for trend = 0.66) for men, and 1.03 (0.90, 1.18), 1.00, 1.09 (0.94, 1.26), 1.19 (1.00, 1.42), 1.32 (1.09, 1.59) and 1.42 (1.23, 1.65) ( p for trend <0.001) for women, respectively. The graded association between HbA 1c during follow-up and stroke risk was observed among women ( p for trend = 0.066). When stratified by race, whether with or without glucose-lowering agents, this graded association of HbA 1c with stroke was still present among women. When stratified by age, the adjusted HRs were significantly higher in women older than 55 years compared with younger women. Conclusions/interpretation The current study suggests a graded association between HbA 1c and the risk of stroke among women with type 2 diabetes. Poor control of blood sugar has a stronger effect in diabetic women older than 55 years. Working on a manuscript? Avoid the common mistakes Introduction Stroke is a leading cause of disability, cognitive impairment and death in the USA and accounts for 1.7% of national health expenditures [ 1 ]. In the USA, nearly 32,000 more women than men died of stroke in 2000, and this number is predicted to be 68,000 in 2050 [ 2 ]. Sex differences in stroke are observed across epidemiological studies, pathophysiology, treatments and outcomes. These sex differences have profound implications for the effective prevention and treatment of stroke. An increased knowledge of stroke risk factors in the population may lead to an improved prevention of stroke. Epidemiological studies have reported that type 2 diabetes is an independent risk factor for stroke [ 3 – 7 ], but how much its effect varies by sex is uncertain. Some studies have shown that type 2 diabetes may have a stronger effect on stroke risk in women [ 3 , 4 , 8 – 10 ], but one study showed a greater effect in men [ 11 ]. Because randomised clinical trials (RCTs) and meta-analyses have failed to show the benefit of intensive glucose control on rates of stroke [ 12 ], and with the under-representation of females in RCTs [ 13 ], more observational data are needed to assess whether there is a sex-specific association between HbA 1c and the risk of stroke. The aim of the present study was to examine whether the associations between HbA 1c at baseline and during follow-up and the risk of incident stroke are different between men and women with type 2 diabetes in the Louisiana State University Hospital-Based Longitudinal Study (LSUHLS). Methods Study population LSU Health Care Services Division (LSU HCSD) operates seven public hospitals and affiliated clinics in Louisiana, which provide quality medical care regardless of the patient’s income or insurance coverage [ 14 – 22 ]. Since 1997, administrative, anthropometric, laboratory, clinical diagnosis and medication data have been available in electronic form. The LSUHLS was established in 2010 by using these data [ 14 ]. Using ICD-9 ( ) (code 250), we established a cohort of diabetic patients who used LSU HCSD hospitals from 1 January 1999 to 31 December 2009. All diabetic patients in the LSU HCSD hospitals were diagnosed using the American Diabetes Association (ADA) criteria: a fasting plasma glucose ≥7.0 mmol/l or 2 h glucose ≥11.1 mmol/l after a 75 g 2 h oral OGTT, or a patient with classic symptoms plus a random plasma glucose level of ≥11.1 mmol/l [ 23 ]. In the present study, we only included patients who had newly diagnosed diabetes. Before the diagnosis of diabetes, these patients had used the LSU HSCD system for a mean of 5.0 years (range 2–11 years). We have carried out a validated study for the diagnosis of diabetes in LSU HCSD hospitals [ 14 ], and 20,919 patients from a sample of 21,566 hospital discharge diagnoses based on ICD-9 codes also had physician-confirmed diabetes using the ADA diabetes criteria (the agreement being 97%) [ 23 ]. After excluding individuals with a history of stroke or CHD at baseline and patients with incomplete data on any of the required variables for analysis, the sample included 30,154 patients with type 2 diabetes (10,876 male and 19,278 female). Both the Pennington Biomedical Research Center and LSU Health Sciences Center Institutional Review Boards, LSU System, approved this study and analysis plan. Informed consent was not obtained from the participants involved in our study because we used pseudo-anonymised data compiled from electronic medical records. Baseline and follow-up measurements The patients’ characteristics, including demographic factors (age of diagnosis of diabetes, sex, race/ethnicity, family income, smoking status and types of health insurance), risk factors (body weight, height, BMI, blood pressure, HbA 1c , total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols, estimated GFR [eGFR]) and information on medication (cholesterol-lowering, antihypertensive and glucose-lowering drugs) within a half year after the diagnosis of diabetes (baseline) and during follow-up after the diabetes diagnosis (follow-up) were extracted from the electronic medical records. The calculation of updated mean values of HbA 1c , LDL-cholesterol, BMI, blood pressure and eGFR were performed as previously described [ 24 , 25 ]. The average number of HbA 1c measurements during the follow-up period was 7.7. Prospective follow-up We obtained follow-up information on the clinical diagnosis (date of diagnosis, diagnosis code, priority assigned", "role": "user" }, { "content": "New research published in Diabetologia shows that diabetes in women is associated with an increased risk of stroke, whereas the data do not show the same association among men. The research is by Dr Wenhui Zhao (the first author), Dr Gang Hu and colleagues at the Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA. Differences in incidence and mortality between sexes have been reported for various conditions, including stroke. More women than men tend to die from stroke in developed countries. For example, in the USA, 77,109 women and 52,367 men died from stroke in 2010. Women accounted for almost 60% of US stroke deaths in 2010. In the UK, 32,828 women and 20,358 men died from stroke in 2007. The authors prospectively investigated the sex-specific association of different levels of HbA1c with incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes in the Louisiana State University Hospital-Based Longitudinal Study (LSUHLS). During a mean follow up of 6.7 years, 2,949 incident cases of stroke were identified. The authors calculated the risk of stroke associated with different levels of HbA1c at baseline (<6.0%, 6.0 ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Aims/hypothesis Sex differences in macrovascular disease, especially in stroke, are observed across studies of epidemiology. We studied a large sample of patients with type 2 diabetes to better understand the relationship between glycaemic control and stroke risk. Methods We prospectively investigated the sex-specific association between different levels of HbA 1c and incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes. Results During a mean follow-up of 6.7 years, 2,949 incident cases of stroke were identified. The multivariable-adjusted HRs of stroke associated with different levels of HbA 1c at baseline (HbA 1c <6.0% [<42 mmol/mol], 6.0–6.9% [42–52 mmol/mol] [reference group], 7.0–7.9% [53–63 mmol/mol], 8.0–8.9% [64–74 mmol/mol], 9.0–9.9% [75–85 mmol/mol] and ≥10.0% [≥86 mmol/mol]) were 0.96 (95% CI 0.80, 1.14), 1.00, 1.04 (0.85, 1.28), 1.11 (0.89, 1.39), 1.10 (0.86, 1.41) and 1.22 (0.92, 1.35) ( p for trend = 0.66) for men, and 1.03 (0.90, 1.18), 1.00, 1.09 (0.94, 1.26), 1.19 (1.00, 1.42), 1.32 (1.09, 1.59) and 1.42 (1.23, 1.65) ( p for trend <0.001) for women, respectively. The graded association between HbA 1c during follow-up and stroke risk was observed among women ( p for trend = 0.066). When stratified by race, whether with or without glucose-lowering agents, this graded association of HbA 1c with stroke was still present among women. When stratified by age, the adjusted HRs were significantly higher in women older than 55 years compared with younger women. Conclusions/interpretation The current study suggests a graded association between HbA 1c and the risk of stroke among women with type 2 diabetes. Poor control of blood sugar has a stronger effect in diabetic women older than 55 years. Working on a manuscript? Avoid the common mistakes Introduction Stroke is a leading cause of disability, cognitive impairment and death in the USA and accounts for 1.7% of national health expenditures [ 1 ]. In the USA, nearly 32,000 more women than men died of stroke in 2000, and this number is predicted to be 68,000 in 2050 [ 2 ]. Sex differences in stroke are observed across epidemiological studies, pathophysiology, treatments and outcomes. These sex differences have profound implications for the effective prevention and treatment of stroke. An increased knowledge of stroke risk factors in the population may lead to an improved prevention of stroke. Epidemiological studies have reported that type 2 diabetes is an independent risk factor for stroke [ 3 – 7 ], but how much its effect varies by sex is uncertain. Some studies have shown that type 2 diabetes may have a stronger effect on stroke risk in women [ 3 , 4 , 8 – 10 ], but one study showed a greater effect in men [ 11 ]. Because randomised clinical trials (RCTs) and meta-analyses have failed to show the benefit of intensive glucose control on rates of stroke [ 12 ], and with the under-representation of females in RCTs [ 13 ], more observational data are needed to assess whether there is a sex-specific association between HbA 1c and the risk of stroke. The aim of the present study was to examine whether the associations between HbA 1c at baseline and during follow-up and the risk of incident stroke are different between men and women with type 2 diabetes in the Louisiana State University Hospital-Based Longitudinal Study (LSUHLS). Methods Study population LSU Health Care Services Division (LSU HCSD) operates seven public hospitals and affiliated clinics in Louisiana, which provide quality medical care regardless of the patient’s income or insurance coverage [ 14 – 22 ]. Since 1997, administrative, anthropometric, laboratory, clinical diagnosis and medication data have been available in electronic form. The LSUHLS was established in 2010 by using these data [ 14 ]. Using ICD-9 ( ) (code 250), we established a cohort of diabetic patients who used LSU HCSD hospitals from 1 January 1999 to 31 December 2009. All diabetic patients in the LSU HCSD hospitals were diagnosed using the American Diabetes Association (ADA) criteria: a fasting plasma glucose ≥7.0 mmol/l or 2 h glucose ≥11.1 mmol/l after a 75 g 2 h oral OGTT, or a patient with classic symptoms plus a random plasma glucose level of ≥11.1 mmol/l [ 23 ]. In the present study, we only included patients who had newly diagnosed diabetes. Before the diagnosis of diabetes, these patients had used the LSU HSCD system for a mean of 5.0 years (range 2–11 years). We have carried out a validated study for the diagnosis of diabetes in LSU HCSD hospitals [ 14 ], and 20,919 patients from a sample of 21,566 hospital discharge diagnoses based on ICD-9 codes also had physician-confirmed diabetes using the ADA diabetes criteria (the agreement being 97%) [ 23 ]. After excluding individuals with a history of stroke or CHD at baseline and patients with incomplete data on any of the required variables for analysis, the sample included 30,154 patients with type 2 diabetes (10,876 male and 19,278 female). Both the Pennington Biomedical Research Center and LSU Health Sciences Center Institutional Review Boards, LSU System, approved this study and analysis plan. Informed consent was not obtained from the participants involved in our study because we used pseudo-anonymised data compiled from electronic medical records. Baseline and follow-up measurements The patients’ characteristics, including demographic factors (age of diagnosis of diabetes, sex, race/ethnicity, family income, smoking status and types of health insurance), risk factors (body weight, height, BMI, blood pressure, HbA 1c , total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols, estimated GFR [eGFR]) and information on medication (cholesterol-lowering, antihypertensive and glucose-lowering drugs) within a half year after the diagnosis of diabetes (baseline) and during follow-up after the diabetes diagnosis (follow-up) were extracted from the electronic medical records. The calculation of updated mean values of HbA 1c , LDL-cholesterol, BMI, blood pressure and eGFR were performed as previously described [ 24 , 25 ]. The average number of HbA 1c measurements during the follow-up period was 7.7. Prospective follow-up We obtained follow-up information on the clinical diagnosis (date of diagnosis, diagnosis code, priority assigned<|im_end|> <|im_start|>assistant New research published in Diabetologia shows that diabetes in women is associated with an increased risk of stroke, whereas the data do not show the same association among men. The research is by Dr Wenhui Zhao (the first author), Dr Gang Hu and colleagues at the Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA. Differences in incidence and mortality between sexes have been reported for various conditions, including stroke. More women than men tend to die from stroke in developed countries. For example, in the USA, 77,109 women and 52,367 men died from stroke in 2010. Women accounted for almost 60% of US stroke deaths in 2010. In the UK, 32,828 women and 20,358 men died from stroke in 2007. The authors prospectively investigated the sex-specific association of different levels of HbA1c with incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes in the Louisiana State University Hospital-Based Longitudinal Study (LSUHLS). During a mean follow up of 6.7 years, 2,949 incident cases of stroke were identified. The authors calculated the risk of stroke associated with different levels of HbA1c at baseline (<6.0%, 6.0 <|im_end|>

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1,884

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses 1 , 2 , 3 , 4 , 5 , 6 . Although pathological innate immune activation is well-documented in severe disease 1 , the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling 7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes. Main Humoral immunity has dichotomous roles in COVID-19. Although neutralizing antibodies protect against SARS-CoV-2 infection 8 , 9 , growing evidence suggests that dysregulated humoral immunity also contributes to the characteristic immunopathology of COVID-19 10 , 11 , 12 , 13 , 14 , 15 , 16 . Recent reports have identified isolated autoantibody reactivities in patients with COVID-19, including reactivities that are characteristic of systemic autoimmune diseases 11 , 12 , 13 , 14 , 15 . Importantly, some autoantibodies—particularly neutralizing autoantibodies against type I interferons (IFNs)—appear to directly contribute to COVID-19 pathophysiology by antagonizing innate antiviral responses 11 , 12 . Although notable examples of disease-modifying autoantibody responses have previously been described, the full breadth of autoantibody reactivities in COVID-19 remains undetermined, as does their immunological and clinical effects. A particularly important class of autoantibodies are those that target the exoproteome. Exoproteome-targeting autoantibodies can exert a wide range of functional effects, such as the perturbation of cell signalling (as with the case of autoantibodies against type I IFNs 11 , 12 ) and targeted killing of specific cell populations via Fc receptors (FcR) and/or complement. We thus sought to identify functional autoantibody responses in patients with COVID-19 by screening for autoantibody reactivities against the human exoproteome. Widespread autoantibody increases in COVID-19 To discover functional autoantibodies that could influence the outcome of COVID-19, we used a high-throughput autoantibody discovery method known as rapid extracellular antigen profiling (REAP) 7 . REAP enables the highly multiplexed detection of antibody reactivities through the biopanning of IgG from patients against a genetically barcoded library of 2,770 human extracellular proteins displayed on the surface of yeast, converting an antibody–antigen binding event into a quantitative sequencing readout (the REAP score) on the basis of the enrichment of the barcodes of each protein (Extended Data Fig. 1a ). To allow for the detection of antibodies against coronavirus proteins, we additionally included the receptor-binding domain (RBD) of SARS-CoV-2 and other common coronaviruses in the library (a full antigen list is provided in Supplementary Table 1 ). We used REAP to screen samples from patients infected with SARS-CoV-2 who were prospectively followed as part of the ‘Yale Implementing Medical and Public Health Action Against Coronavirus CT’ (IMPACT) study (Extended Data Fig. 1b ). This cohort includes 172 patients who were seen at Yale–New Haven Hospital with a range of clinical severities (as previously reported 1 ) and 22 healthcare workers who had mild illness or asymptomatic infection. We screened longitudinal samples for a subset of the cohort. As a control, we screened 30 healthcare workers who tested negative for SARS-CoV-2 by qPCR with reverse transcription (RT–qPCR) throughout their follow-up period in the IMPACT study. Patient demographics can be found in Extended Data Table 1 . To validate the performance of REAP, we compared antibody reactivity to SARS-CoV-2 RBD using REAP to that evaluated using enzyme-linked immunosorbent assays (ELISAs) (Extended Data Fig. 1c ), and also compared IL-6R REAP reactivity in patients who received anti-IL-6R therapeutic antibodies with those who did not (Extended Data Fig. 1d ). We found a strong concordance between REAP scores for SARS-CoV-2 RBD and ELISA positivity for SARS-CoV-2 RBD, as well as between IL-6R REAP scores and anti-IL-6R treatment. Next, we examined the total degree of autoreactivity in patients by quantifying the number of autoantibodies at different REAP score thresholds. Irrespective of the REAP score cut off we used, patients with COVID-19 had a greater number of reactivities compared to uninfected individuals, and the highest scoring reactivities were preferentially enriched in patients with severe disease (Fig. 1a, b , Extended Data Fig. 2a ). There was not a statistically significant difference in days from symptom onset between patients with severe or moderate COVID-19 (Extended Data Fig. 2b ), which suggests that the effects of temporal confounding were minimal. As sex differences in the immune response to SARS-CoV-2 have previously been reported 17 , we compared the number of autoantibody reactivities between men and women with COVID-19 and found no significant differences in reactivity numbers at any score cut off (Extended Data Fig. 2c ). Finally, in a comparison with the REAP profiles of patients with systemic lupus erythematosus (SLE) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), patients with COVID-19 had greater numbers of reactivities than did individuals with SLE but fewer numbers of reactivities than did individuals with APECED (Extended Data Fig. 2d ). The demographics and clinical characteristics of patients with SLE or APECED have previously been described 7 . Altogether, these results indicate that autoantibodies that target the exoproteome are increased in COVID-19. Fig. 1: Immune-targeting autoantibodies are increased in patients with COVID-19. a , Heat map of REAP scores for immune-related proteins and RBDs of the", "role": "user" }, { "content": "The development of antibodies to the COVID-19 virus has been the great long-term hope of ending the pandemic. However, immune system turncoats are also major culprits in severe cases of COVID-19, Yale scientists report in the journal Nature. These autoantibodies target and react with a person's tissues or organs similar to ones that cause autoimmune diseases such as lupus or rheumatoid arthritis. In COVID-19 cases they can attack healthy tissue in brain, blood vessels, platelets, liver, and the gastrointestinal tract, researchers report. The more autoantibodies detected, the greater the disease severity experienced by patients. And the autoantibodies paradoxically also target and interfere with many immune system proteins that are designed to fend off infections, the study found. \"It's a two-edge sword,\" said Aaron Ring, assistant professor of immunobiology at Yale and senior author of the paper. \"Antibodies are crucial to fend off infection, but some COVID-19 patients also develop antibodies that damage their own cells and tissues.\" It is clear that in many cases the presence of coronavirus drove the creation of the damaging autoantibodies, Ring said. But it is also likely that some COVID-19 patients had pre-existing autoantibodies that made them more susceptible to infection, he said. Mice with these same autoantibodies were more susceptible to infection by the COVID-19 virus and more likely to die, the authors report. The existence of these long-lived rogue autoantibodies could also help explain why some people infected with COVID-19 can later develop lasting medical symptoms, so-called long COVID cases. \"This could be the unfortunate legacy of the virus,\" Ring said. \"Our findings reinforce the importance of getting vaccinated,\" added co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale. \"The fact that even mild infections are associated with autoantibody production underscores the potential for long-term health consequences of COVID-19.\" For the study, Ring's lab worked with Iwasaki's lab and members of the Yale IMPACT team—a group of scientists, scholars, and physicians developing research and clinical efforts to combat COVID-19—to screen blood samples from 194 patients who had contracted the virus, with varying degrees of severity, for the presence of autoantibodies. Specifically, they used a novel technology developed by Ring's lab called Rapid Extracellular Antigen Profiling (REAP) to identify autoantibody interactions with nearly 3,000 human proteins. Ring said the findings may lead to strategies to treat or prevent the damaging effects of autoantibodies in COVID-19 patients. In addition, the new REAP technology could be used to pinpoint important antibody responses for many other disease conditions beyond COVID-19. Ring's lab has found a host of novel autoantibodies in patients with autoimmune disease and is now searching for autoantibodies in patients with cancer and neurological illnesses. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses 1 , 2 , 3 , 4 , 5 , 6 . Although pathological innate immune activation is well-documented in severe disease 1 , the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling 7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes. Main Humoral immunity has dichotomous roles in COVID-19. Although neutralizing antibodies protect against SARS-CoV-2 infection 8 , 9 , growing evidence suggests that dysregulated humoral immunity also contributes to the characteristic immunopathology of COVID-19 10 , 11 , 12 , 13 , 14 , 15 , 16 . Recent reports have identified isolated autoantibody reactivities in patients with COVID-19, including reactivities that are characteristic of systemic autoimmune diseases 11 , 12 , 13 , 14 , 15 . Importantly, some autoantibodies—particularly neutralizing autoantibodies against type I interferons (IFNs)—appear to directly contribute to COVID-19 pathophysiology by antagonizing innate antiviral responses 11 , 12 . Although notable examples of disease-modifying autoantibody responses have previously been described, the full breadth of autoantibody reactivities in COVID-19 remains undetermined, as does their immunological and clinical effects. A particularly important class of autoantibodies are those that target the exoproteome. Exoproteome-targeting autoantibodies can exert a wide range of functional effects, such as the perturbation of cell signalling (as with the case of autoantibodies against type I IFNs 11 , 12 ) and targeted killing of specific cell populations via Fc receptors (FcR) and/or complement. We thus sought to identify functional autoantibody responses in patients with COVID-19 by screening for autoantibody reactivities against the human exoproteome. Widespread autoantibody increases in COVID-19 To discover functional autoantibodies that could influence the outcome of COVID-19, we used a high-throughput autoantibody discovery method known as rapid extracellular antigen profiling (REAP) 7 . REAP enables the highly multiplexed detection of antibody reactivities through the biopanning of IgG from patients against a genetically barcoded library of 2,770 human extracellular proteins displayed on the surface of yeast, converting an antibody–antigen binding event into a quantitative sequencing readout (the REAP score) on the basis of the enrichment of the barcodes of each protein (Extended Data Fig. 1a ). To allow for the detection of antibodies against coronavirus proteins, we additionally included the receptor-binding domain (RBD) of SARS-CoV-2 and other common coronaviruses in the library (a full antigen list is provided in Supplementary Table 1 ). We used REAP to screen samples from patients infected with SARS-CoV-2 who were prospectively followed as part of the ‘Yale Implementing Medical and Public Health Action Against Coronavirus CT’ (IMPACT) study (Extended Data Fig. 1b ). This cohort includes 172 patients who were seen at Yale–New Haven Hospital with a range of clinical severities (as previously reported 1 ) and 22 healthcare workers who had mild illness or asymptomatic infection. We screened longitudinal samples for a subset of the cohort. As a control, we screened 30 healthcare workers who tested negative for SARS-CoV-2 by qPCR with reverse transcription (RT–qPCR) throughout their follow-up period in the IMPACT study. Patient demographics can be found in Extended Data Table 1 . To validate the performance of REAP, we compared antibody reactivity to SARS-CoV-2 RBD using REAP to that evaluated using enzyme-linked immunosorbent assays (ELISAs) (Extended Data Fig. 1c ), and also compared IL-6R REAP reactivity in patients who received anti-IL-6R therapeutic antibodies with those who did not (Extended Data Fig. 1d ). We found a strong concordance between REAP scores for SARS-CoV-2 RBD and ELISA positivity for SARS-CoV-2 RBD, as well as between IL-6R REAP scores and anti-IL-6R treatment. Next, we examined the total degree of autoreactivity in patients by quantifying the number of autoantibodies at different REAP score thresholds. Irrespective of the REAP score cut off we used, patients with COVID-19 had a greater number of reactivities compared to uninfected individuals, and the highest scoring reactivities were preferentially enriched in patients with severe disease (Fig. 1a, b , Extended Data Fig. 2a ). There was not a statistically significant difference in days from symptom onset between patients with severe or moderate COVID-19 (Extended Data Fig. 2b ), which suggests that the effects of temporal confounding were minimal. As sex differences in the immune response to SARS-CoV-2 have previously been reported 17 , we compared the number of autoantibody reactivities between men and women with COVID-19 and found no significant differences in reactivity numbers at any score cut off (Extended Data Fig. 2c ). Finally, in a comparison with the REAP profiles of patients with systemic lupus erythematosus (SLE) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), patients with COVID-19 had greater numbers of reactivities than did individuals with SLE but fewer numbers of reactivities than did individuals with APECED (Extended Data Fig. 2d ). The demographics and clinical characteristics of patients with SLE or APECED have previously been described 7 . Altogether, these results indicate that autoantibodies that target the exoproteome are increased in COVID-19. Fig. 1: Immune-targeting autoantibodies are increased in patients with COVID-19. a , Heat map of REAP scores for immune-related proteins and RBDs of the<|im_end|> <|im_start|>assistant The development of antibodies to the COVID-19 virus has been the great long-term hope of ending the pandemic. However, immune system turncoats are also major culprits in severe cases of COVID-19, Yale scientists report in the journal Nature. These autoantibodies target and react with a person's tissues or organs similar to ones that cause autoimmune diseases such as lupus or rheumatoid arthritis. In COVID-19 cases they can attack healthy tissue in brain, blood vessels, platelets, liver, and the gastrointestinal tract, researchers report. The more autoantibodies detected, the greater the disease severity experienced by patients. And the autoantibodies paradoxically also target and interfere with many immune system proteins that are designed to fend off infections, the study found. "It's a two-edge sword," said Aaron Ring, assistant professor of immunobiology at Yale and senior author of the paper. "Antibodies are crucial to fend off infection, but some COVID-19 patients also develop antibodies that damage their own cells and tissues." It is clear that in many cases the presence of coronavirus drove the creation of the damaging autoantibodies, Ring said. But it is also likely that some COVID-19 patients had pre-existing autoantibodies that made them more susceptible to infection, he said. Mice with these same autoantibodies were more susceptible to infection by the COVID-19 virus and more likely to die, the authors report. The existence of these long-lived rogue autoantibodies could also help explain why some people infected with COVID-19 can later develop lasting medical symptoms, so-called long COVID cases. "This could be the unfortunate legacy of the virus," Ring said. "Our findings reinforce the importance of getting vaccinated," added co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale. "The fact that even mild infections are associated with autoantibody production underscores the potential for long-term health consequences of COVID-19." For the study, Ring's lab worked with Iwasaki's lab and members of the Yale IMPACT team—a group of scientists, scholars, and physicians developing research and clinical efforts to combat COVID-19—to screen blood samples from 194 patients who had contracted the virus, with varying degrees of severity, for the presence of autoantibodies. Specifically, they used a novel technology developed by Ring's lab called Rapid Extracellular Antigen Profiling (REAP) to identify autoantibody interactions with nearly 3,000 human proteins. Ring said the findings may lead to strategies to treat or prevent the damaging effects of autoantibodies in COVID-19 patients. In addition, the new REAP technology could be used to pinpoint important antibody responses for many other disease conditions beyond COVID-19. Ring's lab has found a host of novel autoantibodies in patients with autoimmune disease and is now searching for autoantibodies in patients with cancer and neurological illnesses. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant is highly transmissible with potential immune escape. We conducted a test-negative case–control study to evaluate mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with Omicron or Delta. The large, diverse study population included 26,683 SARS-CoV-2 test-positive cases with variants determined by S gene target failure status (16% Delta and 84% Omicron). The two-dose VE against Omicron infection at 14–90 days was 44.0% (95% confidence interval, 35.1–51.6%) but declined quickly. The three-dose VE was 93.7% (92.2–94.9%) and 86.0% (78.1–91.1%) against Delta infection and 71.6% (69.7–73.4%) and 47.4% (40.5–53.5%) against Omicron infection at 14–60 days and >60 days, respectively. The three-dose VE was 29.4% (0.3–50.0%) against Omicron infection in immunocompromised individuals. The three-dose VE against hospitalization with Delta or Omicron was >99% across the entire study population. Our findings demonstrate high, durable three-dose VE against Delta infection but lower effectiveness against Omicron infection, particularly among immunocompromised people. However, three-dose VE of mRNA-1273 was high against hospitalization with Delta and Omicron variants. Main The SARS-CoV-2 Omicron (B.1.1.529) variant that emerged in December 2021 contains multiple novel spike protein mutations, raising concerns about escape from naturally acquired or vaccine-elicited immunity 1 . Several in vitro studies reported reduced vaccine-induced neutralization activity against Omicron 2 , 3 . Specifically, sera from individuals vaccinated with two doses of mRNA Coronavirus Disease 2019 (COVID-19) vaccines, including mRNA-1273 (Moderna), showed substantial reductions in neutralization activity against Omicron compared to wild-type SARS-CoV-2 (refs. 2 , 4 , 5 ). However, an mRNA-1273 booster increased neutralization activity against Omicron, albeit lower than wild-type 2 , 3 . We previously reported high and durable VE of mRNA-1273 against infection and hospitalization from COVID-19 caused by other emerging SARS-CoV-2 variants, including Delta (B.1.617.2) 6 . Although limited data are available on real-world VE of mRNA-1273 against Omicron, an analysis of a US pharmacy-based testing program found that the likelihood of vaccination with three mRNA-1273 vaccine doses (versus unvaccinated) was significantly lower among Omicron symptomatic infections (odds ratio (OR) = 0.31) than SARS-CoV-2-negative controls 7 . Another US study during an Omicron-predominant period found that receipt of a third mRNA vaccine dose was 90% effective in preventing COVID-19-associated hospitalization 8 . As the Omicron BA.1 sub-lineage has a deletion at positions 69–70, initial Omicron-positive specimens exhibit S gene target failure (SGTF). To provide timely results for these analyses, we used SGTF as a marker for Omicron in specimens collected during December 2021. The US Food and Drug Administration (FDA) and World Health Organization advised that SGTF from select COVID-19 RT–PCR assays, including the Thermo Fisher TaqPath COVID-19 Combo Kits, can be used as a screening method for Omicron; 9 , 10 SGTF has served as a proxy in the United Kingdom for identifying Omicron 11 , 12 . In Southern California, where Delta was the dominant strain before Omicron 13 and the proportion of SGTF among SARS-CoV-2-positive specimens increased from 1.2% to 94.1% from 6 December 2021 to 31 December 2021, SGTF can be used as a proxy for Omicron sub-lineage BA.1, whereas positive specimens negative for SGTF can be considered Delta. Using electronic health records (EHRs) from the Kaiser Permanente Southern California (KPSC) healthcare system in the United States, we conducted a test-negative case–control study to evaluate the VE of mRNA-1273 against infection and hospitalization with Omicron and Delta. Results The study included 26,683 cases with SGTF status available. Based on whole-genome sequencing (WGS) results received for a subset of 1,383 positive specimens, we confirmed that all 704 cases exhibiting SGTF were Omicron (100%), and 673 of the 679 SGTF-negative cases were Delta (99.1%), with a kappa of 0.991. The sensitivity and specificity of SGTF in predicting Omicron was 99.2% and 100%, respectively. Of the 26,683 cases, 11,483 (43.0%) individuals were unvaccinated (2,883 Delta and 8,600 Omicron), and 15,200 (57.0%) individuals were vaccinated with mRNA-1273 (1,431 Delta and 13,769 Omicron; 416 vaccinated with one dose, 12,029 vaccinated with two doses and 2,755 vaccinated with three doses). The flow chart depicting the selection steps is provided (Fig. 1 ). The distribution of covariates by test outcomes, separated by variant type, is summarized in Table 1 (two-dose and three-dose analyses) and Supplementary Table 1 (one-dose analysis). Fig. 1: Flowchart of selection of cases and controls. Steps for selection of 26,683 cases and 109,662 controls by inclusion and exclusion criteria and subsequent matching in one-dose, two-dose and three-dose analyses. Full size image Table 1 Characteristics of SARS-CoV-2 cases and controls by variant Full size table Omicron cases more frequently had a history of COVID-19 (SARS-CoV-2 infection) than Delta cases. In the two-dose and three-dose analyses, 13.6% and 15.4% of Omicron cases in the two-dose and three-dose analyses, respectively, had a history of COVID-19 (SARS-CoV-2 infection) versus 2.5% and 3.0% of Delta cases (Table 1 ). Table 2 shows VE against Delta and Omicron infection or hospitalization. Overall, the one-dose VE was 56.7% (95% confidence interval (CI), 40.7–68.4%) and 20.4% (9.5–30.0%) against Delta and Omicron infection, respectively. Table 2 VE of mRNA-1273 against infection and hospitalization with Delta or Omicron variants Full size table In analyses of two-dose VE against Delta infection by time since receipt of dose 2, VE at 14–90 days was 80.2% (68.2–87.7%) and subsequently declined, with VE of 68.9% (60.1–75.8%) at 91–180 days, 63.7% (59.8–67.2%) at 181–270 days and 61.3% (55.0–66.7%) at >270 days (Table 2 and Fig. 2 ). In comparison, the two-dose VE against Omicron infection was 44.0% (35.1–51.6%) at 14–90 days and declined quickly to 23.5% (16.4–30.0%) at 91–180 days, 13.8% (10.2–17.3%) at 181–270 days and 5.9% (0.4–11.0%) at >270 days. The three-dose VE against Delta infection was 93.7% (92.2–94.9%) at 14–60 days and 86.0% (78.1–91.1%) at >60 days. However, the three-dose VE against Omicron infection was 71.6% (69.7–73.4%) at 14–60 days and 47.4% (40.5–53.5%) at >60 days. These estimates were similar in analyses that excluded individuals who were immunocompromised, except that the three-dose VE against Omicron infection increased to 51.2% (44.2–57.3%) among immunocompetent individuals at >60 days", "role": "user" }, { "content": "New Kaiser Permanente research published February 21, 2022 in Nature Medicine shows that while Moderna COVID-19 vaccine protection is strong against coronavirus infection by the Delta variant, it is not as strong against infection from the Omicron variant. Three doses of the Moderna COVID-19 vaccine were highly effective against hospitalization caused by infection from either the Omicron or Delta variant. This study was conducted within the racially and ethnically diverse membership of Kaiser Permanente in Southern California using specimens collected between December 6 and December 31, 2021. It included 26,683 patients who tested positive for COVID-19, 16% of whom had Delta infections and 84% of whom had Omicron infections, and more than 67,000 individuals who tested negative as a comparison group. Specimens were primarily collected using nasopharyngeal or oropharyngeal swabs for people with COVID-19 symptoms and saliva for people who did not have symptoms. Two doses of the Moderna COVID-19 vaccine were 44% effective against Omicron infection within 3 months after vaccination, and effectiveness quickly declined thereafter.Three doses of the Moderna COVID-19 vaccine within 2 months of vaccination were 94% effective against Delta infection and 72% effective against Omicron infection. For people who had compromised immune systems, 3-dose effectiveness against Omicron infection was lower at 29%. The 3-dose effectiveness against hospitalization with Delta or with Omicron was above 99%. \"Our results suggest that third doses may be needed sooner than 6 months after the second dose of the Moderna COVID-19 vaccine to protect against Omicron infection,\" said Hung Fu Tseng, Ph.D., a researcher with the Kaiser Permanente Southern California Department of Research & Evaluation and a faculty member of Kaiser Permanente Bernard J. Tyson School of Medicine, both located in Pasadena, Calif. \"And that 3 doses may be inadequate to protect people who are immunocompromised from Omicron infection.\" He added that \"reassuringly, 3 doses provide strong protection against COVID-19 hospitalization due to either the Omicron or Delta variant.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant is highly transmissible with potential immune escape. We conducted a test-negative case–control study to evaluate mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with Omicron or Delta. The large, diverse study population included 26,683 SARS-CoV-2 test-positive cases with variants determined by S gene target failure status (16% Delta and 84% Omicron). The two-dose VE against Omicron infection at 14–90 days was 44.0% (95% confidence interval, 35.1–51.6%) but declined quickly. The three-dose VE was 93.7% (92.2–94.9%) and 86.0% (78.1–91.1%) against Delta infection and 71.6% (69.7–73.4%) and 47.4% (40.5–53.5%) against Omicron infection at 14–60 days and >60 days, respectively. The three-dose VE was 29.4% (0.3–50.0%) against Omicron infection in immunocompromised individuals. The three-dose VE against hospitalization with Delta or Omicron was >99% across the entire study population. Our findings demonstrate high, durable three-dose VE against Delta infection but lower effectiveness against Omicron infection, particularly among immunocompromised people. However, three-dose VE of mRNA-1273 was high against hospitalization with Delta and Omicron variants. Main The SARS-CoV-2 Omicron (B.1.1.529) variant that emerged in December 2021 contains multiple novel spike protein mutations, raising concerns about escape from naturally acquired or vaccine-elicited immunity 1 . Several in vitro studies reported reduced vaccine-induced neutralization activity against Omicron 2 , 3 . Specifically, sera from individuals vaccinated with two doses of mRNA Coronavirus Disease 2019 (COVID-19) vaccines, including mRNA-1273 (Moderna), showed substantial reductions in neutralization activity against Omicron compared to wild-type SARS-CoV-2 (refs. 2 , 4 , 5 ). However, an mRNA-1273 booster increased neutralization activity against Omicron, albeit lower than wild-type 2 , 3 . We previously reported high and durable VE of mRNA-1273 against infection and hospitalization from COVID-19 caused by other emerging SARS-CoV-2 variants, including Delta (B.1.617.2) 6 . Although limited data are available on real-world VE of mRNA-1273 against Omicron, an analysis of a US pharmacy-based testing program found that the likelihood of vaccination with three mRNA-1273 vaccine doses (versus unvaccinated) was significantly lower among Omicron symptomatic infections (odds ratio (OR) = 0.31) than SARS-CoV-2-negative controls 7 . Another US study during an Omicron-predominant period found that receipt of a third mRNA vaccine dose was 90% effective in preventing COVID-19-associated hospitalization 8 . As the Omicron BA.1 sub-lineage has a deletion at positions 69–70, initial Omicron-positive specimens exhibit S gene target failure (SGTF). To provide timely results for these analyses, we used SGTF as a marker for Omicron in specimens collected during December 2021. The US Food and Drug Administration (FDA) and World Health Organization advised that SGTF from select COVID-19 RT–PCR assays, including the Thermo Fisher TaqPath COVID-19 Combo Kits, can be used as a screening method for Omicron; 9 , 10 SGTF has served as a proxy in the United Kingdom for identifying Omicron 11 , 12 . In Southern California, where Delta was the dominant strain before Omicron 13 and the proportion of SGTF among SARS-CoV-2-positive specimens increased from 1.2% to 94.1% from 6 December 2021 to 31 December 2021, SGTF can be used as a proxy for Omicron sub-lineage BA.1, whereas positive specimens negative for SGTF can be considered Delta. Using electronic health records (EHRs) from the Kaiser Permanente Southern California (KPSC) healthcare system in the United States, we conducted a test-negative case–control study to evaluate the VE of mRNA-1273 against infection and hospitalization with Omicron and Delta. Results The study included 26,683 cases with SGTF status available. Based on whole-genome sequencing (WGS) results received for a subset of 1,383 positive specimens, we confirmed that all 704 cases exhibiting SGTF were Omicron (100%), and 673 of the 679 SGTF-negative cases were Delta (99.1%), with a kappa of 0.991. The sensitivity and specificity of SGTF in predicting Omicron was 99.2% and 100%, respectively. Of the 26,683 cases, 11,483 (43.0%) individuals were unvaccinated (2,883 Delta and 8,600 Omicron), and 15,200 (57.0%) individuals were vaccinated with mRNA-1273 (1,431 Delta and 13,769 Omicron; 416 vaccinated with one dose, 12,029 vaccinated with two doses and 2,755 vaccinated with three doses). The flow chart depicting the selection steps is provided (Fig. 1 ). The distribution of covariates by test outcomes, separated by variant type, is summarized in Table 1 (two-dose and three-dose analyses) and Supplementary Table 1 (one-dose analysis). Fig. 1: Flowchart of selection of cases and controls. Steps for selection of 26,683 cases and 109,662 controls by inclusion and exclusion criteria and subsequent matching in one-dose, two-dose and three-dose analyses. Full size image Table 1 Characteristics of SARS-CoV-2 cases and controls by variant Full size table Omicron cases more frequently had a history of COVID-19 (SARS-CoV-2 infection) than Delta cases. In the two-dose and three-dose analyses, 13.6% and 15.4% of Omicron cases in the two-dose and three-dose analyses, respectively, had a history of COVID-19 (SARS-CoV-2 infection) versus 2.5% and 3.0% of Delta cases (Table 1 ). Table 2 shows VE against Delta and Omicron infection or hospitalization. Overall, the one-dose VE was 56.7% (95% confidence interval (CI), 40.7–68.4%) and 20.4% (9.5–30.0%) against Delta and Omicron infection, respectively. Table 2 VE of mRNA-1273 against infection and hospitalization with Delta or Omicron variants Full size table In analyses of two-dose VE against Delta infection by time since receipt of dose 2, VE at 14–90 days was 80.2% (68.2–87.7%) and subsequently declined, with VE of 68.9% (60.1–75.8%) at 91–180 days, 63.7% (59.8–67.2%) at 181–270 days and 61.3% (55.0–66.7%) at >270 days (Table 2 and Fig. 2 ). In comparison, the two-dose VE against Omicron infection was 44.0% (35.1–51.6%) at 14–90 days and declined quickly to 23.5% (16.4–30.0%) at 91–180 days, 13.8% (10.2–17.3%) at 181–270 days and 5.9% (0.4–11.0%) at >270 days. The three-dose VE against Delta infection was 93.7% (92.2–94.9%) at 14–60 days and 86.0% (78.1–91.1%) at >60 days. However, the three-dose VE against Omicron infection was 71.6% (69.7–73.4%) at 14–60 days and 47.4% (40.5–53.5%) at >60 days. These estimates were similar in analyses that excluded individuals who were immunocompromised, except that the three-dose VE against Omicron infection increased to 51.2% (44.2–57.3%) among immunocompetent individuals at >60 days<|im_end|> <|im_start|>assistant New Kaiser Permanente research published February 21, 2022 in Nature Medicine shows that while Moderna COVID-19 vaccine protection is strong against coronavirus infection by the Delta variant, it is not as strong against infection from the Omicron variant. Three doses of the Moderna COVID-19 vaccine were highly effective against hospitalization caused by infection from either the Omicron or Delta variant. This study was conducted within the racially and ethnically diverse membership of Kaiser Permanente in Southern California using specimens collected between December 6 and December 31, 2021. It included 26,683 patients who tested positive for COVID-19, 16% of whom had Delta infections and 84% of whom had Omicron infections, and more than 67,000 individuals who tested negative as a comparison group. Specimens were primarily collected using nasopharyngeal or oropharyngeal swabs for people with COVID-19 symptoms and saliva for people who did not have symptoms. Two doses of the Moderna COVID-19 vaccine were 44% effective against Omicron infection within 3 months after vaccination, and effectiveness quickly declined thereafter.Three doses of the Moderna COVID-19 vaccine within 2 months of vaccination were 94% effective against Delta infection and 72% effective against Omicron infection. For people who had compromised immune systems, 3-dose effectiveness against Omicron infection was lower at 29%. The 3-dose effectiveness against hospitalization with Delta or with Omicron was above 99%. "Our results suggest that third doses may be needed sooner than 6 months after the second dose of the Moderna COVID-19 vaccine to protect against Omicron infection," said Hung Fu Tseng, Ph.D., a researcher with the Kaiser Permanente Southern California Department of Research & Evaluation and a faculty member of Kaiser Permanente Bernard J. Tyson School of Medicine, both located in Pasadena, Calif. "And that 3 doses may be inadequate to protect people who are immunocompromised from Omicron infection." He added that "reassuringly, 3 doses provide strong protection against COVID-19 hospitalization due to either the Omicron or Delta variant." <|im_end|>

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2,372

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cell mechanical phenotype or ‘mechanotype’ is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes. To validate the method, we compare the filtration of untransformed and HRas V12 -transformed murine ovary cells and find significantly increased deformability of the transformed cells. Inducing epithelial-to-mesenchymal transition (EMT) in human ovarian cancer cells by overexpression of key transcription factors (Snail, Slug, Zeb1) or by acquiring drug resistance produces a similar increase in deformability. Mechanistically, we show that EMT-mediated changes in epithelial (loss of E-Cadherin) and mesenchymal markers (vimentin induction) correlate with altered mechanotype. Our results demonstrate a method to screen cell mechanotype that has potential for broader clinical application. Introduction Cells are viscoelastic materials whose mechanotype is altered in diseases from malaria to cancer 1 , 2 . For example, malignant cells across different types of cancers are consistently 2–5× softer than benign cells both in vitro and in situ 3 , 4 , 5 , 6 . Cell mechanotype also grades metastatic potential: highly invasive human ovarian carcinoma cells are up to 5× softer than less invasive cells 3 , 4 . Mechanotyping of patient samples shows potential for clinical diagnoses of cancer 7 . Moreover, the compliance of cancer cells is altered by chemotherapy drugs. For example, leukemia cells exhibit a ~10 to 100-fold increase in elastic modulus after being treated with dexamethasone and daunorubicin 8 . While cell mechanotype has potential as a biomarker in cancer diagnosis and for identifying effective drug treatments, to efficiently screen cell mechanotype for fundamental research and clinical applications requires a simple and scalable method. Various techniques provide quantitative insight into the viscoelastic behavior of cells including micropipette aspiration 9 , 10 , atomic force microscopy 6 , 11 and cantilever compression 12 , 13 . These methods enable detailed characterization of the force-deformation response of typically <10 2 individual cells, which limit the number of independent samples that can be probed within a reasonable timescale. An alternative way to measure cell deformability is to filter cells through membranes with micron-scale pores 14 , 15 , 16 ; however, these measurements are performed sequentially, which limits scale-up. More recently, microfluidic methods enable more efficient measurements of cell mechanotype: real-time deformability cytometry probes the deformation of single cells at ~100 cells/s 17 and requires over 1 hour to obtain data on a single sample from the initial state of cells in culture. Cells can also be deformed by the shear and compressive stresses generated as cells flow through micron-scale constrictions 18 , 19 , 20 , or through opposing fluid streams 21 ; while these methods enable measurements at rates of up to ~2,000 cells/sec, the total measurement time for a single sample is approximately 1.5 hours as high-speed imaging and intensive computational analysis is required; this also challenges the measurement of different samples in parallel. If we could rapidly assess the deformability of multiple samples in a single measurement, we could harness the intrinsic mechanotype of cells for practical applications. Here we describe a parallel microfiltration (PMF) method that enables simultaneous measurements of cell mechanotype across multiple samples. We use uniform air pressure to drive cell suspensions through porous membranes; the relative deformability of a cell sample is quantified by the fraction of sample retained above the membrane. Herein we describe PMF design principles and operation parameters. Based on our experimental results and theoretical considerations, we develop a simple model that provides a physical explanation of PMF and allows us to relate our experimental data to cell deformability. We validate the method by mechanotyping a variety of cancer cell types, including epithelial and mesenchymal-type cells, as well as cells treated with chemotherapy drugs. We focus on human promyelocytic leukemia (HL-60) and ovarian cancer cells, as the mechanotype of these cells has been characterized using other complementary techniques 3 , 4 , 11 , 22 , 23 . Results Parallel microfiltration concept The essential components of the PMF device are shown in Fig. 1a . Polycarbonate membranes are sandwiched between two custom-fabricated 96-well plates; using membranes with varying pore sizes can enable filtration through multiple pore sizes in a single run. We place cell suspensions in the top wells and apply a uniform pressure gradient across the membrane for a defined period of time. To quantify the filtration of each individual cell sample, we measure the fraction of the initial mass of cell suspension that is retained in the top well, which is the percentage (%) retention; equivalently, the number of retained cells can also be measured ( Supplementary Fig. 1 ). Figure 1 Overview of the parallel microfiltration (PMF) platform. ( a ) Schematic illustration of the parallel filtration platform. 1: Pressure gauge; 2: Aluminum plate for assembling; 3: Pressure chamber. An air pressure source ( Supplementary Fig. 10 ) connects via the blue tube; 4: Silicone sealing pad; 5: 96-well loading plate; 6: Porous membrane; 7: 96-well bottom plate with O-rings (black); 8: Aluminum plate for assembling. ( b ) Dependence of HL-60 cell filtration on cell density through membranes of 5, 8 and 10 μm pores. Black circles: 5 μm pore membrane, 3.4 kPa applied for 20 s; black squares: 8 μm pore membrane, 0.7 kPa applied for 20 s; black triangles: 10 μm pore membrane, 0.7 kPa applied for 20 s. Red squares show filtration of ovarian cancer cells (OVCA433-Snail) through 10 μm pore membrane, 2.1 kPa for 50 s. Lines represent model fitting obtained using the least squares method: solid lines for fitting data shown by black circles and red squares; fitting of the black squares is denoted with a dashed line. ( c ) Pressure dependence of HL-60 control (black squares) versus ATRA-treated (dHL-60, black circles) cell filtration with 5 μm pore membrane for 20", "role": "user" }, { "content": "Scientists have previously established that many types of cancer cells are squishier and more pliable than normal, healthy cells. Now, researchers led by UCLA's Amy Rowat have developed a screening method that utilizes this information to classify many more different types of cancer cells and that could ultimately lead to better treatments for cancer, diabetes, malaria and other diseases. Cancer cells are generally two to five times squishier than normal cells, with a pliability similar to that of a wobbly Jell-O, said Rowat, senior author of the research and an assistant professor of integrative biology and physiology. \"We want to screen cells based on their squishiness or stiffness,\" said Rowat, who is also a member of UCLA's Jonsson Comprehensive Cancer Center. \"We created a technology to probe the deformability of hundreds of cell samples at the same time, so we can identify compounds that make the cells stiffer. Our hope is that we can identify new compounds that can help to prevent the spread of cancer.\" Rowat calls the approach the parallel microfiltration method, or PMF. Researchers place a mixture of cells and liquid on a porous membrane, and apply air pressure to force the mixture down through tiny pores that have a smaller circumference than the cells. Stiffer cells block the pores so that not much liquid can filter through; for squishier cells, more of the cell-and-liquid mixture passes through. Researchers can use parallel microfiltration to test many different small molecules at once by measuring the filtration of fluid into individual compartments. A study detailing the method is published today in the journal Scientific Reports. The team found that drug-resistant human ovarian cancer cells are softer than their drug-sensitive counterparts, and that more-invasive cancer cells are softer than less-invasive ones. In future research, Rowat hopes to establish whether squishier cancer cells are in fact more harmful than stiffer cancer cells, and whether their softness can be reversed. The components of PMF. Credit: Scientific Reports/Benny Gee \"It's easy to imagine softer cells can spread more easily through the body to invade distant tissues, but this is still a hypothesis,\" she said. Some chemotherapy drugs make cancer cells stiffer because they help to stop cells from dividing, Rowat added. But it isn't clear whether this stiffening of the cells is a key mechanism for preventing the spread of cancer or simply a byproduct of the cells being blocked from dividing. Parallel microfiltration may also have broader applications, including the ability to screen molecules that can alter particular genes and protein levels inside a cell, which could be useful in treating a variety of other diseases, Rowat said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cell mechanical phenotype or ‘mechanotype’ is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes. To validate the method, we compare the filtration of untransformed and HRas V12 -transformed murine ovary cells and find significantly increased deformability of the transformed cells. Inducing epithelial-to-mesenchymal transition (EMT) in human ovarian cancer cells by overexpression of key transcription factors (Snail, Slug, Zeb1) or by acquiring drug resistance produces a similar increase in deformability. Mechanistically, we show that EMT-mediated changes in epithelial (loss of E-Cadherin) and mesenchymal markers (vimentin induction) correlate with altered mechanotype. Our results demonstrate a method to screen cell mechanotype that has potential for broader clinical application. Introduction Cells are viscoelastic materials whose mechanotype is altered in diseases from malaria to cancer 1 , 2 . For example, malignant cells across different types of cancers are consistently 2–5× softer than benign cells both in vitro and in situ 3 , 4 , 5 , 6 . Cell mechanotype also grades metastatic potential: highly invasive human ovarian carcinoma cells are up to 5× softer than less invasive cells 3 , 4 . Mechanotyping of patient samples shows potential for clinical diagnoses of cancer 7 . Moreover, the compliance of cancer cells is altered by chemotherapy drugs. For example, leukemia cells exhibit a ~10 to 100-fold increase in elastic modulus after being treated with dexamethasone and daunorubicin 8 . While cell mechanotype has potential as a biomarker in cancer diagnosis and for identifying effective drug treatments, to efficiently screen cell mechanotype for fundamental research and clinical applications requires a simple and scalable method. Various techniques provide quantitative insight into the viscoelastic behavior of cells including micropipette aspiration 9 , 10 , atomic force microscopy 6 , 11 and cantilever compression 12 , 13 . These methods enable detailed characterization of the force-deformation response of typically <10 2 individual cells, which limit the number of independent samples that can be probed within a reasonable timescale. An alternative way to measure cell deformability is to filter cells through membranes with micron-scale pores 14 , 15 , 16 ; however, these measurements are performed sequentially, which limits scale-up. More recently, microfluidic methods enable more efficient measurements of cell mechanotype: real-time deformability cytometry probes the deformation of single cells at ~100 cells/s 17 and requires over 1 hour to obtain data on a single sample from the initial state of cells in culture. Cells can also be deformed by the shear and compressive stresses generated as cells flow through micron-scale constrictions 18 , 19 , 20 , or through opposing fluid streams 21 ; while these methods enable measurements at rates of up to ~2,000 cells/sec, the total measurement time for a single sample is approximately 1.5 hours as high-speed imaging and intensive computational analysis is required; this also challenges the measurement of different samples in parallel. If we could rapidly assess the deformability of multiple samples in a single measurement, we could harness the intrinsic mechanotype of cells for practical applications. Here we describe a parallel microfiltration (PMF) method that enables simultaneous measurements of cell mechanotype across multiple samples. We use uniform air pressure to drive cell suspensions through porous membranes; the relative deformability of a cell sample is quantified by the fraction of sample retained above the membrane. Herein we describe PMF design principles and operation parameters. Based on our experimental results and theoretical considerations, we develop a simple model that provides a physical explanation of PMF and allows us to relate our experimental data to cell deformability. We validate the method by mechanotyping a variety of cancer cell types, including epithelial and mesenchymal-type cells, as well as cells treated with chemotherapy drugs. We focus on human promyelocytic leukemia (HL-60) and ovarian cancer cells, as the mechanotype of these cells has been characterized using other complementary techniques 3 , 4 , 11 , 22 , 23 . Results Parallel microfiltration concept The essential components of the PMF device are shown in Fig. 1a . Polycarbonate membranes are sandwiched between two custom-fabricated 96-well plates; using membranes with varying pore sizes can enable filtration through multiple pore sizes in a single run. We place cell suspensions in the top wells and apply a uniform pressure gradient across the membrane for a defined period of time. To quantify the filtration of each individual cell sample, we measure the fraction of the initial mass of cell suspension that is retained in the top well, which is the percentage (%) retention; equivalently, the number of retained cells can also be measured ( Supplementary Fig. 1 ). Figure 1 Overview of the parallel microfiltration (PMF) platform. ( a ) Schematic illustration of the parallel filtration platform. 1: Pressure gauge; 2: Aluminum plate for assembling; 3: Pressure chamber. An air pressure source ( Supplementary Fig. 10 ) connects via the blue tube; 4: Silicone sealing pad; 5: 96-well loading plate; 6: Porous membrane; 7: 96-well bottom plate with O-rings (black); 8: Aluminum plate for assembling. ( b ) Dependence of HL-60 cell filtration on cell density through membranes of 5, 8 and 10 μm pores. Black circles: 5 μm pore membrane, 3.4 kPa applied for 20 s; black squares: 8 μm pore membrane, 0.7 kPa applied for 20 s; black triangles: 10 μm pore membrane, 0.7 kPa applied for 20 s. Red squares show filtration of ovarian cancer cells (OVCA433-Snail) through 10 μm pore membrane, 2.1 kPa for 50 s. Lines represent model fitting obtained using the least squares method: solid lines for fitting data shown by black circles and red squares; fitting of the black squares is denoted with a dashed line. ( c ) Pressure dependence of HL-60 control (black squares) versus ATRA-treated (dHL-60, black circles) cell filtration with 5 μm pore membrane for 20<|im_end|> <|im_start|>assistant Scientists have previously established that many types of cancer cells are squishier and more pliable than normal, healthy cells. Now, researchers led by UCLA's Amy Rowat have developed a screening method that utilizes this information to classify many more different types of cancer cells and that could ultimately lead to better treatments for cancer, diabetes, malaria and other diseases. Cancer cells are generally two to five times squishier than normal cells, with a pliability similar to that of a wobbly Jell-O, said Rowat, senior author of the research and an assistant professor of integrative biology and physiology. "We want to screen cells based on their squishiness or stiffness," said Rowat, who is also a member of UCLA's Jonsson Comprehensive Cancer Center. "We created a technology to probe the deformability of hundreds of cell samples at the same time, so we can identify compounds that make the cells stiffer. Our hope is that we can identify new compounds that can help to prevent the spread of cancer." Rowat calls the approach the parallel microfiltration method, or PMF. Researchers place a mixture of cells and liquid on a porous membrane, and apply air pressure to force the mixture down through tiny pores that have a smaller circumference than the cells. Stiffer cells block the pores so that not much liquid can filter through; for squishier cells, more of the cell-and-liquid mixture passes through. Researchers can use parallel microfiltration to test many different small molecules at once by measuring the filtration of fluid into individual compartments. A study detailing the method is published today in the journal Scientific Reports. The team found that drug-resistant human ovarian cancer cells are softer than their drug-sensitive counterparts, and that more-invasive cancer cells are softer than less-invasive ones. In future research, Rowat hopes to establish whether squishier cancer cells are in fact more harmful than stiffer cancer cells, and whether their softness can be reversed. The components of PMF. Credit: Scientific Reports/Benny Gee "It's easy to imagine softer cells can spread more easily through the body to invade distant tissues, but this is still a hypothesis," she said. Some chemotherapy drugs make cancer cells stiffer because they help to stop cells from dividing, Rowat added. But it isn't clear whether this stiffening of the cells is a key mechanism for preventing the spread of cancer or simply a byproduct of the cells being blocked from dividing. Parallel microfiltration may also have broader applications, including the ability to screen molecules that can alter particular genes and protein levels inside a cell, which could be useful in treating a variety of other diseases, Rowat said. <|im_end|>

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1,948

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Strong coupling between plasmons and optical modes, such as waveguide or resonator modes, gives rise to a splitting in the plasmon absorption band. As a result, two new hybrid modes are formed that exhibit near-field enhancement effects. These hybrid modes have been exploited to improve light absorption in a number of systems. Here we show that this modal strong coupling between a Fabry–Pérot nanocavity mode and a localized surface plasmon resonance (LSPR) facilitates water splitting reactions. We use a gold nanoparticle (Au-NP)/TiO 2 /Au-film structure as a photoanode. This structure exhibits modal strong coupling between the Fabry–Pérot nanocavity modes of the TiO 2 thin film/Au film and LSPR of the Au NPs. Electronic excitation of the Au NPs is promoted by the optical hybrid modes across a broad range of wavelengths, followed by a hot electron transfer to TiO 2 . A key feature of our structure is that the Au NPs are partially inlaid in the TiO 2 layer, which results in an enhancement of the coupling strength and water-oxidation efficiency. We observe an 11-fold increase in the incident photon-to-current conversion efficiency with respect to a photoanode structure with no Au film. Also, the internal quantum efficiency is enhanced 1.5 times under a strong coupling over that under uncoupled conditions. Main Plasmon-induced hot electron transfer has received considerable attention as a novel mechanism for optoelectronics devices, photovoltaics and artificial photosynthesis 1 , 2 , 3 , 4 , 5 . However, a single layer of gold nanoparticles (Au NPs) cannot efficiently harvest light. To improve the light utilization efficiency, photoelectrodes with three-dimensional architectures were developed 6 , 7 , 8 , 9 , 10 . Among these, plasmonic absorbers using dipole–image interactions are extremely effective for an efficient light absorption, even with a small TiO 2 thickness, and this approach was recently applied to photocurrent generation and water splitting 8 , 9 . Here we demonstrate highly efficient light-harvesting photoanodes with a responsivity over a broad range of wavelengths by strongly coupling Au NPs and a nanocavity for application in a water-splitting system. The strong coupling between the localized surface plasmon resonance (LSPR) and optical modes, such as waveguide modes or surface plasmon Bloch waves, has been utilized for broad-wavelength light-responsive optical antennae 11 , 12 , 13 , 14 . We fabricated a Au-NP/TiO 2 /Au-film structure and demonstrated the strong coupling between the Fabry–Pérot nanocavity modes and LSPR. We then explored the influence of the strong coupling on the water-splitting efficiency. Strong coupling in Au-NP/TiO 2 /Au-film Figure 1a shows a schematic illustration of the Au-NP/TiO 2 /Au-film structure with partially inlaid Au NPs. The Au-NP/TiO 2 /Au-film can be used for light-harvesting optical elements or as a photoelectrode for light-energy conversion devices. Due to the large refractive index of TiO 2 (2.4 at 600 nm) and the phase change of reflection at the TiO 2 /Au-film interface 15 , a TiO 2 /Au-film with a TiO 2 thickness of only several tens of nanometres can support the lowest-order cavity mode at visible-light wavelengths. The reflection spectrum calculated by the finite-difference time-domain (FDTD) method (Supplementary Note 1 ) reveals the cavity mode in the TiO 2 film (Supplementary Fig. 1 ). In typical Au-NP/TiO 2 heterojunctions, Au NPs are decorated on top of the TiO 2 film 8 , 9 , but the interaction of the cavity mode and the LSPR is weak. Therefore, we partially inlaid the Au NPs into the TiO 2 thin film to enhance the interaction between the cavity mode and LSPR. Fig. 1: Au-NP/TiO 2 /Au-film with an ultrathin TiO 2 film. a , Schematic of the Au-NP/TiO 2 /Au-film with partially inlaid Au NPs. b , Photographs of Au-NP/TiO 2 /Au-film structures with inlaid depths of 0, 7 and 14 nm (left panel). Photographs of the 28 nm-TiO 2 /Au-film structure without Au NPs and the Au-NP/28 nm-TiO 2 structure without the Au film are included for comparison. c , Absorption spectra of the Au-NP/TiO 2 /Au-film structures with various TiO 2 thin-film thicknesses. The inlaid depth of the Au NPs was maintained at 7 nm. d , Dispersion curve of the splitting absorption band. The energies of the coupling states (upper branch and lower branch) were obtained from the splitting absorption bands. The red curves are the fittings using a coupled harmonic oscillator model. The blue dashed line depicts the LSPR energy of the Au NPs. e , Energy-level diagram of the strong coupling between the cavity mode in the TiO 2 film and the plasmon resonance of the Au NPs. The ω sp and ω cavity are the resonant frequencies of plasmon and Fabry–Pérot nanocavity modes, respectively. Full size image The average Au NP size analysed by scanning transmission electron microscopy (STEM) was 12 nm. The surface morphology of the Au NPs was characterized by scanning electron microscopy, which also indicates that the average size of the Au NPs was 12 nm with a s.d. of 5.5 nm (Supplementary Fig. 2 ). Figure 1b shows photographs of the Au-NP/TiO 2 /Au-film samples with inlaid depths of 0, 7 and 14 nm. In contrast to the yellow TiO 2 /Au-film without Au NPs, the Au-NP/TiO 2 /Au-film structures appear black, which indicates a strong light absorption. A photograph of Au-NP/TiO 2 /SiO 2 without the Au film is also shown for comparison and clearly confirms that the substrate is translucent, as the single layer of Au NPs does not absorb much light, which can also be confirmed by the absorption spectra (Supplementary Fig. 3 ). To understand the effect of the TiO 2 layer on the optical responses, we fabricated Au-NP/TiO 2 /Au-film structures with different TiO 2 thicknesses (19–44 nm) and compared the absorption spectra (Fig. 1c ). The absorption spectrum was obtained by measuring the transmittance T and reflectance R and calculating ‒log ( T + R ) as a function of wavelength. The inlaid depth of the Au NPs was maintained at 7 nm. Absorption at", "role": "user" }, { "content": "Scientists have developed a photoelectrode that can harvest 85 percent of visible light in a 30 nanometers-thin semiconductor layer between gold layers, converting light energy 11 times more efficiently than previous methods. In the pursuit of realizing a sustainable society, there is an ever-increasing demand to develop revolutionary solar cells or artificial photosynthesis systems that utilize visible light energy from the sun while using as few materials as possible. The research team, led by Professor Hiroaki Misawa of the Research Institute for Electronic Science at Hokkaido University, has been aiming to develop a photoelectrode that can harvest visible light across a wide spectral range by using gold nanoparticles loaded on a semiconductor. But merely applying a layer of gold nanoparticles did not lead to a sufficient amount of light absorption, because they took in light with only a narrow spectral range. In the study published in Nature Nanotechnology, the research team sandwiched a semiconductor, a 30-nanometer titanium dioxide thin-film, between a 100-nanometer gold film and gold nanoparticles to enhance light absorption. When the system is irradiated by light from the gold nanoparticle side, the gold film worked as a mirror, trapping the light in a cavity between two gold layers and helping the nanoparticles absorb more light. To their surprise, more than 85 percent of all visible light was harvested by the photoelectrode, which was far more efficient than previous methods. Gold nanoparticles are known to exhibit a phenomenon called localized plasmon resonance which absorbs a certain wavelength of light. \"Our photoelectrode successfully created a new condition in which plasmon and visible light trapped in the titanium oxide layer strongly interact, allowing light with a broad range of wavelengths to be absorbed by gold nanoparticles,\" says Hiroaki Misawa. When gold nanoparticles absorb light, the additional energy triggers electron excitation in the gold, which transfers electrons to the semiconductor. \"The light energy conversion efficiency is 11 times higher than those without light-trapping functions,\" Misawa explained. The boosted efficiency also led to an enhanced water splitting: the electrons reduced hydrogen ions to hydrogen, while the remaining electron holes oxidized water to produce oxygen—a promising process to yield clean energy. \"Using very small amounts of material, this photoelectrode enables an efficient conversion of sunlight into renewable energy, further contributing to the realization of a sustainable society,\" the researchers concluded. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Strong coupling between plasmons and optical modes, such as waveguide or resonator modes, gives rise to a splitting in the plasmon absorption band. As a result, two new hybrid modes are formed that exhibit near-field enhancement effects. These hybrid modes have been exploited to improve light absorption in a number of systems. Here we show that this modal strong coupling between a Fabry–Pérot nanocavity mode and a localized surface plasmon resonance (LSPR) facilitates water splitting reactions. We use a gold nanoparticle (Au-NP)/TiO 2 /Au-film structure as a photoanode. This structure exhibits modal strong coupling between the Fabry–Pérot nanocavity modes of the TiO 2 thin film/Au film and LSPR of the Au NPs. Electronic excitation of the Au NPs is promoted by the optical hybrid modes across a broad range of wavelengths, followed by a hot electron transfer to TiO 2 . A key feature of our structure is that the Au NPs are partially inlaid in the TiO 2 layer, which results in an enhancement of the coupling strength and water-oxidation efficiency. We observe an 11-fold increase in the incident photon-to-current conversion efficiency with respect to a photoanode structure with no Au film. Also, the internal quantum efficiency is enhanced 1.5 times under a strong coupling over that under uncoupled conditions. Main Plasmon-induced hot electron transfer has received considerable attention as a novel mechanism for optoelectronics devices, photovoltaics and artificial photosynthesis 1 , 2 , 3 , 4 , 5 . However, a single layer of gold nanoparticles (Au NPs) cannot efficiently harvest light. To improve the light utilization efficiency, photoelectrodes with three-dimensional architectures were developed 6 , 7 , 8 , 9 , 10 . Among these, plasmonic absorbers using dipole–image interactions are extremely effective for an efficient light absorption, even with a small TiO 2 thickness, and this approach was recently applied to photocurrent generation and water splitting 8 , 9 . Here we demonstrate highly efficient light-harvesting photoanodes with a responsivity over a broad range of wavelengths by strongly coupling Au NPs and a nanocavity for application in a water-splitting system. The strong coupling between the localized surface plasmon resonance (LSPR) and optical modes, such as waveguide modes or surface plasmon Bloch waves, has been utilized for broad-wavelength light-responsive optical antennae 11 , 12 , 13 , 14 . We fabricated a Au-NP/TiO 2 /Au-film structure and demonstrated the strong coupling between the Fabry–Pérot nanocavity modes and LSPR. We then explored the influence of the strong coupling on the water-splitting efficiency. Strong coupling in Au-NP/TiO 2 /Au-film Figure 1a shows a schematic illustration of the Au-NP/TiO 2 /Au-film structure with partially inlaid Au NPs. The Au-NP/TiO 2 /Au-film can be used for light-harvesting optical elements or as a photoelectrode for light-energy conversion devices. Due to the large refractive index of TiO 2 (2.4 at 600 nm) and the phase change of reflection at the TiO 2 /Au-film interface 15 , a TiO 2 /Au-film with a TiO 2 thickness of only several tens of nanometres can support the lowest-order cavity mode at visible-light wavelengths. The reflection spectrum calculated by the finite-difference time-domain (FDTD) method (Supplementary Note 1 ) reveals the cavity mode in the TiO 2 film (Supplementary Fig. 1 ). In typical Au-NP/TiO 2 heterojunctions, Au NPs are decorated on top of the TiO 2 film 8 , 9 , but the interaction of the cavity mode and the LSPR is weak. Therefore, we partially inlaid the Au NPs into the TiO 2 thin film to enhance the interaction between the cavity mode and LSPR. Fig. 1: Au-NP/TiO 2 /Au-film with an ultrathin TiO 2 film. a , Schematic of the Au-NP/TiO 2 /Au-film with partially inlaid Au NPs. b , Photographs of Au-NP/TiO 2 /Au-film structures with inlaid depths of 0, 7 and 14 nm (left panel). Photographs of the 28 nm-TiO 2 /Au-film structure without Au NPs and the Au-NP/28 nm-TiO 2 structure without the Au film are included for comparison. c , Absorption spectra of the Au-NP/TiO 2 /Au-film structures with various TiO 2 thin-film thicknesses. The inlaid depth of the Au NPs was maintained at 7 nm. d , Dispersion curve of the splitting absorption band. The energies of the coupling states (upper branch and lower branch) were obtained from the splitting absorption bands. The red curves are the fittings using a coupled harmonic oscillator model. The blue dashed line depicts the LSPR energy of the Au NPs. e , Energy-level diagram of the strong coupling between the cavity mode in the TiO 2 film and the plasmon resonance of the Au NPs. The ω sp and ω cavity are the resonant frequencies of plasmon and Fabry–Pérot nanocavity modes, respectively. Full size image The average Au NP size analysed by scanning transmission electron microscopy (STEM) was 12 nm. The surface morphology of the Au NPs was characterized by scanning electron microscopy, which also indicates that the average size of the Au NPs was 12 nm with a s.d. of 5.5 nm (Supplementary Fig. 2 ). Figure 1b shows photographs of the Au-NP/TiO 2 /Au-film samples with inlaid depths of 0, 7 and 14 nm. In contrast to the yellow TiO 2 /Au-film without Au NPs, the Au-NP/TiO 2 /Au-film structures appear black, which indicates a strong light absorption. A photograph of Au-NP/TiO 2 /SiO 2 without the Au film is also shown for comparison and clearly confirms that the substrate is translucent, as the single layer of Au NPs does not absorb much light, which can also be confirmed by the absorption spectra (Supplementary Fig. 3 ). To understand the effect of the TiO 2 layer on the optical responses, we fabricated Au-NP/TiO 2 /Au-film structures with different TiO 2 thicknesses (19–44 nm) and compared the absorption spectra (Fig. 1c ). The absorption spectrum was obtained by measuring the transmittance T and reflectance R and calculating ‒log ( T + R ) as a function of wavelength. The inlaid depth of the Au NPs was maintained at 7 nm. Absorption at<|im_end|> <|im_start|>assistant Scientists have developed a photoelectrode that can harvest 85 percent of visible light in a 30 nanometers-thin semiconductor layer between gold layers, converting light energy 11 times more efficiently than previous methods. In the pursuit of realizing a sustainable society, there is an ever-increasing demand to develop revolutionary solar cells or artificial photosynthesis systems that utilize visible light energy from the sun while using as few materials as possible. The research team, led by Professor Hiroaki Misawa of the Research Institute for Electronic Science at Hokkaido University, has been aiming to develop a photoelectrode that can harvest visible light across a wide spectral range by using gold nanoparticles loaded on a semiconductor. But merely applying a layer of gold nanoparticles did not lead to a sufficient amount of light absorption, because they took in light with only a narrow spectral range. In the study published in Nature Nanotechnology, the research team sandwiched a semiconductor, a 30-nanometer titanium dioxide thin-film, between a 100-nanometer gold film and gold nanoparticles to enhance light absorption. When the system is irradiated by light from the gold nanoparticle side, the gold film worked as a mirror, trapping the light in a cavity between two gold layers and helping the nanoparticles absorb more light. To their surprise, more than 85 percent of all visible light was harvested by the photoelectrode, which was far more efficient than previous methods. Gold nanoparticles are known to exhibit a phenomenon called localized plasmon resonance which absorbs a certain wavelength of light. "Our photoelectrode successfully created a new condition in which plasmon and visible light trapped in the titanium oxide layer strongly interact, allowing light with a broad range of wavelengths to be absorbed by gold nanoparticles," says Hiroaki Misawa. When gold nanoparticles absorb light, the additional energy triggers electron excitation in the gold, which transfers electrons to the semiconductor. "The light energy conversion efficiency is 11 times higher than those without light-trapping functions," Misawa explained. The boosted efficiency also led to an enhanced water splitting: the electrons reduced hydrogen ions to hydrogen, while the remaining electron holes oxidized water to produce oxygen—a promising process to yield clean energy. "Using very small amounts of material, this photoelectrode enables an efficient conversion of sunlight into renewable energy, further contributing to the realization of a sustainable society," the researchers concluded. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Trade-offs play an important role in evolution. Without trade-offs, evolution would maximize fitness of all traits leading to a “master of all traits”. The shape of trade-offs has been shown to determine evolutionary trajectories and is often assumed to be static and independent of the actual evolutionary process. Here we propose that coevolution leads to a dynamical trade-off. We test this hypothesis in a microbial predator–prey system and show that the bacterial growth-defense trade-off changes from concave to convex, i.e., defense is effective and cheap initially, but gets costly when predators coevolve. We further explore the impact of such dynamical trade-offs by a novel mathematical model incorporating de novo mutations for both species. Predator and prey populations diversify rapidly leading to higher prey diversity when the trade-off is concave (cheap). Coevolution results in more convex (costly) trade-offs and lower prey diversity compared to the scenario where only the prey evolves. Introduction Trade-offs exist when there are negative correlations between different traits of an organism. They play an important role in maintaining polymorphisms in populations, where individuals invest in traits differently 1 . One critical trade-off for the evolution of species is between survival and reproduction, e.g., the growth-defense trade-off of a prey population, the growth-resistance trade-off of a host population, or the growth-offense trade-off of a predator or parasite population 2 . A growing number of studies show that evolutionary and ecological changes can occur on similar time scales 3 , 4 , 5 , 6 , 7 , 8 and researchers have moved beyond classical ecological models assuming static traits of species over ecological time scales 9 , 10 , 11 , 12 , 13 . Rapid prey evolution can, for example, shift predator-prey cycles from the classical one-quarter phase lag towards longer cycles, which are nearly out of phase 14 , 15 , 16 . Trade-offs and the shape of the growth-defense trade-off curve among different prey types can further determine the oscillatory behaviors of predator and prey densities over time; 15 , 17 , 18 , 19 , 20 , 21 different efficiencies of prey defense and associated fitness costs can lead to cryptic cycles, where the predator abundance changes, but the total prey abundance remains constant 22 , steady state dynamics where cycling stops 23 , or even reversals in the direction of the predator-prey cycles 20 . Trade-offs hence not only play a major role for the maintenance of polymorphisms within prey populations but may also change their ecological dynamics over time. Previous studies have shown the importance of trade-offs with rapid evolution within a single species, for example, in the evolution of only the prey 15 , 17 , 18 , 19 , 20 , 21 , 24 . Here we focus on the impact of trade-offs in coevolving systems. Coevolution is likely the norm in natural environments where species sharing the same environment will encounter and consequently interact with each other 12 . Coevolution might change the evolutionary potential of species over time 25 , 26 , as an adaptation in one species might result in significant fitness gains initially, which may decrease as its opponent species counter-adapts after some time. We hypothesize that the shapes of trade-off curves are not static as assumed in previous studies, but depend on the evolutionary potential of both species and can become dynamical with coevolution. The dynamical shape of the trade-off is then predicted to further affect the population dynamics of the coevolving populations, e.g., the pattern of predator-prey cycles 15 , 16 . Specifically, multiple prey types coexist and out-of-phase cycles are more prevalent between the total prey and predator abundances when the trade-off curve is more concave and defense is cheap. We first test this dynamical trade-off hypothesis in a microbial predator-prey system after bacteria and ciliate populations ( Pseudomonas fluorescens and Tetrahymena thermophila ) were allowed to coevolve for many generations. Our experimental results confirm that the growth-defense trade-off within the bacteria populations changed depending on the coevolutionary history. Defense was efficient and cheap in the presence of naive ciliates, but less efficient and costly in the presence of coevolved ciliates. Coevolution led to a shift from a cheap to a costly trade-off. Such a dynamical trade-off can potentially be important for the evolutionary and the ecological dynamics of species. Thus, we further investigated the consequences of a dynamical trade-off systematically using a mathematical model. We incorporated de novo mutations as stochastic events in prey and predator populations 27 . This allowed us to describe the coevolutionary process without imposing a predefined number of prey or predator types. We also considered feedbacks between the evolutionary process and demographic fluctuations 28 , where the carrying capacities are not fixed parameters but change with the coevolution of the prey and predator types. Consistent with our experiment, starting from naive populations, the trade-off curve changes from an initial shape of relatively cheap defense to be more costly with coevolution. This ultimately leads to a lower prey diversity compared to only prey evolution. Interestingly, the predator diversity does not monotonically increase with prey diversity due to the dynamical trade-off. Together, our experimental and theoretical results show that dynamical trade-offs arise and significantly affect the evolution and maintenance of intraspecific diversity. Results Bacteria-ciliate coevolution leads to a dynamical trade-off To test our hypothesis that coevolution leads to a dynamical trade-off, i.e., a shift in the shape of the trade-off curve, we measured growth rates and defense against consumption by predatory ciliates for different bacteria and ciliate populations isolated from long-term coevolution selection lines. Replicated selection lines were started from the same ancestral isogenic ciliate stock and were allowed to coevolve together with bacteria populations which were started from the same isogenic stock (hereafter: coevolved ciliates) or were kept as naive ciliates in a bacteria-free environment (hereafter: ancestral ciliates). We isolated coevolved ciliate populations from two selection lines after ~550 generations. At the same time, we isolated bacteria populations (after ~1000 generations) from the same and one additional", "role": "user" }, { "content": "Even bacteria have enemies – in water, for example, single-celled ciliates preferably feed on microbes. The microbes protect themselves against predators by employing a variety of tricks, which the ciliates, in turn, attempt to overcome. There ensues an evolutionary competition for the best attack and defence mechanisms. According to scientists from the Max Planck Institute for Evolutionary Biology in Plön, prey such as bacteria have, in the long run, no choice but to maintain protection mechanisms, even if the effort involved is so high that they can barely produce offspring. Predator and prey maintain a close relationship to each other: if one evolves, the other must keep pace. Such coevolution and its accompanying selection pressure leads to mutual adaptation of the two species. In their experiments, Lutz Becks and his fellow Plön-based researchers from Plön, London, and Finland held bacteria and ciliates together for many weeks and traced their evolution. Here, they observed how the microbes protect themselves against the gluttony of the ciliates when, after a few days, the bacterial cells, normally living in isolation, began to grow in larger associations as a slimy \"biofilm\". This meant they could no longer be foraged as effectively by the ciliates. Costly defence As long as the scientists allowed only the bacteria to evolve in their experiments and computer simulations, the bacteria were able to protect themselves well from being eaten – with acceptable effort. However, as soon as the ciliates were also allowed to evolve, protection came at a high cost to the bacteria: they then only produced few offspring. \"Protection against predators therefore comes at a high cost, because the better the bacteria are equipped, the worse they reproduce\", says Becks. The bacteria cannot therefore optimize both simultaneously – a typical case of evolutionary trade-off. However, what exact form this trade-off takes depends on whether the predator can adapt to the prey's defence mechanisms. If so, defence becomes increasingly costly to the prey and barely any resources remain for reproduction. In contrast, if the predator cannot adapt, the prey requires fewer resources for defence and can invest more in producing progeny\", explains Becks. Less diversity In addition, the researchers demonstrated that predator diversity decreases when there is a dynamical trade-off. The ciliates thus develop fewer different types in order to adapt to bacterial associations and biofilms. \"This is, of course, beneficial to the prey and could reduce the pressure on the bacteria\", says Becks. The study shows that, surprisingly, more prey diversity does not always mean more predator diversity. Lutz Becks: \"What is important are the costs and benefits of traits for prey and predator. As our experiments demonstrate, they can shift depending on whether or not the predator had time to adapt.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Trade-offs play an important role in evolution. Without trade-offs, evolution would maximize fitness of all traits leading to a “master of all traits”. The shape of trade-offs has been shown to determine evolutionary trajectories and is often assumed to be static and independent of the actual evolutionary process. Here we propose that coevolution leads to a dynamical trade-off. We test this hypothesis in a microbial predator–prey system and show that the bacterial growth-defense trade-off changes from concave to convex, i.e., defense is effective and cheap initially, but gets costly when predators coevolve. We further explore the impact of such dynamical trade-offs by a novel mathematical model incorporating de novo mutations for both species. Predator and prey populations diversify rapidly leading to higher prey diversity when the trade-off is concave (cheap). Coevolution results in more convex (costly) trade-offs and lower prey diversity compared to the scenario where only the prey evolves. Introduction Trade-offs exist when there are negative correlations between different traits of an organism. They play an important role in maintaining polymorphisms in populations, where individuals invest in traits differently 1 . One critical trade-off for the evolution of species is between survival and reproduction, e.g., the growth-defense trade-off of a prey population, the growth-resistance trade-off of a host population, or the growth-offense trade-off of a predator or parasite population 2 . A growing number of studies show that evolutionary and ecological changes can occur on similar time scales 3 , 4 , 5 , 6 , 7 , 8 and researchers have moved beyond classical ecological models assuming static traits of species over ecological time scales 9 , 10 , 11 , 12 , 13 . Rapid prey evolution can, for example, shift predator-prey cycles from the classical one-quarter phase lag towards longer cycles, which are nearly out of phase 14 , 15 , 16 . Trade-offs and the shape of the growth-defense trade-off curve among different prey types can further determine the oscillatory behaviors of predator and prey densities over time; 15 , 17 , 18 , 19 , 20 , 21 different efficiencies of prey defense and associated fitness costs can lead to cryptic cycles, where the predator abundance changes, but the total prey abundance remains constant 22 , steady state dynamics where cycling stops 23 , or even reversals in the direction of the predator-prey cycles 20 . Trade-offs hence not only play a major role for the maintenance of polymorphisms within prey populations but may also change their ecological dynamics over time. Previous studies have shown the importance of trade-offs with rapid evolution within a single species, for example, in the evolution of only the prey 15 , 17 , 18 , 19 , 20 , 21 , 24 . Here we focus on the impact of trade-offs in coevolving systems. Coevolution is likely the norm in natural environments where species sharing the same environment will encounter and consequently interact with each other 12 . Coevolution might change the evolutionary potential of species over time 25 , 26 , as an adaptation in one species might result in significant fitness gains initially, which may decrease as its opponent species counter-adapts after some time. We hypothesize that the shapes of trade-off curves are not static as assumed in previous studies, but depend on the evolutionary potential of both species and can become dynamical with coevolution. The dynamical shape of the trade-off is then predicted to further affect the population dynamics of the coevolving populations, e.g., the pattern of predator-prey cycles 15 , 16 . Specifically, multiple prey types coexist and out-of-phase cycles are more prevalent between the total prey and predator abundances when the trade-off curve is more concave and defense is cheap. We first test this dynamical trade-off hypothesis in a microbial predator-prey system after bacteria and ciliate populations ( Pseudomonas fluorescens and Tetrahymena thermophila ) were allowed to coevolve for many generations. Our experimental results confirm that the growth-defense trade-off within the bacteria populations changed depending on the coevolutionary history. Defense was efficient and cheap in the presence of naive ciliates, but less efficient and costly in the presence of coevolved ciliates. Coevolution led to a shift from a cheap to a costly trade-off. Such a dynamical trade-off can potentially be important for the evolutionary and the ecological dynamics of species. Thus, we further investigated the consequences of a dynamical trade-off systematically using a mathematical model. We incorporated de novo mutations as stochastic events in prey and predator populations 27 . This allowed us to describe the coevolutionary process without imposing a predefined number of prey or predator types. We also considered feedbacks between the evolutionary process and demographic fluctuations 28 , where the carrying capacities are not fixed parameters but change with the coevolution of the prey and predator types. Consistent with our experiment, starting from naive populations, the trade-off curve changes from an initial shape of relatively cheap defense to be more costly with coevolution. This ultimately leads to a lower prey diversity compared to only prey evolution. Interestingly, the predator diversity does not monotonically increase with prey diversity due to the dynamical trade-off. Together, our experimental and theoretical results show that dynamical trade-offs arise and significantly affect the evolution and maintenance of intraspecific diversity. Results Bacteria-ciliate coevolution leads to a dynamical trade-off To test our hypothesis that coevolution leads to a dynamical trade-off, i.e., a shift in the shape of the trade-off curve, we measured growth rates and defense against consumption by predatory ciliates for different bacteria and ciliate populations isolated from long-term coevolution selection lines. Replicated selection lines were started from the same ancestral isogenic ciliate stock and were allowed to coevolve together with bacteria populations which were started from the same isogenic stock (hereafter: coevolved ciliates) or were kept as naive ciliates in a bacteria-free environment (hereafter: ancestral ciliates). We isolated coevolved ciliate populations from two selection lines after ~550 generations. At the same time, we isolated bacteria populations (after ~1000 generations) from the same and one additional<|im_end|> <|im_start|>assistant Even bacteria have enemies – in water, for example, single-celled ciliates preferably feed on microbes. The microbes protect themselves against predators by employing a variety of tricks, which the ciliates, in turn, attempt to overcome. There ensues an evolutionary competition for the best attack and defence mechanisms. According to scientists from the Max Planck Institute for Evolutionary Biology in Plön, prey such as bacteria have, in the long run, no choice but to maintain protection mechanisms, even if the effort involved is so high that they can barely produce offspring. Predator and prey maintain a close relationship to each other: if one evolves, the other must keep pace. Such coevolution and its accompanying selection pressure leads to mutual adaptation of the two species. In their experiments, Lutz Becks and his fellow Plön-based researchers from Plön, London, and Finland held bacteria and ciliates together for many weeks and traced their evolution. Here, they observed how the microbes protect themselves against the gluttony of the ciliates when, after a few days, the bacterial cells, normally living in isolation, began to grow in larger associations as a slimy "biofilm". This meant they could no longer be foraged as effectively by the ciliates. Costly defence As long as the scientists allowed only the bacteria to evolve in their experiments and computer simulations, the bacteria were able to protect themselves well from being eaten – with acceptable effort. However, as soon as the ciliates were also allowed to evolve, protection came at a high cost to the bacteria: they then only produced few offspring. "Protection against predators therefore comes at a high cost, because the better the bacteria are equipped, the worse they reproduce", says Becks. The bacteria cannot therefore optimize both simultaneously – a typical case of evolutionary trade-off. However, what exact form this trade-off takes depends on whether the predator can adapt to the prey's defence mechanisms. If so, defence becomes increasingly costly to the prey and barely any resources remain for reproduction. In contrast, if the predator cannot adapt, the prey requires fewer resources for defence and can invest more in producing progeny", explains Becks. Less diversity In addition, the researchers demonstrated that predator diversity decreases when there is a dynamical trade-off. The ciliates thus develop fewer different types in order to adapt to bacterial associations and biofilms. "This is, of course, beneficial to the prey and could reduce the pressure on the bacteria", says Becks. The study shows that, surprisingly, more prey diversity does not always mean more predator diversity. Lutz Becks: "What is important are the costs and benefits of traits for prey and predator. As our experiments demonstrate, they can shift depending on whether or not the predator had time to adapt." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The identity of active species in supported gold catalysts for low temperature carbon monoxide oxidation remains an unsettled debate. With large amounts of experimental evidence supporting theories of either gold nanoparticles or sub-nm gold species being active, it was recently proposed that a size-dependent activity hierarchy should exist. Here we study the diverging catalytic behaviours after heat treatment of Au/FeO x materials prepared via co-precipitation and deposition precipitation methods. After ruling out any support effects, the gold particle size distributions in different catalysts are quantitatively studied using aberration corrected scanning transmission electron microscopy (STEM). A counting protocol is developed to reveal the true particle size distribution from HAADF-STEM images, which reliably includes all the gold species present. Correlation of the populations of the various gold species present with catalysis results demonstrate that a size-dependent activity hierarchy must exist in the Au/FeO x catalyst. Introduction The discovery by Haruta et al . 1 , 2 that CO oxidation was catalysed by Au nanoparticles supported on iron oxide has led to 30 years of scientific debate surrounding the nature of the active species 3 ; however, no unequivocal identification of the active species has been reported to date and often the findings are contradictory 3 , 4 , 5 , 6 . Bond and Thompson 7 initiated the mechanistic debate based solely on Au nanoparticles and Lopez et al . 8 showed that activity increased with decreasing nanoparticle size with the optimum being 1–2 nm. Goodman et al . 9 , 10 explained the role played by the Au/support periphery atoms by showing that extended Au bilayer structures on TiO 2 were extremely active for CO oxidation. Herzing et al . 11 reported a study that utilized high-angle annular dark field (HAADF) imaging in an aberration corrected STEM to investigate, for the first time, the full range of supported Au species present in real Au/FeO x catalysts (namely isolated atoms, sub-nm mono- and bilayer structures and particulate species above 1 nm in size). It was found that by heat treating a highly active dried Au/FeO x catalyst prepared by co-precipitation (CP), the number of isolated atoms observed decreased, the number of monolayer clusters remained relatively constant and the number of bilayer clusters decreased, whereas the number of nanoparticles (>1 nm) increased, all of which coincided with a measured decrease in catalytic activity. They proposed that the active catalysts contained more sub-nm bilayer clusters and fewer nanoparticles >1 nm, which agreed well with Goodman’s work 9 , 10 and also with the observations of Landman et al . 12 , who predicted that a minimum grouping of eight Au atoms is needed to show CO oxidation activity. More recently, Schüth et al . 13 demonstrated that Au/FeO x catalysts prepared by colloid immobilization methods can exhibit high CO oxidation activity while being devoid of any sub-nm clusters. These data combined with that of Herzing et al . 11 suggest that there is not just one distinct active site for CO oxidation over supported Au species and that particles existing over a broad size range may be effective for the reaction. Such a possibility was also recently highlighted by Haruta 3 , who suggested that catalysts consist of a range of co-existing Au nanostructures each with its own characteristic activity. We propose that such an activity hierarchy might have a more general significance and readily exist in many well-studied supported metal systems, but has remained undetected and unrecognized to date because the complex diversity of metal species present, spanning a range of sizes, have not been fully characterized since aberration-corrected STEM imaging was not available to detect them in earlier studies 1 , 2 , 14 , 15 . In this work, we re-visit Au/FeO x catalysts and use a new counting protocol to reveal the true particle size distribution (PSD) from HAADF-STEM images, which reliably includes all the Au species present and we show experimentally that an activity hierarchy does indeed exist. Results Diverging behaviour after heat treatments of two CP catalysts We studied Au/FeO x catalysts prepared by two different co-precipitation (CP) methods previously reported by Haruta et al . 1 (denoted CP-1) and Hutchings et al . 16 , 17 (denoted CP-2). While the methods are similar (see ‘Methods’ section for details), subtle differences exist in the sequence and rate of mixing the acidic and basic precursors. In the CP-1 method, the acidic solution (Fe(NO 3 ) 3 +HAuCl 4 ) was added quickly (within 2 min) into the basic solution (Na 2 CO 3 ), whereas in the CP-2 method, the basic solution was slowly added drop-wise into the acidic solution over 30 min. These subtle preparation differences have dramatic effects on the catalytic behaviour. Figure 1a shows the CO oxidation activities over a range of temperatures after drying and calcination. The acid-into-base (CP-1) and base-into-acid (CP-2) catalysts at the dried-only stage (120 °C, 16 h) had similar CO conversion over the temperature range tested. However, after calcination at 300 °C for 3 h, the base-into-acid (CP-2) catalyst is deactivated, whereas the acid-into-base (CP-1) catalyst becomes more active, especially at lower temperatures as has been reported previously by Haruta 1 . This dramatic difference in activity after calcination treatment provides us with the basis sample set for this comparative structural study. Figure 1: Diverging catalyst behaviour after heat treatment. ( a ) CO conversion at various temperatures. Catalyst mass 150 mg, gas flow 50 ml min −1 1 vol% CO in air. ( b ) Arrhenius plots carried out at low conversion conditions. Empty circles (CP-1, dried, 6 wt% Au by ICP) filled circles (CP-1, calcined, 6 wt% Au by ICP) empty squares (CP-2, dried, 3.5 wt% Au by ICP) filled squares (CP-2, calcined, 3.5 wt% Au by ICP). The arrows shown in a represent the thermal activation behaviour (black arrow) of the CP-1 catalyst and the thermal deactivation behaviour (white arrow) of the CP-2 catalyst. Full size image We studied the reaction kinetics to ascertain whether the higher", "role": "user" }, { "content": "Settling a decades-long debate, new research conclusively shows that a hierarchy of active species exists in gold on iron oxide catalysis designed for low temperature carbon monoxide oxidation; Nanoparticles, sub-nanometer clusters and dispersed atoms—as well as how the material is prepared—are all important for determining catalytic activity. Christopher J. Kiely calls the 1982 discovery by Prof. Masatake Haruta that gold (Au) possessed a high level of catalytic activity for carbon monoxide (CO) oxidation when deposited on a metal-oxide \"a remarkable turn of events in nanotechnology\"—remarkable because gold had long been assumed to be inert for catalysis. Haruta showed that gold dispersed on iron oxide effectively catalyzed the conversion of harmful carbon monoxide into more benign carbon dioxide (CO2) at room temperatures—a reaction that is critical for the construction of fire fighters' breathing masks and for removal of CO from hydrogen feeds for fuel cells. In fact, today gold catalysts are being exploited in a major way for the greening of many important reactions in the chemical industry, because they can lead to cleaner, more efficient reactions with fewer by-products. Haruta and Graham J. Hutchings, who co-discovered the use of gold as a catalyst for different reactions, are noted as Thompson Reuters Citation Laureates and appear annually on the ScienceWatch Nobel Prize prediction list. Their pioneering work opened up a new area of scientific inquiry and kicked off a decades-long debate about which type of supported gold species are most effective for the CO oxidation reaction. In 2008, using electron microscopy technology that was not yet available in the 1980s and 90s, Hutchings, director of the Cardiff Catalysis Institute at Cardiff University worked with Kiely, Harold B. Chambers Senior Professor Materials Science and Engineering at Lehigh, examined the structure of supported gold at the nanoscale. One nanometer (nm) is equal to one one-billionth of a meter or about the diameter of five atoms. Using what was then a rare piece of equipment—Lehigh's aberration-corrected JEOL 2200 FS scanning transmission electron microscope (STEM)—the team identified the co-existence of three distinct gold species: facetted nanoparticles larger than one nanometer in size, sub-clusters containing less than 20 atoms and individual gold atoms strewn over the support. Because only the larger gold nanoparticles had previously been detected, this created debate as to which of these species were responsible for the good catalytic behavior. Haruta, professor of applied chemistry at Tokyo Metropolitan University, Hutchings and Kiely have been working collaboratively on this problem over recent years and are now the first to demonstrate conclusively that it is not the particles or the individual atoms or the clusters which are solely responsible for the catalysis—but that they all contribute to different degrees. Their results have been published in an article in Nature Communications titled: \"Population and hierarchy of active species in gold iron oxide catalysts for carbon monoxide oxidation.\" \"All of the species tend to co-exist in conventionally prepared catalysts and show some level of activity,\" says Kiely. \"They all do something—but some less efficiently than others.\" Their research revealed the sub-nanometer clusters and 1-3nm nanoparticles to be the most efficient for catalyzing this CO oxidation reaction, while larger particles were less so and the atoms even less. Nevertheless, Kiely cautions, all the species present need to be considered to fully explain the overall measured activity of the catalyst. Among the team's other key findings: the measured activity of gold on iron oxide catalysts is exquisitely dependent on exactly how the material is prepared. Very small changes in synthesis parameters influence the relative proportion and spatial distribution of these various Au species on the support material and thus have a big impact on its overall catalytic performance. A golden opportunity Building on their earlier work (published in a 2008 Science article), the team sought to find a robust way to quantitatively analyze the relative population distributions of nanoparticles of various sizes, sub-nm clusters and highly dispersed atoms in a given gold on iron oxide sample. By correlating this information with catalytic performance measurements, they then hoped to determine which species distribution would be optimal to produce the most efficient catalyst, in order to utilize the precious gold component in the most cost effective way. Ultimately, it was a catalyst synthesis problem the team faced that offered them a golden opportunity to do just that. During the collaboration, Haruta's and Hutchings' teams each prepared gold on iron oxide samples in their home labs in Tokyo and Cardiff. Even though both groups nominally utilized the same 'co-precipitation' synthesis method, it turned out that a final heat treatment step was beneficial to the catalytic performance for one set of materials but detrimental to the other. This observation provided a fascinating scientific conundrum that detailed electron microscopy studies performed by Qian He, one of Kiely's PhD students at the time, was key to solving. Qian He is now a University Research Fellow at Cardiff University leading their electron microscopy effort. \"In the end, there were subtle differences in the order and speed in which each group added in their ingredients while preparing the material,\" explains He. \"When examined under the electron microscope, it was clear that the two slightly different methods produced quite different distributions of particles, clusters and dispersed atoms on the support.\" \"Very small variations in the preparation route or thermal history of the sample can alter the relative balance of supported gold nanoparticles-to-clusters-to-atoms in the material and this manifests itself in the measured catalytic activity,\" adds Kiely. The group was able to compare this set of materials and correlate the Au species distributions with catalytic performance measurements, ultimately identifying the species distribution that was associated with greater catalytic efficiency. Now that the team has identified the catalytic activity hierarchy associated with these supported gold species, the next step, says Kiely, will be to modify the synthesis method to positively influence that distribution to optimize the catalyst performance while making the most efficient use of the precious gold metal content. \"As a next stage to this study we would like to be able to observe gold on iron oxide materials in-situ within the electron microscope while the reaction is happening,\" says Kiely. Once again, it is next generation microscopy facilities that may hold the key to fulfilling gold's promise as a pivotal player in green technology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The identity of active species in supported gold catalysts for low temperature carbon monoxide oxidation remains an unsettled debate. With large amounts of experimental evidence supporting theories of either gold nanoparticles or sub-nm gold species being active, it was recently proposed that a size-dependent activity hierarchy should exist. Here we study the diverging catalytic behaviours after heat treatment of Au/FeO x materials prepared via co-precipitation and deposition precipitation methods. After ruling out any support effects, the gold particle size distributions in different catalysts are quantitatively studied using aberration corrected scanning transmission electron microscopy (STEM). A counting protocol is developed to reveal the true particle size distribution from HAADF-STEM images, which reliably includes all the gold species present. Correlation of the populations of the various gold species present with catalysis results demonstrate that a size-dependent activity hierarchy must exist in the Au/FeO x catalyst. Introduction The discovery by Haruta et al . 1 , 2 that CO oxidation was catalysed by Au nanoparticles supported on iron oxide has led to 30 years of scientific debate surrounding the nature of the active species 3 ; however, no unequivocal identification of the active species has been reported to date and often the findings are contradictory 3 , 4 , 5 , 6 . Bond and Thompson 7 initiated the mechanistic debate based solely on Au nanoparticles and Lopez et al . 8 showed that activity increased with decreasing nanoparticle size with the optimum being 1–2 nm. Goodman et al . 9 , 10 explained the role played by the Au/support periphery atoms by showing that extended Au bilayer structures on TiO 2 were extremely active for CO oxidation. Herzing et al . 11 reported a study that utilized high-angle annular dark field (HAADF) imaging in an aberration corrected STEM to investigate, for the first time, the full range of supported Au species present in real Au/FeO x catalysts (namely isolated atoms, sub-nm mono- and bilayer structures and particulate species above 1 nm in size). It was found that by heat treating a highly active dried Au/FeO x catalyst prepared by co-precipitation (CP), the number of isolated atoms observed decreased, the number of monolayer clusters remained relatively constant and the number of bilayer clusters decreased, whereas the number of nanoparticles (>1 nm) increased, all of which coincided with a measured decrease in catalytic activity. They proposed that the active catalysts contained more sub-nm bilayer clusters and fewer nanoparticles >1 nm, which agreed well with Goodman’s work 9 , 10 and also with the observations of Landman et al . 12 , who predicted that a minimum grouping of eight Au atoms is needed to show CO oxidation activity. More recently, Schüth et al . 13 demonstrated that Au/FeO x catalysts prepared by colloid immobilization methods can exhibit high CO oxidation activity while being devoid of any sub-nm clusters. These data combined with that of Herzing et al . 11 suggest that there is not just one distinct active site for CO oxidation over supported Au species and that particles existing over a broad size range may be effective for the reaction. Such a possibility was also recently highlighted by Haruta 3 , who suggested that catalysts consist of a range of co-existing Au nanostructures each with its own characteristic activity. We propose that such an activity hierarchy might have a more general significance and readily exist in many well-studied supported metal systems, but has remained undetected and unrecognized to date because the complex diversity of metal species present, spanning a range of sizes, have not been fully characterized since aberration-corrected STEM imaging was not available to detect them in earlier studies 1 , 2 , 14 , 15 . In this work, we re-visit Au/FeO x catalysts and use a new counting protocol to reveal the true particle size distribution (PSD) from HAADF-STEM images, which reliably includes all the Au species present and we show experimentally that an activity hierarchy does indeed exist. Results Diverging behaviour after heat treatments of two CP catalysts We studied Au/FeO x catalysts prepared by two different co-precipitation (CP) methods previously reported by Haruta et al . 1 (denoted CP-1) and Hutchings et al . 16 , 17 (denoted CP-2). While the methods are similar (see ‘Methods’ section for details), subtle differences exist in the sequence and rate of mixing the acidic and basic precursors. In the CP-1 method, the acidic solution (Fe(NO 3 ) 3 +HAuCl 4 ) was added quickly (within 2 min) into the basic solution (Na 2 CO 3 ), whereas in the CP-2 method, the basic solution was slowly added drop-wise into the acidic solution over 30 min. These subtle preparation differences have dramatic effects on the catalytic behaviour. Figure 1a shows the CO oxidation activities over a range of temperatures after drying and calcination. The acid-into-base (CP-1) and base-into-acid (CP-2) catalysts at the dried-only stage (120 °C, 16 h) had similar CO conversion over the temperature range tested. However, after calcination at 300 °C for 3 h, the base-into-acid (CP-2) catalyst is deactivated, whereas the acid-into-base (CP-1) catalyst becomes more active, especially at lower temperatures as has been reported previously by Haruta 1 . This dramatic difference in activity after calcination treatment provides us with the basis sample set for this comparative structural study. Figure 1: Diverging catalyst behaviour after heat treatment. ( a ) CO conversion at various temperatures. Catalyst mass 150 mg, gas flow 50 ml min −1 1 vol% CO in air. ( b ) Arrhenius plots carried out at low conversion conditions. Empty circles (CP-1, dried, 6 wt% Au by ICP) filled circles (CP-1, calcined, 6 wt% Au by ICP) empty squares (CP-2, dried, 3.5 wt% Au by ICP) filled squares (CP-2, calcined, 3.5 wt% Au by ICP). The arrows shown in a represent the thermal activation behaviour (black arrow) of the CP-1 catalyst and the thermal deactivation behaviour (white arrow) of the CP-2 catalyst. Full size image We studied the reaction kinetics to ascertain whether the higher<|im_end|> <|im_start|>assistant Settling a decades-long debate, new research conclusively shows that a hierarchy of active species exists in gold on iron oxide catalysis designed for low temperature carbon monoxide oxidation; Nanoparticles, sub-nanometer clusters and dispersed atoms—as well as how the material is prepared—are all important for determining catalytic activity. Christopher J. Kiely calls the 1982 discovery by Prof. Masatake Haruta that gold (Au) possessed a high level of catalytic activity for carbon monoxide (CO) oxidation when deposited on a metal-oxide "a remarkable turn of events in nanotechnology"—remarkable because gold had long been assumed to be inert for catalysis. Haruta showed that gold dispersed on iron oxide effectively catalyzed the conversion of harmful carbon monoxide into more benign carbon dioxide (CO2) at room temperatures—a reaction that is critical for the construction of fire fighters' breathing masks and for removal of CO from hydrogen feeds for fuel cells. In fact, today gold catalysts are being exploited in a major way for the greening of many important reactions in the chemical industry, because they can lead to cleaner, more efficient reactions with fewer by-products. Haruta and Graham J. Hutchings, who co-discovered the use of gold as a catalyst for different reactions, are noted as Thompson Reuters Citation Laureates and appear annually on the ScienceWatch Nobel Prize prediction list. Their pioneering work opened up a new area of scientific inquiry and kicked off a decades-long debate about which type of supported gold species are most effective for the CO oxidation reaction. In 2008, using electron microscopy technology that was not yet available in the 1980s and 90s, Hutchings, director of the Cardiff Catalysis Institute at Cardiff University worked with Kiely, Harold B. Chambers Senior Professor Materials Science and Engineering at Lehigh, examined the structure of supported gold at the nanoscale. One nanometer (nm) is equal to one one-billionth of a meter or about the diameter of five atoms. Using what was then a rare piece of equipment—Lehigh's aberration-corrected JEOL 2200 FS scanning transmission electron microscope (STEM)—the team identified the co-existence of three distinct gold species: facetted nanoparticles larger than one nanometer in size, sub-clusters containing less than 20 atoms and individual gold atoms strewn over the support. Because only the larger gold nanoparticles had previously been detected, this created debate as to which of these species were responsible for the good catalytic behavior. Haruta, professor of applied chemistry at Tokyo Metropolitan University, Hutchings and Kiely have been working collaboratively on this problem over recent years and are now the first to demonstrate conclusively that it is not the particles or the individual atoms or the clusters which are solely responsible for the catalysis—but that they all contribute to different degrees. Their results have been published in an article in Nature Communications titled: "Population and hierarchy of active species in gold iron oxide catalysts for carbon monoxide oxidation." "All of the species tend to co-exist in conventionally prepared catalysts and show some level of activity," says Kiely. "They all do something—but some less efficiently than others." Their research revealed the sub-nanometer clusters and 1-3nm nanoparticles to be the most efficient for catalyzing this CO oxidation reaction, while larger particles were less so and the atoms even less. Nevertheless, Kiely cautions, all the species present need to be considered to fully explain the overall measured activity of the catalyst. Among the team's other key findings: the measured activity of gold on iron oxide catalysts is exquisitely dependent on exactly how the material is prepared. Very small changes in synthesis parameters influence the relative proportion and spatial distribution of these various Au species on the support material and thus have a big impact on its overall catalytic performance. A golden opportunity Building on their earlier work (published in a 2008 Science article), the team sought to find a robust way to quantitatively analyze the relative population distributions of nanoparticles of various sizes, sub-nm clusters and highly dispersed atoms in a given gold on iron oxide sample. By correlating this information with catalytic performance measurements, they then hoped to determine which species distribution would be optimal to produce the most efficient catalyst, in order to utilize the precious gold component in the most cost effective way. Ultimately, it was a catalyst synthesis problem the team faced that offered them a golden opportunity to do just that. During the collaboration, Haruta's and Hutchings' teams each prepared gold on iron oxide samples in their home labs in Tokyo and Cardiff. Even though both groups nominally utilized the same 'co-precipitation' synthesis method, it turned out that a final heat treatment step was beneficial to the catalytic performance for one set of materials but detrimental to the other. This observation provided a fascinating scientific conundrum that detailed electron microscopy studies performed by Qian He, one of Kiely's PhD students at the time, was key to solving. Qian He is now a University Research Fellow at Cardiff University leading their electron microscopy effort. "In the end, there were subtle differences in the order and speed in which each group added in their ingredients while preparing the material," explains He. "When examined under the electron microscope, it was clear that the two slightly different methods produced quite different distributions of particles, clusters and dispersed atoms on the support." "Very small variations in the preparation route or thermal history of the sample can alter the relative balance of supported gold nanoparticles-to-clusters-to-atoms in the material and this manifests itself in the measured catalytic activity," adds Kiely. The group was able to compare this set of materials and correlate the Au species distributions with catalytic performance measurements, ultimately identifying the species distribution that was associated with greater catalytic efficiency. Now that the team has identified the catalytic activity hierarchy associated with these supported gold species, the next step, says Kiely, will be to modify the synthesis method to positively influence that distribution to optimize the catalyst performance while making the most efficient use of the precious gold metal content. "As a next stage to this study we would like to be able to observe gold on iron oxide materials in-situ within the electron microscope while the reaction is happening," says Kiely. Once again, it is next generation microscopy facilities that may hold the key to fulfilling gold's promise as a pivotal player in green technology. <|im_end|>

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6761, 389, 11245, 51180, 34454, 4548, 6319, 369, 3428, 9499, 12782, 1647, 55189, 71162, 26, 33242, 454, 16641, 11, 1207, 5392, 276, 21037, 28066, 323, 77810, 33299, 60654, 1664, 439, 1268, 279, 3769, 374, 10235, 83872, 682, 3062, 369, 26679, 34454, 70504, 5820, 13, 26035, 622, 13, 30558, 989, 6880, 279, 220, 3753, 17, 18841, 555, 8626, 13, 20459, 460, 441, 5340, 16382, 430, 6761, 320, 66432, 8, 43890, 264, 1579, 2237, 315, 34454, 70504, 5820, 369, 12782, 1647, 55189, 320, 8445, 8, 71162, 994, 54568, 389, 264, 9501, 12, 55189, 330, 64, 23649, 2543, 315, 4455, 304, 20622, 52536, 66101, 38548, 481, 1606, 6761, 1047, 1317, 1027, 19655, 311, 387, 81073, 369, 34454, 4548, 13, 5340, 16382, 8710, 430, 6761, 77810, 389, 11245, 51180, 13750, 34454, 88, 16284, 279, 14747, 315, 28856, 12782, 1647, 55189, 1139, 810, 65309, 12782, 40589, 320, 8445, 17, 8, 520, 3130, 20472, 29096, 13010, 430, 374, 9200, 369, 279, 8246, 315, 4027, 24080, 6, 27027, 27227, 323, 369, 17065, 315, 7432, 505, 35784, 35496, 369, 10633, 7917, 13, 763, 2144, 11, 3432, 6761, 51483, 82, 527, 1694, 51763, 304, 264, 3682, 1648, 369, 279, 2886, 6147, 315, 1690, 3062, 25481, 304, 279, 11742, 5064, 11, 1606, 814, 649, 3063, 311, 32981, 11, 810, 11297, 25481, 449, 17162, 555, 68973, 13, 5340, 16382, 323, 26181, 622, 13, 60787, 826, 11, 889, 1080, 10694, 21468, 279, 1005, 315, 6761, 439, 264, 51483, 369, 2204, 25481, 11, 527, 10555, 439, 26224, 23688, 70423, 33767, 988, 323, 5101, 30171, 389, 279, 10170, 14581, 48078, 32293, 20212, 1160, 13, 11205, 71674, 990, 9107, 709, 264, 502, 3158, 315, 12624, 26981, 323, 28219, 1022, 264, 11026, 24725, 11249, 922, 902, 955, 315, 7396, 6761, 9606, 527, 1455, 7524, 369, 279, 7432, 71162, 13010, 13, 763, 220, 1049, 23, 11, 1701, 17130, 92914, 5557, 430, 574, 539, 3686, 2561, 304, 279, 220, 3753, 15, 82, 323, 220, 1954, 82, 11, 60787, 826, 11, 7690, 315, 279, 61692, 32544, 4548, 10181, 520, 61692, 3907, 6575, 449, 30558, 989, 11, 53215, 426, 13, 65276, 19903, 17054, 32009, 10170, 323, 17005, 520, 2009, 12156, 11, 25078, 279, 6070, 315, 7396, 6761, 520, 279, 20622, 437, 2296, 13, 3861, 20622, 21037, 320, 20211, 8, 374, 6273, 311, 832, 832, 70173, 339, 315, 264, 23819, 477, 922, 279, 23899, 315, 4330, 33299, 13, 12362, 1148, 574, 1243, 264, 9024, 6710, 315, 7241, 2345, 2356, 12156, 596, 82102, 367, 1824, 28132, 291, 71430, 1971, 220, 8610, 15, 25275, 36201, 18874, 17130, 73757, 320, 15642, 68850, 1820, 2128, 11054, 279, 1080, 10397, 81624, 315, 2380, 12742, 6761, 9606, 25, 45607, 6702, 94753, 8294, 1109, 832, 20622, 21037, 304, 1404, 11, 1207, 31717, 14947, 8649, 2753, 1109, 220, 508, 33299, 323, 3927, 6761, 33299, 5527, 1551, 927, 279, 1862, 13, 9393, 1193, 279, 8294, 6761, 94753, 1047, 8767, 1027, 16914, 11, 420, 3549, 11249, 439, 311, 902, 315, 1521, 9606, 1051, 8647, 369, 279, 1695, 34454, 70504, 7865, 13, 5340, 16382, 11, 14561, 315, 9435, 30903, 520, 27286, 45878, 3907, 11, 60787, 826, 323, 30558, 989, 617, 1027, 3318, 11430, 8046, 389, 420, 3575, 927, 3293, 1667, 323, 527, 1457, 279, 1176, 311, 20461, 84082, 3210, 430, 433, 374, 539, 279, 19252, 477, 279, 3927, 33299, 477, 279, 28066, 902, 527, 21742, 8647, 369, 279, 34454, 4548, 38542, 430, 814, 682, 17210, 311, 2204, 12628, 13, 11205, 3135, 617, 1027, 4756, 304, 459, 4652, 304, 22037, 26545, 25891, 25, 330, 54471, 323, 30022, 315, 4642, 9606, 304, 6761, 11245, 51180, 51483, 82, 369, 12782, 1647, 55189, 71162, 1210, 330, 2460, 315, 279, 9606, 8541, 311, 1080, 10397, 380, 304, 21977, 750, 10235, 51483, 82, 323, 1501, 1063, 2237, 315, 5820, 1359, 2795, 30558, 989, 13, 330, 7009, 682, 656, 2555, 38542, 1063, 2753, 30820, 1109, 3885, 1210, 11205, 3495, 10675, 279, 1207, 5392, 276, 21037, 28066, 323, 220, 16, 12, 18, 20211, 94753, 311, 387, 279, 1455, 11297, 369, 34454, 18854, 287, 420, 7432, 71162, 13010, 11, 1418, 8294, 19252, 1051, 2753, 779, 323, 279, 33299, 1524, 2753, 13, 35053, 11, 30558, 989, 2211, 4065, 11, 682, 279, 9606, 3118, 1205, 311, 387, 6646, 311, 7373, 10552, 279, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Methods for site-selective chemistry on proteins are in high demand for the synthesis of chemically modified biopharmaceuticals, as well as for applications in chemical biology, biosensors and more. Inadvertent N-terminal gluconoylation has been reported during expression of proteins with an N-terminal His tag. Here we report the development of this side-reaction into a general method for highly selective N-terminal acylation of proteins to introduce functional groups. We identify an optimized N-terminal sequence, GHHH n − for the reaction with gluconolactone and 4-methoxyphenyl esters as acylating agents, facilitating the introduction of functionalities in a highly selective and efficient manner. Azides, biotin or a fluorophore are introduced at the N-termini of four unrelated proteins by effective and selective acylation with the 4-methoxyphenyl esters. This Gly-His n tag adds the unique capability for highly selective N-terminal chemical acylation of expressed proteins. We anticipate that it can find wide application in chemical biology and for biopharmaceuticals. Introduction Methods for site-selective modification of peptides and proteins are required for different fields, such as the development of biopharmaceutical conjugates (e.g., PEGylation, lipidation, and antibody–drug conjugates) 1 , bioimaging 2 , medical diagnostics 3 , and material sciences 4 . Most proteins display multiple copies of the same side-chain at different locations. Reactions that target a particular functional group, e.g., the primary amine in Lys or thiol in Cys, potentially modify all occurrences of this residue, leading to the formation of a heterogeneous mixture of modified protein. Reactions involving proteins must also proceed in aqueous solutions under mild pH and temperature. These factors make it challenging to modify proteins in a regioselective manner. Several strategies have been developed to address this challenge. Some methods rely on genetic code expansion 5 , 6 , 7 , which allows for the site-specific, ribosomal incorporation of non-canonical amino acids that exhibit suitable functionalities for bioorthogonal chemistry 8 , 9 . However, selective chemical methods applicable to proteins consisting of only canonical amino acids are an attractive alternative, as these proteins can be produced using standard, higher-yielding expression methods. N-termini of proteins tend to reside on the surface of proteins 10 and are thus often well accessible to chemical modification 11 . Also, they can often be extended with additional amino acids without interference with protein function 11 . The N-terminal α-amine can be targeted for selective, pH-controlled acylation or alkylation due to its p K a value that is lower (p K a 7.6–8.0) than for Lys side-chain ε-amines (p K a 10.5 ± 1.1) 12 . Nevertheless, the selectivity is often challenged by the presence of a high number of competing ε-amines on Lys residues and the fact that their p K a can be lower due to the local environment. Also, direct acylation with NHS esters and reductive alkylation require a low-to-neutral pH. Alternatively, particular amino acids can be specifically targeted when located at the N-terminus, such as Cys via native chemical ligation 13 or 2-cyanobenzothiazole (CBT) condensation chemistry 14 , Trp via Pictet–Spengler reactions 15 , 16 , Ser and Thr via periodate oxidation to yield aldehydes for subsequent conjugation with α-nucleophiles 17 , 18 , 19 , 20 , or Pro via oxidative coupling with aminophenols 11 , 21 . A small number of more general approaches for site-selective N-terminal modification without specific residue requirements have been described. A site-selective diazotransfer reaction for azide introduction has been achieved with imidazole-1-sulfonyl azide at pH 8–8.5 22 , a phenyl ketene derivative has been used for alkyne introduction 23 , a transamination reaction with 2-pyridinecarboxyaldehydes has been reported 24 , as well as reductive alkylation 25 . In addition to these methods for N-terminal labeling, the use of a four amino acid sequence (Phe-Cys-Pro-Phe) that enhances the reactivity of its cysteine residue for site-selective reaction with perfluoroaryl compounds has been reported 26 . Other small peptide sequences with high affinity for molecules of interest, e.g., fluorophores, have been reported. For instance, a tetracysteine tag (Cys-Cys-Xxx-Xxx-Cys-Cys) for selective reaction with an arsenic-modified fluorescein derivative 26 , 27 and a tetraserine motif (Ser-Ser-Pro-Gly-Ser-Ser) that binds a rhodamine-derived bisboronic acid 28 . Polyhistidine tags (His tags) are widely used for protein purification by immobilized-metal ion affinity chromatography 29 . However, it has been reported that during their expression His-tagged proteins can undergo N-terminal acylation with d -gluconic acid δ-lactone (GDL, 1 ) as an inadvertent side-reaction 30 . Geoghegan et al. observed gluconoylation of proteins when expressed in Escherichia coli , while using His tags with the N-terminal sequence GSSHHHHHHSSGLVPR–. They also reported that synthetic peptides GSSHHHHHHSSGLVPR, GSAHHHHAAR, GASHHHHAAR, and GAAHHHHAAR could be modified with GDL in HEPES buffer at pH 7.5 30 . Here, we convert an undesirable side-reaction into a highly selective chemical method for modification of peptides and proteins (Fig. 1 ). We identify an optimal N-terminal sequence (GHHH n ) using GDL as inexpensive, water-soluble acylating agent. Studying the reactivity with other acylating agents, 4-methoxyphenyl esters gave good selectivity for acylation of this N-terminal tag. 4-Methoxyphenyl esters facilitate the introduction of small reactive groups, such as azides, or the direct conjugation of functional molecules such as biotin. We demonstrate the potential on several peptides and proteins. The GHHHHHH tag, which can be fused to the N-terminus of any protein of interest, offers a dual functionality His tag as it can still be used for affinity purification. We believe that this methodology will be a valuable contribution to the toolbox for N-terminal modification. We propose the name His tag acylation to describe this method. Fig. 1 Concept for N-terminal His tag acylation of Gly-His n sequences. a Optimization of the His tag sequence for acylation with GDL; b identification of 4-methoxyphenyl esters as functional acylating agents; and c application of the His tag acylation to proteins Full size image Results d -Gluconic acid δ-lactone for peptide modifications We hypothesized that highly site-selective gluconoylation of the Nα-amine could be achieved with an optimized N-terminal sequence. We synthesized 11 peptides with different N-terminal tags attached to the sequence LRFKFY-NH", "role": "user" }, { "content": "Protein research is one of the hottest areas in medical research because proteins make it possible to develop far more effective pharmaceuticals for the treatment of diabetes, cancer and other illnesses. However, while proteins have great potential, they also present great challenges for scientists. Proteins have incredibly complex chemical structures that make them difficult to modify. As a result, researchers have been looking for a tool to modify them more precisely without increasing a potential drug's side-effects. \"We often run the risk of not being approved by health authorities because protein-based drugs lack precision and may have side-effects. Among other things, this is because of the serious limitations with the tools that have been used up until now,\" says Professor Knud J. Jensen of the University of Copenhagen's Department of Chemistry. Together with his research colleague, Sanne Schoffelen, he has developed a new protein-modifying method that promises fewer side-effects and could be pivotal in furthering the development of protein-based pharmaceuticals. Their work has been published in the distinguished journal, Nature Communications. Protein structure is like an intricate ball of yarn Researchers call the method His-tag acylation. Among other things, it makes it possible the addition of a toxic molecule to proteins that can attack sick cells in a cancer-stricken body without attacking healthy ones. \"Proteins are like a ball of yarn, a long thread of amino acids, which are turned up. This method allows us to precisely target these intricate structures, as opposed to making uncertain modifications when we don't know what is being hit within the ball of yarn. In short, it will help produce drugs with far more confidence about where modifications are being made, so that side effects can be minimized in the future,\" says Knud J. Jensen. Modified proteins must target precisely The fact that His-tag acylation can accurately target these complex yarn-like protein structures also makes it possible to produce drugs with entirely new characteristics. For example, researchers can now attach a fluorescent molecule to proteins in such a way that a microscope can be used to track a protein's path through cells. The primary function of these proteins is to transport cancer fighting molecules around to sick cells, so it is important to carefully follow their path throughout the body in order to safely produce medications that don't have unintended side-effects. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Methods for site-selective chemistry on proteins are in high demand for the synthesis of chemically modified biopharmaceuticals, as well as for applications in chemical biology, biosensors and more. Inadvertent N-terminal gluconoylation has been reported during expression of proteins with an N-terminal His tag. Here we report the development of this side-reaction into a general method for highly selective N-terminal acylation of proteins to introduce functional groups. We identify an optimized N-terminal sequence, GHHH n − for the reaction with gluconolactone and 4-methoxyphenyl esters as acylating agents, facilitating the introduction of functionalities in a highly selective and efficient manner. Azides, biotin or a fluorophore are introduced at the N-termini of four unrelated proteins by effective and selective acylation with the 4-methoxyphenyl esters. This Gly-His n tag adds the unique capability for highly selective N-terminal chemical acylation of expressed proteins. We anticipate that it can find wide application in chemical biology and for biopharmaceuticals. Introduction Methods for site-selective modification of peptides and proteins are required for different fields, such as the development of biopharmaceutical conjugates (e.g., PEGylation, lipidation, and antibody–drug conjugates) 1 , bioimaging 2 , medical diagnostics 3 , and material sciences 4 . Most proteins display multiple copies of the same side-chain at different locations. Reactions that target a particular functional group, e.g., the primary amine in Lys or thiol in Cys, potentially modify all occurrences of this residue, leading to the formation of a heterogeneous mixture of modified protein. Reactions involving proteins must also proceed in aqueous solutions under mild pH and temperature. These factors make it challenging to modify proteins in a regioselective manner. Several strategies have been developed to address this challenge. Some methods rely on genetic code expansion 5 , 6 , 7 , which allows for the site-specific, ribosomal incorporation of non-canonical amino acids that exhibit suitable functionalities for bioorthogonal chemistry 8 , 9 . However, selective chemical methods applicable to proteins consisting of only canonical amino acids are an attractive alternative, as these proteins can be produced using standard, higher-yielding expression methods. N-termini of proteins tend to reside on the surface of proteins 10 and are thus often well accessible to chemical modification 11 . Also, they can often be extended with additional amino acids without interference with protein function 11 . The N-terminal α-amine can be targeted for selective, pH-controlled acylation or alkylation due to its p K a value that is lower (p K a 7.6–8.0) than for Lys side-chain ε-amines (p K a 10.5 ± 1.1) 12 . Nevertheless, the selectivity is often challenged by the presence of a high number of competing ε-amines on Lys residues and the fact that their p K a can be lower due to the local environment. Also, direct acylation with NHS esters and reductive alkylation require a low-to-neutral pH. Alternatively, particular amino acids can be specifically targeted when located at the N-terminus, such as Cys via native chemical ligation 13 or 2-cyanobenzothiazole (CBT) condensation chemistry 14 , Trp via Pictet–Spengler reactions 15 , 16 , Ser and Thr via periodate oxidation to yield aldehydes for subsequent conjugation with α-nucleophiles 17 , 18 , 19 , 20 , or Pro via oxidative coupling with aminophenols 11 , 21 . A small number of more general approaches for site-selective N-terminal modification without specific residue requirements have been described. A site-selective diazotransfer reaction for azide introduction has been achieved with imidazole-1-sulfonyl azide at pH 8–8.5 22 , a phenyl ketene derivative has been used for alkyne introduction 23 , a transamination reaction with 2-pyridinecarboxyaldehydes has been reported 24 , as well as reductive alkylation 25 . In addition to these methods for N-terminal labeling, the use of a four amino acid sequence (Phe-Cys-Pro-Phe) that enhances the reactivity of its cysteine residue for site-selective reaction with perfluoroaryl compounds has been reported 26 . Other small peptide sequences with high affinity for molecules of interest, e.g., fluorophores, have been reported. For instance, a tetracysteine tag (Cys-Cys-Xxx-Xxx-Cys-Cys) for selective reaction with an arsenic-modified fluorescein derivative 26 , 27 and a tetraserine motif (Ser-Ser-Pro-Gly-Ser-Ser) that binds a rhodamine-derived bisboronic acid 28 . Polyhistidine tags (His tags) are widely used for protein purification by immobilized-metal ion affinity chromatography 29 . However, it has been reported that during their expression His-tagged proteins can undergo N-terminal acylation with d -gluconic acid δ-lactone (GDL, 1 ) as an inadvertent side-reaction 30 . Geoghegan et al. observed gluconoylation of proteins when expressed in Escherichia coli , while using His tags with the N-terminal sequence GSSHHHHHHSSGLVPR–. They also reported that synthetic peptides GSSHHHHHHSSGLVPR, GSAHHHHAAR, GASHHHHAAR, and GAAHHHHAAR could be modified with GDL in HEPES buffer at pH 7.5 30 . Here, we convert an undesirable side-reaction into a highly selective chemical method for modification of peptides and proteins (Fig. 1 ). We identify an optimal N-terminal sequence (GHHH n ) using GDL as inexpensive, water-soluble acylating agent. Studying the reactivity with other acylating agents, 4-methoxyphenyl esters gave good selectivity for acylation of this N-terminal tag. 4-Methoxyphenyl esters facilitate the introduction of small reactive groups, such as azides, or the direct conjugation of functional molecules such as biotin. We demonstrate the potential on several peptides and proteins. The GHHHHHH tag, which can be fused to the N-terminus of any protein of interest, offers a dual functionality His tag as it can still be used for affinity purification. We believe that this methodology will be a valuable contribution to the toolbox for N-terminal modification. We propose the name His tag acylation to describe this method. Fig. 1 Concept for N-terminal His tag acylation of Gly-His n sequences. a Optimization of the His tag sequence for acylation with GDL; b identification of 4-methoxyphenyl esters as functional acylating agents; and c application of the His tag acylation to proteins Full size image Results d -Gluconic acid δ-lactone for peptide modifications We hypothesized that highly site-selective gluconoylation of the Nα-amine could be achieved with an optimized N-terminal sequence. We synthesized 11 peptides with different N-terminal tags attached to the sequence LRFKFY-NH<|im_end|> <|im_start|>assistant Protein research is one of the hottest areas in medical research because proteins make it possible to develop far more effective pharmaceuticals for the treatment of diabetes, cancer and other illnesses. However, while proteins have great potential, they also present great challenges for scientists. Proteins have incredibly complex chemical structures that make them difficult to modify. As a result, researchers have been looking for a tool to modify them more precisely without increasing a potential drug's side-effects. "We often run the risk of not being approved by health authorities because protein-based drugs lack precision and may have side-effects. Among other things, this is because of the serious limitations with the tools that have been used up until now," says Professor Knud J. Jensen of the University of Copenhagen's Department of Chemistry. Together with his research colleague, Sanne Schoffelen, he has developed a new protein-modifying method that promises fewer side-effects and could be pivotal in furthering the development of protein-based pharmaceuticals. Their work has been published in the distinguished journal, Nature Communications. Protein structure is like an intricate ball of yarn Researchers call the method His-tag acylation. Among other things, it makes it possible the addition of a toxic molecule to proteins that can attack sick cells in a cancer-stricken body without attacking healthy ones. "Proteins are like a ball of yarn, a long thread of amino acids, which are turned up. This method allows us to precisely target these intricate structures, as opposed to making uncertain modifications when we don't know what is being hit within the ball of yarn. In short, it will help produce drugs with far more confidence about where modifications are being made, so that side effects can be minimized in the future," says Knud J. Jensen. Modified proteins must target precisely The fact that His-tag acylation can accurately target these complex yarn-like protein structures also makes it possible to produce drugs with entirely new characteristics. For example, researchers can now attach a fluorescent molecule to proteins in such a way that a microscope can be used to track a protein's path through cells. The primary function of these proteins is to transport cancer fighting molecules around to sick cells, so it is important to carefully follow their path throughout the body in order to safely produce medications that don't have unintended side-effects. <|im_end|>

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2,041

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mars Science Laboratory (MSL) Curiosity rover data are used to describe the morphology of desiccation cracks observed in ancient lacustrine strata at Gale crater, Mars, and to interpret their paleoenvironmental setting. The desiccation cracks indicate subaerial exposure of lacustrine facies in the Sutton Island member of the Murray formation. In association with ripple cross-stratification and possible eolian cross-bedding, these facies indicate a transition from longer-lived perennial lakes recorded by older strata to younger lakes characterized by intermittent exposure. The transition from perennial to episodically exposed lacustrine environments provides evidence for local to regional climate change that can help constrain Mars climate models. INTRODUCTION Reconstructions of ancient habitable environments on Mars increasingly depend on detailed analysis of sedimentary facies recording aqueous environments. Over the past decade, the Mars Exploration Rover Opportunity encountered ancient eolian, fluvial, and lacustrine environments deposited in hypersaline, acidic, sulfate- and hematite-enriched playas formed in interdune depressions at Meridiani Planum (e.g. Grotzinger et al., 2005 ). This setting contrasts with the clay- and magnetite-bearing, moderate pH, perennial lacustrine facies in Gale crater ( Grotzinger et al., 2014 , 2015 ; Hurowitz et al., 2017 ; Rampe et al., 2017 ). Suites of sedimentary structures, facies associations, and authigenic and diagenetic mineral assemblages were essential to recognize these paleoenvironmental settings. Previously, potential martian desiccation cracks were identified in multiple sedimentary deposits from orbit (e.g., El-Maarry et al., 2014 ) and in situ by rovers ( Grotzinger et al., 2005 , 2014 ). The kilometers-thick sedimentary succession in Gale crater provides an opportunity to observe changes in surface environments over extended periods in martian history. Studies of basal strata in the informally named Murray formation demonstrated the presence of long-lived perennial lakes in Gale crater at ca. 3.6–3.2 Ga ( Grotzinger et al., 2014 , 2015 ; Hurowitz et al., 2017 ). Recent facies observations at higher stratigraphic levels ( Fedo et al., 2017 ) may record an evolution of the environment over time. Here we present in situ evidence for lithified desiccation cracks in the Murray formation, indicating that the lakes may have partially dried in its younger history. During Sols 1555–1571, Curiosity investigated a series of distinctive centimeter-scale reticulate ridges on the surfaces of several slabs of rock that expose bedding planes in the Sutton Island member of the Murray formation. Their morphology and composition is characterized to determine if they formed via desiccation and to examine implications for the deposition of associated strata. GEOLOGIC SETTING As of Sol 1700, the Curiosity rover has explored more than 200 m of strata consisting of fluvial, deltaic, lacustrine, and eolian sediments ( Williams et al., 2013 ; Grotzinger et al., 2014 , 2015 ; Banham et al., 2016; Edgar et al., 2017) represented by the Bradbury group, the interfingering and overlying Murray formation (Mount Sharp group), and the unconformably overlying Stimson formation (Siccar Point group) ( Fig. 1 ). The first ∼25-m-thick Murray interval consists dominantly of finely laminated mudstones with minor siltstones and sandstones of lacustrine origin ( Grotzinger et al., 2015 ). It is overlain by an ∼25-m-thick interval with decimeter- to meter-scale cross-stratification that suggests sediment transport as large bedforms or in channels ( Fedo et al., 2017 ), followed by >30 m of finely laminated red/purple-hued mudstone with intervals of very fine sandstone, consistent with sediment accumulation in subaqueous lacustrine environments ( Grotzinger et al., 2015 ; Fedo et al., 2017 ). These younger strata, comprising the Sutton Island member of the Murray formation, expose broken and tilted slabs of bedrock, including finely laminated red mudstones, centimeter-scale ripple cross-laminated mudstone, decimeter-scale cross-stratification, and massively bedded intervals of siltstone ( Fedo et al. 2017 ). OLD SOAKER CAMPAIGN The focus of the investigation is an ∼80-cm-long, 40-cm-wide rock slab called “Old Soaker” (OS) that exposes a bedding plane with a red surface marked by a network of ridges that form polygons ( Fig. 2A ). The red mudstone is ∼1 cm thick and overlies a gray sandstone bed containing bedding-parallel seams of calcium sulfate (CaSO 4 ). OS and a similar nearby slab called “Squid Cove” (SC) were imaged with the Mast Camera (Mastcam) and the Mars Hand Lens Imager (MAHLI) to characterize the geometry and fill of the ridges. Their elemental compositions were examined with the rover’s ChemCam Laser Induced Breakdown Spectrometer (LIBS) and Alpha-Particle X-Ray Spectrometer (APXS). Methods The geometries of the polygonal ridges were determined using MAHLI images to evaluate whether their shape is consistent with desiccation. Images of ridges and their junctions were traced to calculate vertex angle distributions, widths of ridges and the polygons they form, and ridge surface area. A three-dimensional (3-D) model of OS was generated from 76 MAHLI images processed using photogrammetry software. The grain sizes of the red and gray beds were measured with ∼16 µm/pixel MAHLI images. RESULTS Morphology of the Ridges and Surrounding Beds The red surfaces of OS and SC are covered by networks of arcuate ridges with up to 5 mm of positive relief that define predominantly four-sided and some five-sided, 0.5–3.5-cm-wide polygons ( Figs. 2B and 3A ). Red surfaces of adjacent slabs also show raised ridges spanning an area of a few square meters. The ridges range in length from a few centimeters to ∼0.3 m and mostly meet orthogonally, forming T-junctions ( Fig. 3B ). The ridges are made of red-to-gray sediment similar in color to the surrounding bed ( Figs. 2B and 2C ) and comprise ∼20% of OS’s surface. No grains in the ridges or surrounding surface are resolved in MAHLI images ( Fig. 2C ), indicating a maximum grain size of coarse silt. CaSO 4 veins distinct from ridge material follow most, but not all, of the ridges ( Figs. 2B and 2C ) and in some cases cross-cut the ridges (e.g., Fig. 2E ). Sub-millimeter-wide fractures occur within the polygons ( Fig. 2C ). Gray, semi-circular, millimeter-scale patches dot the red beds on OS and SC. They can show raised relief and in places are cross-cut", "role": "user" }, { "content": "As Curiosity rover marches across Mars, the red planet's watery past comes into clearer focus. In early 2017 scientists announced the discovery of possible desiccation cracks in Gale Crater, which was filled by lakes 3.5 billion years ago. Now, a new study has confirmed that these features are indeed desiccation cracks, and reveals fresh details about Mars' ancient climate. \"We are now confident that these are mudcracks,\" explains lead author Nathaniel Stein, a geologist at the California Institute of Technology in Pasadena. Since desiccation mudcracks form only where wet sediment is exposed to air, their position closer to the center of the ancient lake bed rather than the edge also suggests that lake levels rose and fell dramatically over time. \"The mudcracks show that the lakes in Gale Crater had gone through the same type of cycles that we see on Earth,\" says Stein. The study was published in Geology online ahead of print on 16 April 2018. The researchers focused on a coffee table-sized slab of rock nicknamed \"Old Soaker.\" Old Soaker is crisscrossed with polygons identical in appearance to desiccation features on Earth. The team took a close physical and chemical look at those polygons using Curiosity's Mastcam, Mars Hand Lens Imager, ChemCam Laser Induced Breakdown Spectrometer (LIBS), and Alpha-Particle X-Ray Spectrometer (APXS). Curiosity Mastcam image of the Squid Cove rock slab taken on Sol 1555. The red-toned bed is covered by ridges that are the remnants of sediment that filled cracks that formed in drying lake in Gale Crater some ~3.5 billion years ago. The cracks terminate at the underlying bed, which is coarser and did not fracture. The slab is about 60 cm across. Credit: NASA. That close look proved that the polygons—confined to a single layer of rock and with sediment filling the cracks between them—formed from exposure to air, rather than other mechanisms such as thermal or hydraulic fracturing. And although scientists have known almost since the moment Curiosity landed in 2012 that Gale Crater once contained lakes, explains Stein, \"the mudcracks are exciting because they add context to our understanding of this ancient lacustrine system.\" \"We are capturing a moment in time,\" he adds. \"This research is just a chapter in a story that Curiosity has been building since the beginning of its mission.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mars Science Laboratory (MSL) Curiosity rover data are used to describe the morphology of desiccation cracks observed in ancient lacustrine strata at Gale crater, Mars, and to interpret their paleoenvironmental setting. The desiccation cracks indicate subaerial exposure of lacustrine facies in the Sutton Island member of the Murray formation. In association with ripple cross-stratification and possible eolian cross-bedding, these facies indicate a transition from longer-lived perennial lakes recorded by older strata to younger lakes characterized by intermittent exposure. The transition from perennial to episodically exposed lacustrine environments provides evidence for local to regional climate change that can help constrain Mars climate models. INTRODUCTION Reconstructions of ancient habitable environments on Mars increasingly depend on detailed analysis of sedimentary facies recording aqueous environments. Over the past decade, the Mars Exploration Rover Opportunity encountered ancient eolian, fluvial, and lacustrine environments deposited in hypersaline, acidic, sulfate- and hematite-enriched playas formed in interdune depressions at Meridiani Planum (e.g. Grotzinger et al., 2005 ). This setting contrasts with the clay- and magnetite-bearing, moderate pH, perennial lacustrine facies in Gale crater ( Grotzinger et al., 2014 , 2015 ; Hurowitz et al., 2017 ; Rampe et al., 2017 ). Suites of sedimentary structures, facies associations, and authigenic and diagenetic mineral assemblages were essential to recognize these paleoenvironmental settings. Previously, potential martian desiccation cracks were identified in multiple sedimentary deposits from orbit (e.g., El-Maarry et al., 2014 ) and in situ by rovers ( Grotzinger et al., 2005 , 2014 ). The kilometers-thick sedimentary succession in Gale crater provides an opportunity to observe changes in surface environments over extended periods in martian history. Studies of basal strata in the informally named Murray formation demonstrated the presence of long-lived perennial lakes in Gale crater at ca. 3.6–3.2 Ga ( Grotzinger et al., 2014 , 2015 ; Hurowitz et al., 2017 ). Recent facies observations at higher stratigraphic levels ( Fedo et al., 2017 ) may record an evolution of the environment over time. Here we present in situ evidence for lithified desiccation cracks in the Murray formation, indicating that the lakes may have partially dried in its younger history. During Sols 1555–1571, Curiosity investigated a series of distinctive centimeter-scale reticulate ridges on the surfaces of several slabs of rock that expose bedding planes in the Sutton Island member of the Murray formation. Their morphology and composition is characterized to determine if they formed via desiccation and to examine implications for the deposition of associated strata. GEOLOGIC SETTING As of Sol 1700, the Curiosity rover has explored more than 200 m of strata consisting of fluvial, deltaic, lacustrine, and eolian sediments ( Williams et al., 2013 ; Grotzinger et al., 2014 , 2015 ; Banham et al., 2016; Edgar et al., 2017) represented by the Bradbury group, the interfingering and overlying Murray formation (Mount Sharp group), and the unconformably overlying Stimson formation (Siccar Point group) ( Fig. 1 ). The first ∼25-m-thick Murray interval consists dominantly of finely laminated mudstones with minor siltstones and sandstones of lacustrine origin ( Grotzinger et al., 2015 ). It is overlain by an ∼25-m-thick interval with decimeter- to meter-scale cross-stratification that suggests sediment transport as large bedforms or in channels ( Fedo et al., 2017 ), followed by >30 m of finely laminated red/purple-hued mudstone with intervals of very fine sandstone, consistent with sediment accumulation in subaqueous lacustrine environments ( Grotzinger et al., 2015 ; Fedo et al., 2017 ). These younger strata, comprising the Sutton Island member of the Murray formation, expose broken and tilted slabs of bedrock, including finely laminated red mudstones, centimeter-scale ripple cross-laminated mudstone, decimeter-scale cross-stratification, and massively bedded intervals of siltstone ( Fedo et al. 2017 ). OLD SOAKER CAMPAIGN The focus of the investigation is an ∼80-cm-long, 40-cm-wide rock slab called “Old Soaker” (OS) that exposes a bedding plane with a red surface marked by a network of ridges that form polygons ( Fig. 2A ). The red mudstone is ∼1 cm thick and overlies a gray sandstone bed containing bedding-parallel seams of calcium sulfate (CaSO 4 ). OS and a similar nearby slab called “Squid Cove” (SC) were imaged with the Mast Camera (Mastcam) and the Mars Hand Lens Imager (MAHLI) to characterize the geometry and fill of the ridges. Their elemental compositions were examined with the rover’s ChemCam Laser Induced Breakdown Spectrometer (LIBS) and Alpha-Particle X-Ray Spectrometer (APXS). Methods The geometries of the polygonal ridges were determined using MAHLI images to evaluate whether their shape is consistent with desiccation. Images of ridges and their junctions were traced to calculate vertex angle distributions, widths of ridges and the polygons they form, and ridge surface area. A three-dimensional (3-D) model of OS was generated from 76 MAHLI images processed using photogrammetry software. The grain sizes of the red and gray beds were measured with ∼16 µm/pixel MAHLI images. RESULTS Morphology of the Ridges and Surrounding Beds The red surfaces of OS and SC are covered by networks of arcuate ridges with up to 5 mm of positive relief that define predominantly four-sided and some five-sided, 0.5–3.5-cm-wide polygons ( Figs. 2B and 3A ). Red surfaces of adjacent slabs also show raised ridges spanning an area of a few square meters. The ridges range in length from a few centimeters to ∼0.3 m and mostly meet orthogonally, forming T-junctions ( Fig. 3B ). The ridges are made of red-to-gray sediment similar in color to the surrounding bed ( Figs. 2B and 2C ) and comprise ∼20% of OS’s surface. No grains in the ridges or surrounding surface are resolved in MAHLI images ( Fig. 2C ), indicating a maximum grain size of coarse silt. CaSO 4 veins distinct from ridge material follow most, but not all, of the ridges ( Figs. 2B and 2C ) and in some cases cross-cut the ridges (e.g., Fig. 2E ). Sub-millimeter-wide fractures occur within the polygons ( Fig. 2C ). Gray, semi-circular, millimeter-scale patches dot the red beds on OS and SC. They can show raised relief and in places are cross-cut<|im_end|> <|im_start|>assistant As Curiosity rover marches across Mars, the red planet's watery past comes into clearer focus. In early 2017 scientists announced the discovery of possible desiccation cracks in Gale Crater, which was filled by lakes 3.5 billion years ago. Now, a new study has confirmed that these features are indeed desiccation cracks, and reveals fresh details about Mars' ancient climate. "We are now confident that these are mudcracks," explains lead author Nathaniel Stein, a geologist at the California Institute of Technology in Pasadena. Since desiccation mudcracks form only where wet sediment is exposed to air, their position closer to the center of the ancient lake bed rather than the edge also suggests that lake levels rose and fell dramatically over time. "The mudcracks show that the lakes in Gale Crater had gone through the same type of cycles that we see on Earth," says Stein. The study was published in Geology online ahead of print on 16 April 2018. The researchers focused on a coffee table-sized slab of rock nicknamed "Old Soaker." Old Soaker is crisscrossed with polygons identical in appearance to desiccation features on Earth. The team took a close physical and chemical look at those polygons using Curiosity's Mastcam, Mars Hand Lens Imager, ChemCam Laser Induced Breakdown Spectrometer (LIBS), and Alpha-Particle X-Ray Spectrometer (APXS). Curiosity Mastcam image of the Squid Cove rock slab taken on Sol 1555. The red-toned bed is covered by ridges that are the remnants of sediment that filled cracks that formed in drying lake in Gale Crater some ~3.5 billion years ago. The cracks terminate at the underlying bed, which is coarser and did not fracture. The slab is about 60 cm across. Credit: NASA. That close look proved that the polygons—confined to a single layer of rock and with sediment filling the cracks between them—formed from exposure to air, rather than other mechanisms such as thermal or hydraulic fracturing. And although scientists have known almost since the moment Curiosity landed in 2012 that Gale Crater once contained lakes, explains Stein, "the mudcracks are exciting because they add context to our understanding of this ancient lacustrine system." "We are capturing a moment in time," he adds. "This research is just a chapter in a story that Curiosity has been building since the beginning of its mission." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1–3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression ( P< 0.0001) in the frontal cortex during fetal development and in the temporal–parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function ( P< 0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID. Introduction Intellectual disability (ID) is a common neurodevelopmental disorder with an onset of cognitive impairment before the age of 18 years 1 , 2 , 3 and is characterized by significant limitations in intellectual functioning and adaptive behavior. 1 The disease affects 1–3% of the world population; however, its prevalence in the developing world is almost twice that of the affluent world. 4 , 5 The causes of nearly 40% of ID remain ambiguous. 6 Among the known causes, ~50% of ID cases have an environmental etiology such as poor nutrition, multiple pregnancies with little gap, prenatal/perinatal brain ischemia, postnatal infections and inadequate medical services. The other half of ID cases has a genetic etiology, such as chromosomal abnormalities or mutations in specific genes. 3 , 5 In the western world, de novo heterozygous mutations and genomic copy number changes account for the majority of ID cases. 7 In contrast, recessive ID appears to be more common in consanguineous populations. Identification of gene mutations that cause non-syndromic autosomal recessive ID (ARID) has been notoriously slow because of the scarcity of sizeable families. By 2006, only three genes, CC2D1A , CRBN and PRSS12 had been associated with ARID. 8 , 9 , 10 After 2006, research studies involving highly inbred populations from North Africa, the Middle East and South East Asia, greatly accelerated the pace of identification of gene mutations that cause ARID. These studies were further augmented by the use of next-generation sequencing. In 2011, Najmabadi et al. 11 applied targeted next-generation sequencing to 136 consanguineous Iranian families, in which homozygosity mapping had previously identified a locus, and reported 23 known and 50 new candidate ARID genes. More recently, exome sequencing (ES) of 143 large consanguineous Saudi Arabian families revealed 33 novel candidate genes involved in different neurological disorders. 12 These studies further highlighted the clinical and genetic complexity of ID and other neurodevelopmental disorders. Intriguingly, not a single gene with pathogenic variants emerged across various populations. Despite this progress, a large number of potential pathogenic gene mutations remain unidentified and warrant further studies in extended families from communities with endogamy. Consanguineous marriages are practiced by about 20% of the human population, and the extent of consanguinity varies among different citizenry in the world. The rate of consanguineous marriages is 38% in Iran, 13 , 14 over 40% in several Middle Eastern countries 15 and above 50% in Pakistan. 16 The elevated level of endogamy in Pakistan has led to the increased prevalence of genetic disorders, including ARID, with an average of 1.1 cases of severe ID and 6.2 cases of mild ID per 100 live births. 17 The present study is designed to identify pathogenic gene mutations that cause ARID in the highly inbred population of Pakistan. In all, 121 families of 8 different ethnicities, exhibiting recessive ID, were enrolled mostly from the rural population of Pakistan. Through a systematic exome-sequencing approach we have identified potential pathogenic variants in 68 of these families: 30 families with a single homozygous DNA variant affecting previously known ID genes and another 30 families with a single homozygous or compound heterozygous variants in novel candidate ID genes. In eight families multiple homozygous variants were identified. We report the phenotype–genotype relationships, the predicted pathogenicity of the newly discovered candidate genes, their co-expression in functional networks in the developing and adult human brain, and possible involvement in various cellular processes. Materials and methods Family ascertainment and phenotype analysis This study was approved by the Institutional Review Board of the Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan and the Medical Ethical Committee Arnhem-Nijmegen, The Netherlands. The families of our cohort were obtained mainly from the rural populations of all five provinces of Pakistan ( Supplementary Tables S1 and S2 ). Written informed consents were obtained from healthy adult subjects and the parents/legal guardians of minor subjects and ID patients. Specific informed consent was obtained for showing images of patients ( Supplementary Figure S1 ). Participating individuals were evaluated with medical history interviews, and ID-related phenotypic features of patients were recorded. All affected individuals were clinically evaluated by both a geneticist and a general medical practitioner, with particular attention to neurological, morphological, ophthalmological, dermatological and skeletal symptoms. Photographs of the face and uncovered limbs were also taken ( Supplementary Figure S1 ). In some cases, magnetic resonance imaging and computerized tomography scans were also obtained. A description of developmental milestones was used to evaluate the severity of", "role": "user" }, { "content": "An international group of researchers has for the first time identified a set of 30 inherited recessive genes that play a role in intellectual disability (ID), a neurodevelopmental disorder that, according to the Centers for Disease Control (CDC), affects as many as 213 million people around the world. The research team was led in in part by Principal Investigator Saima Riazuddin, PhD, MPH, MBA Professor of Otorhinolaryngology Head & Neck Surgery and Professor of Biochemistry & Molecular Biology at the University of Maryland School of Medicine (UM SOM). Other principal researchers included Hans van Bokhoven, PhD, of the Department of Human Genetics at Radboud University Medical Center in the Netherlands, and Sheikh Riazuddin, PhD, of the Allama Iqbal Medical College, the University of Health Sciences in Pakistan. Intellectual disability, or ID (previously known as mental retardation), becomes apparent in children before the age of 18. The disorder, which is measured by an intelligence quotient below 70, significantly limits an individual's intellectual ability and practical skills. ID also can be a significant burden to families, society and the healthcare system. According to CDC, the lifetime cost for caring for a person with an intellectual disability is over $1 million. Currently, about 1-3 percent of the world's population possess some form of ID. While about half of all ID cases can be linked to environmental causes like poor nutrition, unknown genetic factors, such as gene mutations, are responsible for the remaining 50 percent. The new study, which was published recently in the online journal Molecular Psychiatry, presents the outcomes of a five-year investigation that was conducted over three continents. In order to identify potential genetic causes for ID, investigators assembled a test group of 121 families in rural Pakistan, in which there was a higher incidence of ID and consanguineous marriages (marriages between blood relations). More than 15,000 DNA samples were collected, which were analyzed both in the Netherlands and at UM SOM's Institute of Genomic Sciences (IGS), using next-generation genetic sequencing. From an initial pool of 2,000 possible genes, the study has categorized 30 novel candidate genes possessing a strong potential for causing ID—and possibly other brain disorders as well. In addition, this information now can be applied to DNA screenings in determining the possibility of a couple producing an ID child. \"The implications are enormous,\" said Dr. Riazuddin. \"The next phase of our study is to come up with therapeutic options and personalized protocols that could help patients improve their intellectual function.\" \"This study by Dr. Riazuddin and her colleagues marks a major breakthrough in uncovering new solutions to such crippling brain disorders as ID,\" said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also Vice President of Medical Affairs at the University of Maryland and the John Z. and Akiko Bowers Distinguished Professor at UM SOM. \"Their innovative work now has opened the door to other potential discoveries that will change the way we treat such disabilities in the future.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1–3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression ( P< 0.0001) in the frontal cortex during fetal development and in the temporal–parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function ( P< 0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID. Introduction Intellectual disability (ID) is a common neurodevelopmental disorder with an onset of cognitive impairment before the age of 18 years 1 , 2 , 3 and is characterized by significant limitations in intellectual functioning and adaptive behavior. 1 The disease affects 1–3% of the world population; however, its prevalence in the developing world is almost twice that of the affluent world. 4 , 5 The causes of nearly 40% of ID remain ambiguous. 6 Among the known causes, ~50% of ID cases have an environmental etiology such as poor nutrition, multiple pregnancies with little gap, prenatal/perinatal brain ischemia, postnatal infections and inadequate medical services. The other half of ID cases has a genetic etiology, such as chromosomal abnormalities or mutations in specific genes. 3 , 5 In the western world, de novo heterozygous mutations and genomic copy number changes account for the majority of ID cases. 7 In contrast, recessive ID appears to be more common in consanguineous populations. Identification of gene mutations that cause non-syndromic autosomal recessive ID (ARID) has been notoriously slow because of the scarcity of sizeable families. By 2006, only three genes, CC2D1A , CRBN and PRSS12 had been associated with ARID. 8 , 9 , 10 After 2006, research studies involving highly inbred populations from North Africa, the Middle East and South East Asia, greatly accelerated the pace of identification of gene mutations that cause ARID. These studies were further augmented by the use of next-generation sequencing. In 2011, Najmabadi et al. 11 applied targeted next-generation sequencing to 136 consanguineous Iranian families, in which homozygosity mapping had previously identified a locus, and reported 23 known and 50 new candidate ARID genes. More recently, exome sequencing (ES) of 143 large consanguineous Saudi Arabian families revealed 33 novel candidate genes involved in different neurological disorders. 12 These studies further highlighted the clinical and genetic complexity of ID and other neurodevelopmental disorders. Intriguingly, not a single gene with pathogenic variants emerged across various populations. Despite this progress, a large number of potential pathogenic gene mutations remain unidentified and warrant further studies in extended families from communities with endogamy. Consanguineous marriages are practiced by about 20% of the human population, and the extent of consanguinity varies among different citizenry in the world. The rate of consanguineous marriages is 38% in Iran, 13 , 14 over 40% in several Middle Eastern countries 15 and above 50% in Pakistan. 16 The elevated level of endogamy in Pakistan has led to the increased prevalence of genetic disorders, including ARID, with an average of 1.1 cases of severe ID and 6.2 cases of mild ID per 100 live births. 17 The present study is designed to identify pathogenic gene mutations that cause ARID in the highly inbred population of Pakistan. In all, 121 families of 8 different ethnicities, exhibiting recessive ID, were enrolled mostly from the rural population of Pakistan. Through a systematic exome-sequencing approach we have identified potential pathogenic variants in 68 of these families: 30 families with a single homozygous DNA variant affecting previously known ID genes and another 30 families with a single homozygous or compound heterozygous variants in novel candidate ID genes. In eight families multiple homozygous variants were identified. We report the phenotype–genotype relationships, the predicted pathogenicity of the newly discovered candidate genes, their co-expression in functional networks in the developing and adult human brain, and possible involvement in various cellular processes. Materials and methods Family ascertainment and phenotype analysis This study was approved by the Institutional Review Board of the Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan and the Medical Ethical Committee Arnhem-Nijmegen, The Netherlands. The families of our cohort were obtained mainly from the rural populations of all five provinces of Pakistan ( Supplementary Tables S1 and S2 ). Written informed consents were obtained from healthy adult subjects and the parents/legal guardians of minor subjects and ID patients. Specific informed consent was obtained for showing images of patients ( Supplementary Figure S1 ). Participating individuals were evaluated with medical history interviews, and ID-related phenotypic features of patients were recorded. All affected individuals were clinically evaluated by both a geneticist and a general medical practitioner, with particular attention to neurological, morphological, ophthalmological, dermatological and skeletal symptoms. Photographs of the face and uncovered limbs were also taken ( Supplementary Figure S1 ). In some cases, magnetic resonance imaging and computerized tomography scans were also obtained. A description of developmental milestones was used to evaluate the severity of<|im_end|> <|im_start|>assistant An international group of researchers has for the first time identified a set of 30 inherited recessive genes that play a role in intellectual disability (ID), a neurodevelopmental disorder that, according to the Centers for Disease Control (CDC), affects as many as 213 million people around the world. The research team was led in in part by Principal Investigator Saima Riazuddin, PhD, MPH, MBA Professor of Otorhinolaryngology Head & Neck Surgery and Professor of Biochemistry & Molecular Biology at the University of Maryland School of Medicine (UM SOM). Other principal researchers included Hans van Bokhoven, PhD, of the Department of Human Genetics at Radboud University Medical Center in the Netherlands, and Sheikh Riazuddin, PhD, of the Allama Iqbal Medical College, the University of Health Sciences in Pakistan. Intellectual disability, or ID (previously known as mental retardation), becomes apparent in children before the age of 18. The disorder, which is measured by an intelligence quotient below 70, significantly limits an individual's intellectual ability and practical skills. ID also can be a significant burden to families, society and the healthcare system. According to CDC, the lifetime cost for caring for a person with an intellectual disability is over $1 million. Currently, about 1-3 percent of the world's population possess some form of ID. While about half of all ID cases can be linked to environmental causes like poor nutrition, unknown genetic factors, such as gene mutations, are responsible for the remaining 50 percent. The new study, which was published recently in the online journal Molecular Psychiatry, presents the outcomes of a five-year investigation that was conducted over three continents. In order to identify potential genetic causes for ID, investigators assembled a test group of 121 families in rural Pakistan, in which there was a higher incidence of ID and consanguineous marriages (marriages between blood relations). More than 15,000 DNA samples were collected, which were analyzed both in the Netherlands and at UM SOM's Institute of Genomic Sciences (IGS), using next-generation genetic sequencing. From an initial pool of 2,000 possible genes, the study has categorized 30 novel candidate genes possessing a strong potential for causing ID—and possibly other brain disorders as well. In addition, this information now can be applied to DNA screenings in determining the possibility of a couple producing an ID child. "The implications are enormous," said Dr. Riazuddin. "The next phase of our study is to come up with therapeutic options and personalized protocols that could help patients improve their intellectual function." "This study by Dr. Riazuddin and her colleagues marks a major breakthrough in uncovering new solutions to such crippling brain disorders as ID," said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also Vice President of Medical Affairs at the University of Maryland and the John Z. and Akiko Bowers Distinguished Professor at UM SOM. "Their innovative work now has opened the door to other potential discoveries that will change the way we treat such disabilities in the future." <|im_end|>

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19624, 17076, 11, 304, 902, 1070, 574, 264, 5190, 39775, 315, 3110, 323, 1615, 2379, 483, 788, 47451, 320, 5730, 38132, 1990, 6680, 4398, 570, 4497, 1109, 220, 868, 11, 931, 15922, 10688, 1051, 14890, 11, 902, 1051, 30239, 2225, 304, 279, 26746, 323, 520, 58222, 74390, 596, 10181, 315, 9500, 3151, 23199, 320, 1953, 50, 705, 1701, 1828, 43927, 19465, 62119, 13, 5659, 459, 2926, 7463, 315, 220, 17, 11, 931, 3284, 21389, 11, 279, 4007, 706, 71974, 220, 966, 11775, 9322, 21389, 60662, 264, 3831, 4754, 369, 14718, 3110, 17223, 11000, 1023, 8271, 24673, 439, 1664, 13, 763, 5369, 11, 420, 2038, 1457, 649, 387, 9435, 311, 15922, 84606, 304, 26679, 279, 13336, 315, 264, 5743, 17843, 459, 3110, 1716, 13, 330, 791, 25127, 527, 23205, 1359, 1071, 2999, 13, 432, 28073, 8512, 258, 13, 330, 791, 1828, 10474, 315, 1057, 4007, 374, 311, 2586, 709, 449, 37471, 2671, 323, 35649, 32885, 430, 1436, 1520, 6978, 7417, 872, 20207, 734, 1210, 330, 2028, 4007, 555, 2999, 13, 432, 28073, 8512, 258, 323, 1077, 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2,025

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Integrins are membrane receptors that mediate cell adhesion and mechanosensing. The structure–function relationship of integrins remains incompletely understood, despite the extensive studies carried out because of its importance to basic cell biology and translational medicine. Using a fluorescence dual biomembrane force probe, microfluidics and cone-and-plate rheometry, we applied precisely controlled mechanical stimulations to platelets and identified an intermediate state of integrin α IIb β 3 that is characterized by an ectodomain conformation, ligand affinity and bond lifetimes that are all intermediate between the well-known inactive and active states. This intermediate state is induced by ligand engagement of glycoprotein (GP) Ibα via a mechanosignalling pathway and potentiates the outside-in mechanosignalling of α IIb β 3 for further transition to the active state during integrin mechanical affinity maturation. Our work reveals distinct α IIb β 3 state transitions in response to biomechanical and biochemical stimuli, and identifies a role for the α IIb β 3 intermediate state in promoting biomechanical platelet aggregation. Main Platelets participate in many physiological and pathological processes—for example, haemostasis and thrombosis, immune responses, atherosclerosis, lymphatic vessel development, angiogenesis and tumour metastasis 1 —most of which occur in a stressful mechanical milieu. To play such roles, platelets activate integrin α IIb β 3 to carry out adhesive and signalling functions 2 , 3 , 4 . Strikingly, platelets can rapidly sense and respond to haemodynamic forces to allow the mechanical environment to regulate their activation 4 , 5 , 6 , 7 . Disturbed blood flows, as occur with vessel stenosis or medical device intervention, stimulate platelet adhesion and aggregation, and facilitate the formation and propagation of thrombi 8 , 9 , thereby increasing the risk of occlusive thrombosis 10 . The ability of platelets to sense haemodynamic forces largely depends on the mechanosensing of integrin α IIb β 3 (refs. 9 , 11 ) and glycoprotein Ibα (GPIbα) 5 , 12 , 13 , 14 through engaged ligands such as fibrinogen (Fg), fibronectin and von Willebrand factor (VWF), although the detailed mechanisms remain incompletely understood. Understanding how force stimulates platelet aggregation is clinically relevant, because the prothrombotic effects of disturbed blood flow cannot be eliminated by conventional antiplatelet agents that inhibit agonist-induced platelet aggregation mechanisms 8 , 10 . However, whether the α IIb β 3 integrins are activated similarly or differently by biomechanical versus biochemical (agonists, such as adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2)) stimuli is still elusive, hindering our understanding of the mechanisms underlying shear-induced thrombosis. Moreover, how GPIbα and α IIb β 3 interplay to coordinate platelet mechanosensing remains poorly defined. Integrins are αβ heterodimers that have multiple states with distinct conformations and affinities. According to the switch-blade model 15 , inactive integrins are bent (B) with a closed headpiece (C) where the hybrid domain swings in; its ligand binding is undetectable unless using ultrasensitive techniques 16 . On activation, integrins may unbend to an extended-closed (EC) conformation, followed by headpiece opening with the hybrid domain swung out, resulting in an extended-open (EO) conformation 17 , 18 (Fig. 1a ). Integrin α IIb β 3 can be activated bidirectionally, via inside-out signalling induced by GPIbα 19 , 20 or soluble agonist receptors 4 , and via outside–in signalling, which requires ligand association 21 . The EO α IIb β 3 binds ligand with high affinity 17 , 22 . In contrast, only standalone, unliganded EC α IIb β 3 is seen in crystal structures 23 , and is hypothesized to have low affinity, similar to its BC conformer 24 . Nonetheless, whether EC α IIb β 3 exists physiologically (and its function and regulation) remains unclear. Fig. 1: Mapping α IIb β 3 conformations on platelet aggregates. a , Current model of three α IIb β 3 conformations: BC, bent-closed; EC, extended-closed; EO, extended-open. In the EO integrin, the oval notch spanning parts of the βI and β-propeller domains indicates the high-affinity ligand binding state recognizable by PAC-1. The binding sites for α IIb β 3 conformation-dependent (MBC370.2, AP5, PAC-1) and -independent (SZ22) monoclonal antibodies (mAbs) are indicated. b , Biomechanical platelet aggregation model showing the dimensions of the microfluidic channel, in-built stenosis hump and platelet accumulation and imaging area (dashed box). c , d , Blood was mixed with SZ22-Alexa488 and either MBC370.2-, AP5- or PAC-1-Alexa647, and perfused through the microfluidic channels at 1,800 s −1 bulk shear rate for 10 min. Differential interference contrast (DIC) and confocal images were taken to show platelet aggregates and mAb binding (1st column, merge; 2nd column, SZ22; 3rd column, MBC370.2; top, MBC370.2; middle, AP5; bottom, PAC-1). Biomechanical ( c ) or biochemical ( d ) platelet aggregations were induced by treating blood with amplification loop blockers (ALBs) ( c ) or without ALB but adding 50 µM ADP 2 min after platelets started to aggregate on the stenosis downstream ( d ). Images are representatives of ≥3 independent experiments of different human donors in duplicate. Scale bars, 10 μm. e , Quantitation of α IIb β 3 reporter mAb binding (intensity ratio of reporter mAb over SZ22) following biomechanical and biochemical stimulations. Data are presented as median ± 25th/75th percentile and min/max values (from left to right, n = 7, 7, 8, 14, 7, 7, 8, 7, 8). NS, not significant; * P < 0.05; ** P < 0.01; *** P < 0.001, assessed by unpaired t -test with Welch’s correction. f–h , Mean ± s.e.m. of SZ22 + and MBC370.2 + areas on platelet aggregates at indicated perfusion times without ( h ) or with 50 μg ml −1 ALMA12 ( f ) or 20 μg ml −1 Abciximab ( g ). Full size image By using our recently developed dual biomembrane force probe (dBFP) 20 and fluorescence biomembrane force probe (fBFP) 13 combined with microfluidic perfusion assays, we identified an intermediate affinity state of α IIb β 3 in the EC conformation, which exists in—and is critical to—the development of biomechanical platelet aggregation. Furthermore, our work mapped the activation landscape of integrin", "role": "user" }, { "content": "Researchers at the University of Sydney have used biomechanical engineering techniques to unlock the mystery surrounding the mechanical forces that influence blood clotting. The findings take researchers one step closer to developing new anti-thrombotic drugs without the serious side effects that cause fatal bleeding. While coagulation—the activation of platelets clumping together—is key to stopping blood loss from a cut or wound, overactivation can lead to deadly blood clots, heart attack or stroke. Researchers have used a microfluidic channel, mimicking the narrowing of vessels that cause blood clots, to observe the activation of platelets at the single-molecular level. Published in the journal Nature Materials, the researchers demonstrated blood flow could be controlled by the activation of integrin, an adhesion receptor that mediates platelet aggregation to form a clot. Integrin is a mechanosensory protein that platelets use to sense mechanical force that drives dynamic blood flow. \"Integrins basically facilitate how cells bind to and respond to their environment,\" said Dr. Arnold Lining Ju, co-lead author from the University of Sydney's School of Aerospace, Mechanical and Mechatronic Engineering (AMME), Heart Research Institute (HRI) and Charles Perkins Centre (CPC). \"They allow cells to cling to each other, and are great communicators, transmitting bi-directional signals to activate the binding function; and outside-in, allowing the cell to sense and react to the extracellular environment. The integrin can instruct the platelet cells' clotting behaviours.\" Dr. Ju, an Australian Research Council DECRA Fellow in Biomedical Engineering at AMME and HRI, worked with a team of international researchers to develop a single-molecule biomechanical nanotool called \"dual biomembrance force probe (BFP)\" to observe how platelets harness mechanical force in blood flow to exert adhesive clotting functions. The researchers say the finding – that biomechanical thrombus growth is mainly mediated by an intermediate state triggered by a unique integrin biomechanical activation pathway – has the potential to guide the development of new anti-thrombotic strategies. This could benefit many of the 55,000 Australians who suffer a heart attack each year. \"Our finding may also offer help to diabetic patients since diabetic platelets are more prone resistant to conventional anti-clotting drugs,\" said Dr. Ju. \"Targeting biomechanical pathways may also have the advantage of preventing deadly clots without bleeding side effects. \"Each year, about 55,000 Australians suffer from heart attacks—one every 10 minutes. Excessive activation of platelets and subsequent blood clotting leads to heart attack and stroke.\" What the findings mean for current treatments Dr. Ju's research also provides a new explanation for the poor efficacy of conventional antiplatelet drugs in the treatment of thrombotic cardiovascular diseases. Although these drugs inhibit the biochemical activation of platelets, they may not block the platelet biomechanical signaling pathways. \"Antiplatelet drugs such as Aspirin and platelet ADP receptor drugs are commonly used for the treatment of thrombotic diseases. However, these drugs have serious side effects that cause fatal bleeding,\" said Dr. Ju. \"For a long time, studies in the field of thrombosis have attempted to understand the mechanism of platelet activation at the cellular and molecular levels, and hope to provide ideas for the development of new antithrombotic drugs with strong efficacy and few side effects.\" Senior Fellow at HRI Yuping Yuan said, \"Since diabetes represents the biggest threat to the Australian health system, this discovery sheds light on protecting vulnerable diabetic individuals from heart diseases.\" The \"mechanically driven platelet activation\" phenomenon found in the study explains why platelets can aggregate and accumulate by mechanical stimulation of high-speed turbulence alone, leading to blockage of a blood vessel. Therefore, this research provides new ideas for the development of novel and highly effective antithrombotic drugs with no serious bleeding side effects. The paper, titled \"When integrin αIIbβ3 takes an intermediate structure, it has an intermediate affinity, and this intermediate state mediates 1 biomechanical platelet aggregation,\" was published in Nature Materials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Integrins are membrane receptors that mediate cell adhesion and mechanosensing. The structure–function relationship of integrins remains incompletely understood, despite the extensive studies carried out because of its importance to basic cell biology and translational medicine. Using a fluorescence dual biomembrane force probe, microfluidics and cone-and-plate rheometry, we applied precisely controlled mechanical stimulations to platelets and identified an intermediate state of integrin α IIb β 3 that is characterized by an ectodomain conformation, ligand affinity and bond lifetimes that are all intermediate between the well-known inactive and active states. This intermediate state is induced by ligand engagement of glycoprotein (GP) Ibα via a mechanosignalling pathway and potentiates the outside-in mechanosignalling of α IIb β 3 for further transition to the active state during integrin mechanical affinity maturation. Our work reveals distinct α IIb β 3 state transitions in response to biomechanical and biochemical stimuli, and identifies a role for the α IIb β 3 intermediate state in promoting biomechanical platelet aggregation. Main Platelets participate in many physiological and pathological processes—for example, haemostasis and thrombosis, immune responses, atherosclerosis, lymphatic vessel development, angiogenesis and tumour metastasis 1 —most of which occur in a stressful mechanical milieu. To play such roles, platelets activate integrin α IIb β 3 to carry out adhesive and signalling functions 2 , 3 , 4 . Strikingly, platelets can rapidly sense and respond to haemodynamic forces to allow the mechanical environment to regulate their activation 4 , 5 , 6 , 7 . Disturbed blood flows, as occur with vessel stenosis or medical device intervention, stimulate platelet adhesion and aggregation, and facilitate the formation and propagation of thrombi 8 , 9 , thereby increasing the risk of occlusive thrombosis 10 . The ability of platelets to sense haemodynamic forces largely depends on the mechanosensing of integrin α IIb β 3 (refs. 9 , 11 ) and glycoprotein Ibα (GPIbα) 5 , 12 , 13 , 14 through engaged ligands such as fibrinogen (Fg), fibronectin and von Willebrand factor (VWF), although the detailed mechanisms remain incompletely understood. Understanding how force stimulates platelet aggregation is clinically relevant, because the prothrombotic effects of disturbed blood flow cannot be eliminated by conventional antiplatelet agents that inhibit agonist-induced platelet aggregation mechanisms 8 , 10 . However, whether the α IIb β 3 integrins are activated similarly or differently by biomechanical versus biochemical (agonists, such as adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2)) stimuli is still elusive, hindering our understanding of the mechanisms underlying shear-induced thrombosis. Moreover, how GPIbα and α IIb β 3 interplay to coordinate platelet mechanosensing remains poorly defined. Integrins are αβ heterodimers that have multiple states with distinct conformations and affinities. According to the switch-blade model 15 , inactive integrins are bent (B) with a closed headpiece (C) where the hybrid domain swings in; its ligand binding is undetectable unless using ultrasensitive techniques 16 . On activation, integrins may unbend to an extended-closed (EC) conformation, followed by headpiece opening with the hybrid domain swung out, resulting in an extended-open (EO) conformation 17 , 18 (Fig. 1a ). Integrin α IIb β 3 can be activated bidirectionally, via inside-out signalling induced by GPIbα 19 , 20 or soluble agonist receptors 4 , and via outside–in signalling, which requires ligand association 21 . The EO α IIb β 3 binds ligand with high affinity 17 , 22 . In contrast, only standalone, unliganded EC α IIb β 3 is seen in crystal structures 23 , and is hypothesized to have low affinity, similar to its BC conformer 24 . Nonetheless, whether EC α IIb β 3 exists physiologically (and its function and regulation) remains unclear. Fig. 1: Mapping α IIb β 3 conformations on platelet aggregates. a , Current model of three α IIb β 3 conformations: BC, bent-closed; EC, extended-closed; EO, extended-open. In the EO integrin, the oval notch spanning parts of the βI and β-propeller domains indicates the high-affinity ligand binding state recognizable by PAC-1. The binding sites for α IIb β 3 conformation-dependent (MBC370.2, AP5, PAC-1) and -independent (SZ22) monoclonal antibodies (mAbs) are indicated. b , Biomechanical platelet aggregation model showing the dimensions of the microfluidic channel, in-built stenosis hump and platelet accumulation and imaging area (dashed box). c , d , Blood was mixed with SZ22-Alexa488 and either MBC370.2-, AP5- or PAC-1-Alexa647, and perfused through the microfluidic channels at 1,800 s −1 bulk shear rate for 10 min. Differential interference contrast (DIC) and confocal images were taken to show platelet aggregates and mAb binding (1st column, merge; 2nd column, SZ22; 3rd column, MBC370.2; top, MBC370.2; middle, AP5; bottom, PAC-1). Biomechanical ( c ) or biochemical ( d ) platelet aggregations were induced by treating blood with amplification loop blockers (ALBs) ( c ) or without ALB but adding 50 µM ADP 2 min after platelets started to aggregate on the stenosis downstream ( d ). Images are representatives of ≥3 independent experiments of different human donors in duplicate. Scale bars, 10 μm. e , Quantitation of α IIb β 3 reporter mAb binding (intensity ratio of reporter mAb over SZ22) following biomechanical and biochemical stimulations. Data are presented as median ± 25th/75th percentile and min/max values (from left to right, n = 7, 7, 8, 14, 7, 7, 8, 7, 8). NS, not significant; * P < 0.05; ** P < 0.01; *** P < 0.001, assessed by unpaired t -test with Welch’s correction. f–h , Mean ± s.e.m. of SZ22 + and MBC370.2 + areas on platelet aggregates at indicated perfusion times without ( h ) or with 50 μg ml −1 ALMA12 ( f ) or 20 μg ml −1 Abciximab ( g ). Full size image By using our recently developed dual biomembrane force probe (dBFP) 20 and fluorescence biomembrane force probe (fBFP) 13 combined with microfluidic perfusion assays, we identified an intermediate affinity state of α IIb β 3 in the EC conformation, which exists in—and is critical to—the development of biomechanical platelet aggregation. Furthermore, our work mapped the activation landscape of integrin<|im_end|> <|im_start|>assistant Researchers at the University of Sydney have used biomechanical engineering techniques to unlock the mystery surrounding the mechanical forces that influence blood clotting. The findings take researchers one step closer to developing new anti-thrombotic drugs without the serious side effects that cause fatal bleeding. While coagulation—the activation of platelets clumping together—is key to stopping blood loss from a cut or wound, overactivation can lead to deadly blood clots, heart attack or stroke. Researchers have used a microfluidic channel, mimicking the narrowing of vessels that cause blood clots, to observe the activation of platelets at the single-molecular level. Published in the journal Nature Materials, the researchers demonstrated blood flow could be controlled by the activation of integrin, an adhesion receptor that mediates platelet aggregation to form a clot. Integrin is a mechanosensory protein that platelets use to sense mechanical force that drives dynamic blood flow. "Integrins basically facilitate how cells bind to and respond to their environment," said Dr. Arnold Lining Ju, co-lead author from the University of Sydney's School of Aerospace, Mechanical and Mechatronic Engineering (AMME), Heart Research Institute (HRI) and Charles Perkins Centre (CPC). "They allow cells to cling to each other, and are great communicators, transmitting bi-directional signals to activate the binding function; and outside-in, allowing the cell to sense and react to the extracellular environment. The integrin can instruct the platelet cells' clotting behaviours." Dr. Ju, an Australian Research Council DECRA Fellow in Biomedical Engineering at AMME and HRI, worked with a team of international researchers to develop a single-molecule biomechanical nanotool called "dual biomembrance force probe (BFP)" to observe how platelets harness mechanical force in blood flow to exert adhesive clotting functions. The researchers say the finding – that biomechanical thrombus growth is mainly mediated by an intermediate state triggered by a unique integrin biomechanical activation pathway – has the potential to guide the development of new anti-thrombotic strategies. This could benefit many of the 55,000 Australians who suffer a heart attack each year. "Our finding may also offer help to diabetic patients since diabetic platelets are more prone resistant to conventional anti-clotting drugs," said Dr. Ju. "Targeting biomechanical pathways may also have the advantage of preventing deadly clots without bleeding side effects. "Each year, about 55,000 Australians suffer from heart attacks—one every 10 minutes. Excessive activation of platelets and subsequent blood clotting leads to heart attack and stroke." What the findings mean for current treatments Dr. Ju's research also provides a new explanation for the poor efficacy of conventional antiplatelet drugs in the treatment of thrombotic cardiovascular diseases. Although these drugs inhibit the biochemical activation of platelets, they may not block the platelet biomechanical signaling pathways. "Antiplatelet drugs such as Aspirin and platelet ADP receptor drugs are commonly used for the treatment of thrombotic diseases. However, these drugs have serious side effects that cause fatal bleeding," said Dr. Ju. "For a long time, studies in the field of thrombosis have attempted to understand the mechanism of platelet activation at the cellular and molecular levels, and hope to provide ideas for the development of new antithrombotic drugs with strong efficacy and few side effects." Senior Fellow at HRI Yuping Yuan said, "Since diabetes represents the biggest threat to the Australian health system, this discovery sheds light on protecting vulnerable diabetic individuals from heart diseases." The "mechanically driven platelet activation" phenomenon found in the study explains why platelets can aggregate and accumulate by mechanical stimulation of high-speed turbulence alone, leading to blockage of a blood vessel. Therefore, this research provides new ideas for the development of novel and highly effective antithrombotic drugs with no serious bleeding side effects. The paper, titled "When integrin αIIbβ3 takes an intermediate structure, it has an intermediate affinity, and this intermediate state mediates 1 biomechanical platelet aggregation," was published in Nature Materials. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Tardigrades, also known as water bears, are small aquatic animals. Some tardigrade species tolerate almost complete dehydration and exhibit extraordinary tolerance to various physical extremes in the dehydrated state. Here we determine a high-quality genome sequence of Ramazzottius varieornatus , one of the most stress-tolerant tardigrade species. Precise gene repertoire analyses reveal the presence of a small proportion (1.2% or less) of putative foreign genes, loss of gene pathways that promote stress damage, expansion of gene families related to ameliorating damage, and evolution and high expression of novel tardigrade-unique proteins. Minor changes in the gene expression profiles during dehydration and rehydration suggest constitutive expression of tolerance-related genes. Using human cultured cells, we demonstrate that a tardigrade-unique DNA-associating protein suppresses X-ray-induced DNA damage by ∼ 40% and improves radiotolerance. These findings indicate the relevance of tardigrade-unique proteins to tolerability and tardigrades could be a bountiful source of new protection genes and mechanisms. Introduction Tardigrades, also known as water bears, are tiny aquatic animals having four pairs of legs 1 . More than 1,000 species have been reported from various habitats such as marine, fresh water or limno-terrestrial environments. All tardigrades require surrounding water to grow and reproduce, but some species—typically those living in the limno-terrestrial environments—have the ability to tolerate almost complete dehydration. When encountering desiccation, tolerant tardigrades lose body water and enter a contracted dehydrated state called anhydrobiosis, which is a reversible ametabolic state. The dehydrated tardigrades withstand a wide range of physical extremes that normally disallow the survival of most organisms, such as extreme temperatures (from −273 °C 2 to nearly 100 °C 3 , 4 ), high pressure (7.5 GPa) 5 , immersion in organic solvent 4 , 6 , exposure to high dose of irradiation 7 , 8 and even direct exposure to open space 9 . Although such unusual tolerance of some tardigrades has long fascinated researchers, the molecular mechanisms enabling such exceptional tolerance have remained largely unknown. Recently, a finding was reported by a research group at the University of North Carolina (UNC) claiming the presence of extensive horizontal gene transfer (HGT) in a tardigrade genome (17.5% of genes have foreign origin) as a potential basis of tolerant ability, based on their own draft genome assembly of a freshwater tardigrade, Hypsibius dujardini (N50=15.9 kb; hereafter referred to as the UNC assembly) 10 . In contrast, another research group offered a counterargument, suggesting that a substantial portion of the UNC assembly were derived from contaminating microorganisms 11 . There is also a significant discrepancy between the estimated genome size of the species (80–110 Mbp) 11 and the span of the UNC assembly (212.3 Mb), which could be explained by the presence of contaminating sequences at least partially. It is controversial whether extensive HGT is real or an inaccurate interpretation of contaminating sequences. Contaminating sequences substantially affect genome analyses, leading to misinterpretation of the gene repertoire in the target organisms, as well as poor assembly or even chimeric misassembly. Metagenomic approaches could be used to identify putative contaminating sequences based on sequence similarity to phylogenetically distant taxa 11 , but possible misidentification and erroneous elimination from the assembly may lead to a biased representation of the gene repertoire for the target organism. A bona fide tardigrade genome sequence largely free from contamination is therefore needed. The possible contribution of foreign genes was discussed in the presumed tolerant ability of the sequenced species, H. dujardini 10 . However, freshwater tardigrades, including H. dujardini , are among the least tolerant members of the phylum Tardigrada and H. dujardini cannot withstand exposure to low humidity conditions without a long pre-exposure to high-humidity conditions 12 , 13 . Furthermore, no data have been reported for their tolerability against extreme stress in a dehydrated state, although they exhibit some tolerance to radiation in a hydrated state 14 . The controversial extensive HGT was thoroughly examined in the poorly tolerant H.dujardini , but no other gene repertoire analysis has been reported for tardigrades. Therefore, the genomic basis for the exceptional tolerance of tardigrades remains to be elucidated. To this end, we conducted a precise genome analysis using one of the most stress-tolerant tardigrade species, R. varieornatus , which tolerates direct exposure to low-humidity conditions and withstands various extremes in the dehydrated state 4 , 15 . We determined a high-quality genome sequence largely free from contamination that allows us to precisely analyse the gene repertoire, such as the proportion of HGT, and characteristic gene expansion or deletion. We also analysed the gene expression profiles during dehydration and rehydration. Furthermore, we focused on the abundantly expressed tardigrade-unique genes and present evidence for the relevance of tardigrade-unique proteins to tolerability, based on our investigation of the effect of a novel tardigrade-unique DNA-associating protein on DNA protection and radiotolerance in human cultured cells. Results High-quality genome sequence of extremotolerant tardigrade R. varieornatus is an extremotolerant tardigrade species, which becomes almost completely dehydrated on desiccation ( Fig. 1a,b ) and withstands various physical extremes 4 . The genome sequence of R. varieornatus was determined by using a combination of the Sanger and Illumina technologies ( Supplementary Table 1 ). To minimize microbial contamination we cleansed egg surfaces with diluted hypochlorite and before sampling the tardigrades were starved and treated with antibiotics for 2 days. After the removal of short scaffolds (<1 kb) and mitochondrial sequences, we obtained the assembly spanning 56.0 Mbp (301 scaffolds). Coverage analysis (160 × Illumina sequencing) revealed that 199 scaffolds (99.7% in span) had considerable coverage (>40), whereas 102 scaffolds had exceptionally low coverage (<1; Supplementary Fig. 1 and Supplementary Data 1 ). We considered these 102 scaffolds (153 kb in span) as derived from contaminating organisms and excluded them from our assembly. As a result, our final assembly spans 55.8 Mbp (199 scaffolds; N50=4.74 Mbp; N90=1.3 Mbp; Supplementary Table 2 ). The span is highly concordant with the genome size estimated by DNA staining in the tardigrade cells ( ∼ 55 Mbp; Supplementary Fig. 2 ), suggesting sufficiency of our assembly", "role": "user" }, { "content": "A protein unique to a miniscule creature called a water bear, reputedly the most indestructible animal on Earth, protects human DNA from X-ray damage, stunned researchers reported Tuesday. Human cells cultivated with the newly-discovered protein, dubbed \"Dsup\" for \"damage suppressor\", experienced half as much decay as normal cells when blasted with radiation. \"We were really surprised,\" said lead author Takuma Hashimoto, a biologist at the University of Tokyo who designed the experiments. \"It is striking that a single gene is enough to improve the radiation tolerance of human cultured cells,\" he told AFP, referring to the tardigrade-derived protein. Tardigrades, as the water bears are more prosaically known, have long fascinated scientists with their veritable superpowers of survival. Barely the size of a grain of sand, they look as if they escaped from a Star Trek sequel. Seemingly eyeless, they have bodies resembling hazmat suits, eight puffy legs with bear-like claws, and a vacuum-cleaner nozzle of a snout. Most eat moss and lichen. Some feed on other water bears. Remarkably, these primitive water-dwellers can withstand environments more extreme than anything found in Nature. That includes being plunged into scalding liquids or frozen at temperatures just shy of absolute zero. A facial view of a tardigrade or 'water bear' (Ramazzottius varieornatus), in an image released by Nature on September 20, 2016 In an earlier experiment, water bears were given a 26-hour bath in -253 degree Celsius (-423 degree Fahrenheit) liquid nitrogen. The deepest chill ever recorded on Earth was a relatively balmy −89.2 C (−128.6 F) in Antarctica. All it took was a few drops of water for the critters to spring back to life. And it gets better. Some tardigrade species—there are about 1,000 in all—can handle crushing pressure at least six times greater than found at the 11-kilometre (seven-mile) deep Mariana Trench in the Pacific Ocean. X-ray shield Even the ravages of outer space don't seem to faze them. In 2007, thousands of water bears, attached to a satellite, were exposed directly to potentially-deadly space radiation in vacuum conditions and then brought back to Earth. Not only did many survive, some females later laid eggs which yielded healthy offspring. When the the tardigrade Ramazzottius varieornatus encounters dryness, their body water characteristically drops down to 2.5% wt./wt. accompanied by body shrinkage. The contracted dry animal, referred to as a tun, shows no visible signs of life, but it can resume their activity if a drop of water is added. Credit: Daiki D. Horikawa. To survive extreme conditions, water bears can also slip into a state of suspended animation in which they lose almost all the liquid in their tiny bodies, and metabolism slows to 10,000 times below the normal rate. Scientists still do not know how they do all this. Most research has concluded that water bears have a heightened capacity to repair damaged DNA, especially as they emerge from a state of extreme dessication, which can last for decades. However, in their experiments with human cells, Hashimoto and colleagues found the tardigrade's Dsup protein could also \"work as a kind of physical shield to protect DNA\"—especially from X-ray harm. The findings were published in the scientific journal Nature Communications. The results may resolve a controversy that erupted after another team of researchers published the first complete genome of a tardigrade—from the species Ramazzottius hypsibius—last December in the US Proceeding of the National Academy of Sciences. That study had found that nearly a fifth of the species' DNA had been obtained from other plants and animals, a new record in the animal kingdom for so-called horizontal gene transfer between species. This, they hypothesised, accounted for the remarkable resistence of water bears. A tardigrade walking on moss. Credit: Kunieda. Almost immediately, other scientists speculated that the high percentage of foreign DNA found was more likely the result of sample contamination. Hashimoto's results suggest the critics were right. His team sequenced the genome of a different species, R. varieoranatus—thought to be the hardiest of all tardigrades—with a precision 100 times greater, and found that foreign genes accounted for only 1.2 percent. \"This suggests that horizontal gene transfer is not a major cause of tolerability,\" said Hashimoto. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Tardigrades, also known as water bears, are small aquatic animals. Some tardigrade species tolerate almost complete dehydration and exhibit extraordinary tolerance to various physical extremes in the dehydrated state. Here we determine a high-quality genome sequence of Ramazzottius varieornatus , one of the most stress-tolerant tardigrade species. Precise gene repertoire analyses reveal the presence of a small proportion (1.2% or less) of putative foreign genes, loss of gene pathways that promote stress damage, expansion of gene families related to ameliorating damage, and evolution and high expression of novel tardigrade-unique proteins. Minor changes in the gene expression profiles during dehydration and rehydration suggest constitutive expression of tolerance-related genes. Using human cultured cells, we demonstrate that a tardigrade-unique DNA-associating protein suppresses X-ray-induced DNA damage by ∼ 40% and improves radiotolerance. These findings indicate the relevance of tardigrade-unique proteins to tolerability and tardigrades could be a bountiful source of new protection genes and mechanisms. Introduction Tardigrades, also known as water bears, are tiny aquatic animals having four pairs of legs 1 . More than 1,000 species have been reported from various habitats such as marine, fresh water or limno-terrestrial environments. All tardigrades require surrounding water to grow and reproduce, but some species—typically those living in the limno-terrestrial environments—have the ability to tolerate almost complete dehydration. When encountering desiccation, tolerant tardigrades lose body water and enter a contracted dehydrated state called anhydrobiosis, which is a reversible ametabolic state. The dehydrated tardigrades withstand a wide range of physical extremes that normally disallow the survival of most organisms, such as extreme temperatures (from −273 °C 2 to nearly 100 °C 3 , 4 ), high pressure (7.5 GPa) 5 , immersion in organic solvent 4 , 6 , exposure to high dose of irradiation 7 , 8 and even direct exposure to open space 9 . Although such unusual tolerance of some tardigrades has long fascinated researchers, the molecular mechanisms enabling such exceptional tolerance have remained largely unknown. Recently, a finding was reported by a research group at the University of North Carolina (UNC) claiming the presence of extensive horizontal gene transfer (HGT) in a tardigrade genome (17.5% of genes have foreign origin) as a potential basis of tolerant ability, based on their own draft genome assembly of a freshwater tardigrade, Hypsibius dujardini (N50=15.9 kb; hereafter referred to as the UNC assembly) 10 . In contrast, another research group offered a counterargument, suggesting that a substantial portion of the UNC assembly were derived from contaminating microorganisms 11 . There is also a significant discrepancy between the estimated genome size of the species (80–110 Mbp) 11 and the span of the UNC assembly (212.3 Mb), which could be explained by the presence of contaminating sequences at least partially. It is controversial whether extensive HGT is real or an inaccurate interpretation of contaminating sequences. Contaminating sequences substantially affect genome analyses, leading to misinterpretation of the gene repertoire in the target organisms, as well as poor assembly or even chimeric misassembly. Metagenomic approaches could be used to identify putative contaminating sequences based on sequence similarity to phylogenetically distant taxa 11 , but possible misidentification and erroneous elimination from the assembly may lead to a biased representation of the gene repertoire for the target organism. A bona fide tardigrade genome sequence largely free from contamination is therefore needed. The possible contribution of foreign genes was discussed in the presumed tolerant ability of the sequenced species, H. dujardini 10 . However, freshwater tardigrades, including H. dujardini , are among the least tolerant members of the phylum Tardigrada and H. dujardini cannot withstand exposure to low humidity conditions without a long pre-exposure to high-humidity conditions 12 , 13 . Furthermore, no data have been reported for their tolerability against extreme stress in a dehydrated state, although they exhibit some tolerance to radiation in a hydrated state 14 . The controversial extensive HGT was thoroughly examined in the poorly tolerant H.dujardini , but no other gene repertoire analysis has been reported for tardigrades. Therefore, the genomic basis for the exceptional tolerance of tardigrades remains to be elucidated. To this end, we conducted a precise genome analysis using one of the most stress-tolerant tardigrade species, R. varieornatus , which tolerates direct exposure to low-humidity conditions and withstands various extremes in the dehydrated state 4 , 15 . We determined a high-quality genome sequence largely free from contamination that allows us to precisely analyse the gene repertoire, such as the proportion of HGT, and characteristic gene expansion or deletion. We also analysed the gene expression profiles during dehydration and rehydration. Furthermore, we focused on the abundantly expressed tardigrade-unique genes and present evidence for the relevance of tardigrade-unique proteins to tolerability, based on our investigation of the effect of a novel tardigrade-unique DNA-associating protein on DNA protection and radiotolerance in human cultured cells. Results High-quality genome sequence of extremotolerant tardigrade R. varieornatus is an extremotolerant tardigrade species, which becomes almost completely dehydrated on desiccation ( Fig. 1a,b ) and withstands various physical extremes 4 . The genome sequence of R. varieornatus was determined by using a combination of the Sanger and Illumina technologies ( Supplementary Table 1 ). To minimize microbial contamination we cleansed egg surfaces with diluted hypochlorite and before sampling the tardigrades were starved and treated with antibiotics for 2 days. After the removal of short scaffolds (<1 kb) and mitochondrial sequences, we obtained the assembly spanning 56.0 Mbp (301 scaffolds). Coverage analysis (160 × Illumina sequencing) revealed that 199 scaffolds (99.7% in span) had considerable coverage (>40), whereas 102 scaffolds had exceptionally low coverage (<1; Supplementary Fig. 1 and Supplementary Data 1 ). We considered these 102 scaffolds (153 kb in span) as derived from contaminating organisms and excluded them from our assembly. As a result, our final assembly spans 55.8 Mbp (199 scaffolds; N50=4.74 Mbp; N90=1.3 Mbp; Supplementary Table 2 ). The span is highly concordant with the genome size estimated by DNA staining in the tardigrade cells ( ∼ 55 Mbp; Supplementary Fig. 2 ), suggesting sufficiency of our assembly<|im_end|> <|im_start|>assistant A protein unique to a miniscule creature called a water bear, reputedly the most indestructible animal on Earth, protects human DNA from X-ray damage, stunned researchers reported Tuesday. Human cells cultivated with the newly-discovered protein, dubbed "Dsup" for "damage suppressor", experienced half as much decay as normal cells when blasted with radiation. "We were really surprised," said lead author Takuma Hashimoto, a biologist at the University of Tokyo who designed the experiments. "It is striking that a single gene is enough to improve the radiation tolerance of human cultured cells," he told AFP, referring to the tardigrade-derived protein. Tardigrades, as the water bears are more prosaically known, have long fascinated scientists with their veritable superpowers of survival. Barely the size of a grain of sand, they look as if they escaped from a Star Trek sequel. Seemingly eyeless, they have bodies resembling hazmat suits, eight puffy legs with bear-like claws, and a vacuum-cleaner nozzle of a snout. Most eat moss and lichen. Some feed on other water bears. Remarkably, these primitive water-dwellers can withstand environments more extreme than anything found in Nature. That includes being plunged into scalding liquids or frozen at temperatures just shy of absolute zero. A facial view of a tardigrade or 'water bear' (Ramazzottius varieornatus), in an image released by Nature on September 20, 2016 In an earlier experiment, water bears were given a 26-hour bath in -253 degree Celsius (-423 degree Fahrenheit) liquid nitrogen. The deepest chill ever recorded on Earth was a relatively balmy −89.2 C (−128.6 F) in Antarctica. All it took was a few drops of water for the critters to spring back to life. And it gets better. Some tardigrade species—there are about 1,000 in all—can handle crushing pressure at least six times greater than found at the 11-kilometre (seven-mile) deep Mariana Trench in the Pacific Ocean. X-ray shield Even the ravages of outer space don't seem to faze them. In 2007, thousands of water bears, attached to a satellite, were exposed directly to potentially-deadly space radiation in vacuum conditions and then brought back to Earth. Not only did many survive, some females later laid eggs which yielded healthy offspring. When the the tardigrade Ramazzottius varieornatus encounters dryness, their body water characteristically drops down to 2.5% wt./wt. accompanied by body shrinkage. The contracted dry animal, referred to as a tun, shows no visible signs of life, but it can resume their activity if a drop of water is added. Credit: Daiki D. Horikawa. To survive extreme conditions, water bears can also slip into a state of suspended animation in which they lose almost all the liquid in their tiny bodies, and metabolism slows to 10,000 times below the normal rate. Scientists still do not know how they do all this. Most research has concluded that water bears have a heightened capacity to repair damaged DNA, especially as they emerge from a state of extreme dessication, which can last for decades. However, in their experiments with human cells, Hashimoto and colleagues found the tardigrade's Dsup protein could also "work as a kind of physical shield to protect DNA"—especially from X-ray harm. The findings were published in the scientific journal Nature Communications. The results may resolve a controversy that erupted after another team of researchers published the first complete genome of a tardigrade—from the species Ramazzottius hypsibius—last December in the US Proceeding of the National Academy of Sciences. That study had found that nearly a fifth of the species' DNA had been obtained from other plants and animals, a new record in the animal kingdom for so-called horizontal gene transfer between species. This, they hypothesised, accounted for the remarkable resistence of water bears. A tardigrade walking on moss. Credit: Kunieda. Almost immediately, other scientists speculated that the high percentage of foreign DNA found was more likely the result of sample contamination. Hashimoto's results suggest the critics were right. His team sequenced the genome of a different species, R. varieoranatus—thought to be the hardiest of all tardigrades—with a precision 100 times greater, and found that foreign genes accounted for only 1.2 percent. "This suggests that horizontal gene transfer is not a major cause of tolerability," said Hashimoto. <|im_end|>

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2,416

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Fourier transform holography is a highly efficient and robust imaging method, suitable for single-shot imaging at coherent X-ray sources. In its common implementation, the image contrast is limited by the reference signal generated by a small pinhole aperture. Increased pinhole diameters improve the signal, whereas the resolution is diminished. Here we report a new concept to decouple the spatial resolution from the image contrast by employing a Fresnel zone plate to provide the reference beam. Superimposed on-axis images of distinct foci are separated with a novel algorithm. Our method is insensitive to mechanical drift or vibrations and allows for long integration times common at low-flux facilities like high harmonic generation sources. The application of monolithic focused reference beams improves the efficiency of high-resolution X-ray Fourier transform holography beyond all present approaches and paves the path towards sub-10 nm single-shot X-ray imaging. Introduction The development of highly efficient and robust X-ray imaging methods is of particular interest for single-shot applications 1 , 2 , 3 , 4 , 5 , in which all information has to be encoded by the limited number of photons of a single femtosecond X-ray pulse, requiring outstanding efficiency of the method used. One of the few approaches that fulfil such requirements is X-ray Fourier transform holography (FTH) 6 , 7 . In FTH, the far-field scattering pattern of a specimen is recorded on a two-dimensional detector. The phase information is encoded in the interference of the scattered beam with an unperturbed reference beam, forming the hologram 1 , 6 , 8 , 9 , 10 , 11 , 12 . With an off-axis reference beam originating ideally from a point source in the object plane, the image is reconstructed by an inverse Fourier transform of the hologram as the cross-correlation of the specimen with the reference transmission function 13 . Since the FTH scattering geometry allows for recording large scattering angles, the resolution is typically limited by the spatial extent of the reference source while the image contrast is determined by the photon flux in the reference beam. (We here consider the typical case in high-resolution imaging that the reference wave is significantly weaker than the object wave and hence the limiting factor for the hologram fringe visibility). In addition, the number of pixels of the detector defines a maximum lateral size of the combined object and reference structures of the sample for a given spatial resolution 13 . In the most common implementation of FTH, the reference wave originates from a small pinhole aperture fabricated into an X-ray-opaque metal film adjacent to an object aperture that defines the field of view 6 . This integrated, monolithic design is the reason for the remarkable stability of mask-based FTH against drift and vibration of the set-up. In conjunction with the flexibility in sample environments afforded by the absence of further optical elements in the vicinity of the sample and the robust and unambiguous image reconstruction process, this approach is applied—beyond method development—for example, in material science research of magnetic nanostructures 7 , 14 , 15 . The drawback of point-like apertures generating reference waves is the entanglement of spatial resolution and contrast in the reconstruction. If the reference diameter is decreased, the resolution limit will scale linearly with the reference size while the reference signal strength, and ultimately the image contrast, is reduced quadratically. A high-resolution FTH imaging experiment is therefore commonly designed as a compromise between the desired resolution and the required reference signal. As long as the reference signal exceeds the detector’s noise level, the decrease in flux through an ever smaller reference could in principle be accounted for by extending exposure times up to a certain practical limit. However, resolution limits as reported for Fresnel zone plate (FZP)-based X-ray microscopy 16 have not been achieved for FTH using reference pinholes with high aspect ratio up to now. Moreover, for the growing class of dynamic studies relying on femtosecond X-ray pulses, the signal has to be collected from a limited number of photons 3 , 4 , 5 , 7 . It has been demonstrated that the image contrast can be improved in a monolithic approach by using multiple reference pinholes. The final image is then retrieved either by the sum of all independent reconstructions 10 , 17 or by a Hadamard convolution if the references have been arranged in a so-called uniform redundant array 1 . However, the number of pinholes required to keep the total reference beam intensity constant while decreasing the pinhole diameters scales with the inverse square of the spatial resolution. At the same time, the space available for the object-reference arrangement shrinks according to the detector specifications 13 . With present-day nanofabrication tools, the density of pinholes is insufficient to prepare an adequate number of such reference holes in sub-10 nm spatial resolution-imaging experiments. To avoid the dilemma of entanglement between resolution and contrast in the object reconstruction, the reference beam cannot be provided by pinhole apertures. Following the original idea of holography as proposed by Denis Gabor 18 , we have replaced the pinhole aperture by an X-ray lens, realized by a FZP. The flux in the FZP focus, that is, the intensity integrated over the size of the focus, which determines the contrast in the image reconstruction, is proportional to the FZP’s diameter D , whereas the focal spot size is defined by the outermost zone width Δ r (ref. 19 ). The FZP diameter D can easily be adjusted by altering the number of zones N such that ideally the flux through the FZP approximates the flux through the object. For conventional lens-based imaging techniques like X-ray microscopy, the small focal length f of high-resolution FZPs complicates sample positioning and limits the space available for additional instruments in the vicinity of the sample. Similar to conventional soft-X-ray FTH 6 , and contrary to previous off-axis and in-line holography experiments employing FZPs 8 , 9 , 20 , 21 , we have fabricated the FZP directly into", "role": "user" }, { "content": "A team headed by Stefan Eisebitt has developed a new X-ray holography method that will enable snap-shots of dynamic processes at highest spatial resolution. The efficiency of the new method is based on a X-ray focussing optics being firmly fixed to the object to be imaged. While this approach initially provides a blurry image, this can be focussed in the computer based on the hologram information. At the same time, the rigid connection between the object and the focussing optics elegantly solves the problem of vibration induced jitter that plays an enormous role at the nanometre scale. Prof. Stefan Eisebitt, who heads the division Nanometre and X-Ray Optics at Technische Universität Berlin and the joint research group Functional Nanostructures at Helmholtz-Zentrum Berlin (HZB), explains: \"Just as a fast objective lens on a camera enables you to get a sharp image even under conditions of weak lighting, our optical element here enables the X-ray light to be used more efficiently as well. At the same time, we have firmly coupled this X-ray lens with the object to be imaged so that vibrations no longer have any detrimental influence and the image is stabilised.\" As a consequence, low-contrast or moving nanoobjects can be imaged notably better. For X-ray holography, you need coherent light – light whose electromagnetic waves oscillate synchronously. This is the kind of light produced by lasers or by synchrotron sources like BESSY II. In the holographic process used here, part of the X-ray light falls on the object and part of it carries on through a pinhole aperture placed laterally beside the object to create the reference wave. A hologram is formed by superposing the two waves and recording the result with a detector. A holographic image of the illuminated object is then reconstructed on a computer. However, the pinhole aperture approach has a disadvantage. In order to produce a sharp image, the aperture must be very small, which therefore transmits too little light to create a good image from low-contrast objects or during short exposure times – a dilemma. Optical element increases brightness Physicists working with Eisebitt found a solution by using an optical element known as a Fresnel zone plate. This is placed in the plane of the object itself as a substitute for the pinhole aperture and considerably increases the brightness of the reference wave. However, the focal point of this optical element is not in the plane of the object (as the pinhole aperture would be), so that the image is out of focus. In contrast to photography, however, this blur in the image can be precisely corrected for via the information stored in the hologram. Due to the efficiency of the method, exposure times can be significantly reduced, allowing the study of fast dynamic processes. Test objects to measure the resolution Ph.D. student Jan Geilhufe worked out this idea and implemented it. He was also the one who introduced the image of a lizard as a filigreed test object. Its outline was reduced by a factor of 10,000 and transferred onto gold foil. \"It was important to us to find a test object with some originality for demonstrating how well the method works\", says Geilhufe. The seashell in the centre of the test object displays a section of what is called a Siemens star, a test pattern used to determine spatial resolution. Similar to how the converging rays of a Siemens star can be used to measure how well narrow lines will be reproduced in an image, you can also use the lizard's tail. With a diameter of six thousandths of a millimetre, the entire test object is about the size of a red blood cell. The smallest resolved structure has a width of no more than 46 nanometres. X-ray camera with an image stabiliser The well-known problem of jitter due to vibrations of the object in relation to the optics becomes increasingly dramatic at higher resolution of an optical system. \"In current research for high-resolution X-ray imaging, a resolution of less than ten nanometres is the target. That distance is tiny - less than a chain of one hundred single atoms. For that reason, even the smallest fluctuations are noticeable. A streetcar passing by a kilometre away can be a disturbance\", says Geilhufe. \"In our process, we have firmly coupled the object to the reference optics so that the lens fluctuates exactly synchronized with the object. We have built an X-ray camera with an image stabiliser, so to speak.\" Eisebitt emphasizes: \"The combination of the world-renowned expertise in manufacturing Fresnel zone plates at HZB, together with the structuring flexibility afforded by the \"Nano-Workbench\" at TU Berlin, has made this progress possible.\" New method will be implemented at BESSY II as part of the RICXS instrument The work is being published today in Nature Communications. The improvement in imaging efficiency and resulting possibilities for improvement in spatial and temporal resolution promises new insights into dynamic nanoscale processes, such as fastest magnetic switching in data storage. \"We hope that our approach is useful for many areas of research and contributes to understanding the world at the nanometre scale\", says Eisebitt. He and his team are looking forward to offering their new holographic technique to researchers from all over the world at BESSY II as part of the RICXS instrument. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Fourier transform holography is a highly efficient and robust imaging method, suitable for single-shot imaging at coherent X-ray sources. In its common implementation, the image contrast is limited by the reference signal generated by a small pinhole aperture. Increased pinhole diameters improve the signal, whereas the resolution is diminished. Here we report a new concept to decouple the spatial resolution from the image contrast by employing a Fresnel zone plate to provide the reference beam. Superimposed on-axis images of distinct foci are separated with a novel algorithm. Our method is insensitive to mechanical drift or vibrations and allows for long integration times common at low-flux facilities like high harmonic generation sources. The application of monolithic focused reference beams improves the efficiency of high-resolution X-ray Fourier transform holography beyond all present approaches and paves the path towards sub-10 nm single-shot X-ray imaging. Introduction The development of highly efficient and robust X-ray imaging methods is of particular interest for single-shot applications 1 , 2 , 3 , 4 , 5 , in which all information has to be encoded by the limited number of photons of a single femtosecond X-ray pulse, requiring outstanding efficiency of the method used. One of the few approaches that fulfil such requirements is X-ray Fourier transform holography (FTH) 6 , 7 . In FTH, the far-field scattering pattern of a specimen is recorded on a two-dimensional detector. The phase information is encoded in the interference of the scattered beam with an unperturbed reference beam, forming the hologram 1 , 6 , 8 , 9 , 10 , 11 , 12 . With an off-axis reference beam originating ideally from a point source in the object plane, the image is reconstructed by an inverse Fourier transform of the hologram as the cross-correlation of the specimen with the reference transmission function 13 . Since the FTH scattering geometry allows for recording large scattering angles, the resolution is typically limited by the spatial extent of the reference source while the image contrast is determined by the photon flux in the reference beam. (We here consider the typical case in high-resolution imaging that the reference wave is significantly weaker than the object wave and hence the limiting factor for the hologram fringe visibility). In addition, the number of pixels of the detector defines a maximum lateral size of the combined object and reference structures of the sample for a given spatial resolution 13 . In the most common implementation of FTH, the reference wave originates from a small pinhole aperture fabricated into an X-ray-opaque metal film adjacent to an object aperture that defines the field of view 6 . This integrated, monolithic design is the reason for the remarkable stability of mask-based FTH against drift and vibration of the set-up. In conjunction with the flexibility in sample environments afforded by the absence of further optical elements in the vicinity of the sample and the robust and unambiguous image reconstruction process, this approach is applied—beyond method development—for example, in material science research of magnetic nanostructures 7 , 14 , 15 . The drawback of point-like apertures generating reference waves is the entanglement of spatial resolution and contrast in the reconstruction. If the reference diameter is decreased, the resolution limit will scale linearly with the reference size while the reference signal strength, and ultimately the image contrast, is reduced quadratically. A high-resolution FTH imaging experiment is therefore commonly designed as a compromise between the desired resolution and the required reference signal. As long as the reference signal exceeds the detector’s noise level, the decrease in flux through an ever smaller reference could in principle be accounted for by extending exposure times up to a certain practical limit. However, resolution limits as reported for Fresnel zone plate (FZP)-based X-ray microscopy 16 have not been achieved for FTH using reference pinholes with high aspect ratio up to now. Moreover, for the growing class of dynamic studies relying on femtosecond X-ray pulses, the signal has to be collected from a limited number of photons 3 , 4 , 5 , 7 . It has been demonstrated that the image contrast can be improved in a monolithic approach by using multiple reference pinholes. The final image is then retrieved either by the sum of all independent reconstructions 10 , 17 or by a Hadamard convolution if the references have been arranged in a so-called uniform redundant array 1 . However, the number of pinholes required to keep the total reference beam intensity constant while decreasing the pinhole diameters scales with the inverse square of the spatial resolution. At the same time, the space available for the object-reference arrangement shrinks according to the detector specifications 13 . With present-day nanofabrication tools, the density of pinholes is insufficient to prepare an adequate number of such reference holes in sub-10 nm spatial resolution-imaging experiments. To avoid the dilemma of entanglement between resolution and contrast in the object reconstruction, the reference beam cannot be provided by pinhole apertures. Following the original idea of holography as proposed by Denis Gabor 18 , we have replaced the pinhole aperture by an X-ray lens, realized by a FZP. The flux in the FZP focus, that is, the intensity integrated over the size of the focus, which determines the contrast in the image reconstruction, is proportional to the FZP’s diameter D , whereas the focal spot size is defined by the outermost zone width Δ r (ref. 19 ). The FZP diameter D can easily be adjusted by altering the number of zones N such that ideally the flux through the FZP approximates the flux through the object. For conventional lens-based imaging techniques like X-ray microscopy, the small focal length f of high-resolution FZPs complicates sample positioning and limits the space available for additional instruments in the vicinity of the sample. Similar to conventional soft-X-ray FTH 6 , and contrary to previous off-axis and in-line holography experiments employing FZPs 8 , 9 , 20 , 21 , we have fabricated the FZP directly into<|im_end|> <|im_start|>assistant A team headed by Stefan Eisebitt has developed a new X-ray holography method that will enable snap-shots of dynamic processes at highest spatial resolution. The efficiency of the new method is based on a X-ray focussing optics being firmly fixed to the object to be imaged. While this approach initially provides a blurry image, this can be focussed in the computer based on the hologram information. At the same time, the rigid connection between the object and the focussing optics elegantly solves the problem of vibration induced jitter that plays an enormous role at the nanometre scale. Prof. Stefan Eisebitt, who heads the division Nanometre and X-Ray Optics at Technische Universität Berlin and the joint research group Functional Nanostructures at Helmholtz-Zentrum Berlin (HZB), explains: "Just as a fast objective lens on a camera enables you to get a sharp image even under conditions of weak lighting, our optical element here enables the X-ray light to be used more efficiently as well. At the same time, we have firmly coupled this X-ray lens with the object to be imaged so that vibrations no longer have any detrimental influence and the image is stabilised." As a consequence, low-contrast or moving nanoobjects can be imaged notably better. For X-ray holography, you need coherent light – light whose electromagnetic waves oscillate synchronously. This is the kind of light produced by lasers or by synchrotron sources like BESSY II. In the holographic process used here, part of the X-ray light falls on the object and part of it carries on through a pinhole aperture placed laterally beside the object to create the reference wave. A hologram is formed by superposing the two waves and recording the result with a detector. A holographic image of the illuminated object is then reconstructed on a computer. However, the pinhole aperture approach has a disadvantage. In order to produce a sharp image, the aperture must be very small, which therefore transmits too little light to create a good image from low-contrast objects or during short exposure times – a dilemma. Optical element increases brightness Physicists working with Eisebitt found a solution by using an optical element known as a Fresnel zone plate. This is placed in the plane of the object itself as a substitute for the pinhole aperture and considerably increases the brightness of the reference wave. However, the focal point of this optical element is not in the plane of the object (as the pinhole aperture would be), so that the image is out of focus. In contrast to photography, however, this blur in the image can be precisely corrected for via the information stored in the hologram. Due to the efficiency of the method, exposure times can be significantly reduced, allowing the study of fast dynamic processes. Test objects to measure the resolution Ph.D. student Jan Geilhufe worked out this idea and implemented it. He was also the one who introduced the image of a lizard as a filigreed test object. Its outline was reduced by a factor of 10,000 and transferred onto gold foil. "It was important to us to find a test object with some originality for demonstrating how well the method works", says Geilhufe. The seashell in the centre of the test object displays a section of what is called a Siemens star, a test pattern used to determine spatial resolution. Similar to how the converging rays of a Siemens star can be used to measure how well narrow lines will be reproduced in an image, you can also use the lizard's tail. With a diameter of six thousandths of a millimetre, the entire test object is about the size of a red blood cell. The smallest resolved structure has a width of no more than 46 nanometres. X-ray camera with an image stabiliser The well-known problem of jitter due to vibrations of the object in relation to the optics becomes increasingly dramatic at higher resolution of an optical system. "In current research for high-resolution X-ray imaging, a resolution of less than ten nanometres is the target. That distance is tiny - less than a chain of one hundred single atoms. For that reason, even the smallest fluctuations are noticeable. A streetcar passing by a kilometre away can be a disturbance", says Geilhufe. "In our process, we have firmly coupled the object to the reference optics so that the lens fluctuates exactly synchronized with the object. We have built an X-ray camera with an image stabiliser, so to speak." Eisebitt emphasizes: "The combination of the world-renowned expertise in manufacturing Fresnel zone plates at HZB, together with the structuring flexibility afforded by the "Nano-Workbench" at TU Berlin, has made this progress possible." New method will be implemented at BESSY II as part of the RICXS instrument The work is being published today in Nature Communications. The improvement in imaging efficiency and resulting possibilities for improvement in spatial and temporal resolution promises new insights into dynamic nanoscale processes, such as fastest magnetic switching in data storage. "We hope that our approach is useful for many areas of research and contributes to understanding the world at the nanometre scale", says Eisebitt. He and his team are looking forward to offering their new holographic technique to researchers from all over the world at BESSY II as part of the RICXS instrument. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Drylands represent the planet’s largest terrestrial biome and evidence suggests these landscapes have large potential for creating feedbacks to future climate. Recent studies also indicate that dryland ecosystems are responding markedly to climate change. Biological soil crusts (biocrusts) ‒ soil surface communities of lichens, mosses, and/or cyanobacteria ‒ comprise up to 70% of dryland cover and help govern fundamental ecosystem functions, including soil stabilization and carbon uptake. Drylands are expected to experience significant changes in temperature and precipitation regimes, and such alterations may impact biocrust communities by promoting rapid mortality of foundational species. In turn, biocrust community shifts affect land surface cover and roughness—changes that can dramatically alter albedo. We tested this hypothesis in a full-factorial warming (+4 °C above ambient) and altered precipitation (increased frequency of 1.2 mm monsoon-type watering events) experiment on the Colorado Plateau, USA. We quantified changes in shortwave albedo via multi-angle, solar-reflectance measurements. Warming and watering treatments each led to large increases in albedo (>30%). This increase was driven by biophysical factors related to treatment effects on cyanobacteria cover and soil surface roughness following treatment-induced moss and lichen mortality. A rise in dryland surface albedo may represent a previously unidentified feedback to future climate. Introduction Land surfaces in drylands are characterized by sparse, heterogeneous vegetation cover with large interspaces between the vascular plants 1 . In undisturbed settings, these interspaces are predominately colonized by biocrusts, which consist of a diverse soil surface community of cyanobacteria, mosses, lichens, and heterotrophs held together by cyanobacteria filaments 2 , 3 . In many drylands, biocrusts are likely the dominant source of new nitrogen (N) via N 2 fixation 4 , are a substantial pathway of gaseous N loss 5 , and represent a significant input of carbon (C) via biocrust photosynthesis 6 , 7 . Recent studies utilizing climate manipulation treatments suggest that climate change may have dramatic effects on biocrust community composition by eliminating key species of mosses and lichens, which are large contributors to biogeochemical and hydrological functions in drylands 8 , 9 , 10 . This climate-induced loss of mosses and lichens in favor of early successional cyanobacteria-dominated biocrusts also reduces the characteristically dark, textured soil surface, which in turn increases the abundance of lighter, smoother surface cover ( Fig. 1a–d ). Thus, a shift in biocrust community states could cause rapid alteration of dryland albedo and energy balance by returning energy to the atmosphere that was once absorbed by the dark biocrust surfaces 11 , 12 , 13 . Figure 1: Biocrust cover and albedo by treatment. The photographs ( a – d ) illustrate representative effects of the treatments (control, watering, warming, watering + warming) on biocrust cover identified along the horizontal axis corresponding to box and whisker plots. Photographs were taken in areas of little to no vegetation or litter. In the box and whisker panel, boxes show medians for albedo (heavy central line) and 1st and 3rd quartiles; whiskers indicate 1.5 inter-quartile range. Climate manipulation treatments caused a significant increase in albedo of the warming ( P < 0.01) and warming + watering ( P < 0.05) treatments compared to untreated controls, but the watering only plots had more variable responses ( P = 0.06). Full size image This effect is analogous (although opposite in sign) to climate-induced woody encroachment in high latitude ecosystems, which dramatically alters albedo via the transformation of white, snow-covered landscapes to dark vegetative cover 14 . Despite a growing concern over how climate-driven disturbances will affect biogeophysical processes, little empirical evidence exists regarding how and at what magnitude climate change effects in drylands will create feedbacks to future climate via changes to energy balance. To evaluate the impact of climate change on dryland energy balance, we assessed short-wave (solar spectrum) albedo in relation to biocrust community composition in 20, 5 m 2 plots subjected to warming and altered precipitation patterns (supplemental watering). Treatments were applied over 10 years (2005–2014) in a full-factorial design (control, watering, warming, and watering + warming). The warming (+2 °C above ambient for the first three years, then +4 °C for the remaining years) and watering (increased frequency of 1.2 mm summer rainfall events) treatments were selected to meet climate model projections 15 . A rapid mortality of the dominant moss ( Syntrichia caninervis ), which constituted ~25% of the biocrust community cover in our plots, occurred over the first year of treatments in the watering and watering + warming treatments 8 , while significant moss decline in the warming-only treatment took more than 6 years to emerge 9 . Thus, dramatic mortality of this common moss, which is one of the most abundant desert mosses in the world 16 , was observed with both increased temperature and altered precipitation treatments. Significant responses due to warming and watering + warming were also seen in reduced cover of the dominant lichens ( Collema tenax and Collema coccophorum ) 9 . Over time, the decline in moss and lichen species in all treatments produced a shift to a heavily cyanobacteria-dominated biocrust community (i.e., a shift to an early successional state in this system; Fig. 1 ). We assessed the effect that this change in community had on albedo by integrating hyperspectral solar-reflectance measurements over four view azimuth and five zenith angles (see Supplementary Information Fig. S5 ) to account for reflected light scattering in all treatments during the autumn of 2014. Biocrust community composition was determined from point-intercept frames and was used to correlate plot-level albedo with biocrust community cover. We used soil surface roughness and soil moisture [determined via the chain method (see methods) and volumetric water content probes at 2 and 5 cm soil depths, respectively] measured at the time of albedo measurements to investigate the relationships between albedo and climate treatment effects on surface micro-topography, moisture content, and biocrust community structure. Finally, albedo measurements across treatments and communities were combined with global irradiance and biocrust composition distribution data to provide a conceptual estimate of dryland energy balance effects. This novel", "role": "user" }, { "content": "Arid and semiarid ecosystems are expected to experience significant changes in temperature and precipitation patterns, which may affect soil organisms in ways that cause surfaces to become lighter in color and thus reflect more sunlight, according to a new U.S. Geological Survey study. This change will bounce more energy back into the atmosphere, which can alter global climate. Drylands make up more than 40 percent of the earth's land surface. The living skin of the desert, called biological soil crusts or biocrusts, is a community of mosses, lichens and/or cyanobacteria that is critical to human and ecosystem health and climate in the Southwest and other dryland areas. \"The discovery that climate change impacts on biocrusts could feedback to future climate is a critical factor that hasn't been considered in the past,\" said Austin Rutherford, lead author of the new USGS study. \"This information is an important step in understanding climate, and may be helpful in developing future global climate models.\" USGS scientists created outdoor testing plots located on the Colorado Plateau, where large squares of biocrusts were exposed to different warming and precipitation factors over time. Researchers not only looked at how the biocrusts responded, but also measured the amount of energy that the different biocrust communities reflected back into the atmosphere relative to how much energy came in from the sun. This effect is known as albedo. On the Colorado Plateau, mature biocrusts are bumpy and dark-colored due to the presence of lichens, mosses, and high densities of cyanobacteria and other organisms. These organisms perform critical functions, such as fertilizing soils and increasing soil stability, therefore reducing dust. Credit: Jennifer LaVista, USGSPublic domain Warming and watering treatments had large impacts on biocrust communities, transforming them from the dark to light-colored communities, and causing energy that was previously absorbed by the dark surfaces to reflect back into the atmosphere. These factors led to large increases in albedo and may represent a previously unidentified effect on future climate by slowing how fast the earth warms. The replacement of biocrust mosses and lichens with light-colored cyanobacteria may also result in increased soil erosion, decreased soil fertility and decreased removal of the greenhouse gas carbon dioxide from the air. Biocrusts provide soil stability and prevent erosion, and could help prevent the large dust storms that move through big southwestern cities such as Phoenix. Dust storms are a human health issue, as airborne particles can cause lung cancer, asthma and other respiratory problems. USGS scientist Sasha Reed studies sites where different climate conditions are being mimicked to determine effect on biocrusts. Credit: Jennifer LaVista, USGSPublic domain Many human activities can be unintentionally harmful to biological crusts. The biocrusts are no match for the compressional stress caused by footprints of livestock or people or the tracks from vehicles. \"Our study shows that effects of human activity may not only alter soil stability and fertility, but also the way energy is exchanged between the planet and its atmosphere,\" Rutherford said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Drylands represent the planet’s largest terrestrial biome and evidence suggests these landscapes have large potential for creating feedbacks to future climate. Recent studies also indicate that dryland ecosystems are responding markedly to climate change. Biological soil crusts (biocrusts) ‒ soil surface communities of lichens, mosses, and/or cyanobacteria ‒ comprise up to 70% of dryland cover and help govern fundamental ecosystem functions, including soil stabilization and carbon uptake. Drylands are expected to experience significant changes in temperature and precipitation regimes, and such alterations may impact biocrust communities by promoting rapid mortality of foundational species. In turn, biocrust community shifts affect land surface cover and roughness—changes that can dramatically alter albedo. We tested this hypothesis in a full-factorial warming (+4 °C above ambient) and altered precipitation (increased frequency of 1.2 mm monsoon-type watering events) experiment on the Colorado Plateau, USA. We quantified changes in shortwave albedo via multi-angle, solar-reflectance measurements. Warming and watering treatments each led to large increases in albedo (>30%). This increase was driven by biophysical factors related to treatment effects on cyanobacteria cover and soil surface roughness following treatment-induced moss and lichen mortality. A rise in dryland surface albedo may represent a previously unidentified feedback to future climate. Introduction Land surfaces in drylands are characterized by sparse, heterogeneous vegetation cover with large interspaces between the vascular plants 1 . In undisturbed settings, these interspaces are predominately colonized by biocrusts, which consist of a diverse soil surface community of cyanobacteria, mosses, lichens, and heterotrophs held together by cyanobacteria filaments 2 , 3 . In many drylands, biocrusts are likely the dominant source of new nitrogen (N) via N 2 fixation 4 , are a substantial pathway of gaseous N loss 5 , and represent a significant input of carbon (C) via biocrust photosynthesis 6 , 7 . Recent studies utilizing climate manipulation treatments suggest that climate change may have dramatic effects on biocrust community composition by eliminating key species of mosses and lichens, which are large contributors to biogeochemical and hydrological functions in drylands 8 , 9 , 10 . This climate-induced loss of mosses and lichens in favor of early successional cyanobacteria-dominated biocrusts also reduces the characteristically dark, textured soil surface, which in turn increases the abundance of lighter, smoother surface cover ( Fig. 1a–d ). Thus, a shift in biocrust community states could cause rapid alteration of dryland albedo and energy balance by returning energy to the atmosphere that was once absorbed by the dark biocrust surfaces 11 , 12 , 13 . Figure 1: Biocrust cover and albedo by treatment. The photographs ( a – d ) illustrate representative effects of the treatments (control, watering, warming, watering + warming) on biocrust cover identified along the horizontal axis corresponding to box and whisker plots. Photographs were taken in areas of little to no vegetation or litter. In the box and whisker panel, boxes show medians for albedo (heavy central line) and 1st and 3rd quartiles; whiskers indicate 1.5 inter-quartile range. Climate manipulation treatments caused a significant increase in albedo of the warming ( P < 0.01) and warming + watering ( P < 0.05) treatments compared to untreated controls, but the watering only plots had more variable responses ( P = 0.06). Full size image This effect is analogous (although opposite in sign) to climate-induced woody encroachment in high latitude ecosystems, which dramatically alters albedo via the transformation of white, snow-covered landscapes to dark vegetative cover 14 . Despite a growing concern over how climate-driven disturbances will affect biogeophysical processes, little empirical evidence exists regarding how and at what magnitude climate change effects in drylands will create feedbacks to future climate via changes to energy balance. To evaluate the impact of climate change on dryland energy balance, we assessed short-wave (solar spectrum) albedo in relation to biocrust community composition in 20, 5 m 2 plots subjected to warming and altered precipitation patterns (supplemental watering). Treatments were applied over 10 years (2005–2014) in a full-factorial design (control, watering, warming, and watering + warming). The warming (+2 °C above ambient for the first three years, then +4 °C for the remaining years) and watering (increased frequency of 1.2 mm summer rainfall events) treatments were selected to meet climate model projections 15 . A rapid mortality of the dominant moss ( Syntrichia caninervis ), which constituted ~25% of the biocrust community cover in our plots, occurred over the first year of treatments in the watering and watering + warming treatments 8 , while significant moss decline in the warming-only treatment took more than 6 years to emerge 9 . Thus, dramatic mortality of this common moss, which is one of the most abundant desert mosses in the world 16 , was observed with both increased temperature and altered precipitation treatments. Significant responses due to warming and watering + warming were also seen in reduced cover of the dominant lichens ( Collema tenax and Collema coccophorum ) 9 . Over time, the decline in moss and lichen species in all treatments produced a shift to a heavily cyanobacteria-dominated biocrust community (i.e., a shift to an early successional state in this system; Fig. 1 ). We assessed the effect that this change in community had on albedo by integrating hyperspectral solar-reflectance measurements over four view azimuth and five zenith angles (see Supplementary Information Fig. S5 ) to account for reflected light scattering in all treatments during the autumn of 2014. Biocrust community composition was determined from point-intercept frames and was used to correlate plot-level albedo with biocrust community cover. We used soil surface roughness and soil moisture [determined via the chain method (see methods) and volumetric water content probes at 2 and 5 cm soil depths, respectively] measured at the time of albedo measurements to investigate the relationships between albedo and climate treatment effects on surface micro-topography, moisture content, and biocrust community structure. Finally, albedo measurements across treatments and communities were combined with global irradiance and biocrust composition distribution data to provide a conceptual estimate of dryland energy balance effects. This novel<|im_end|> <|im_start|>assistant Arid and semiarid ecosystems are expected to experience significant changes in temperature and precipitation patterns, which may affect soil organisms in ways that cause surfaces to become lighter in color and thus reflect more sunlight, according to a new U.S. Geological Survey study. This change will bounce more energy back into the atmosphere, which can alter global climate. Drylands make up more than 40 percent of the earth's land surface. The living skin of the desert, called biological soil crusts or biocrusts, is a community of mosses, lichens and/or cyanobacteria that is critical to human and ecosystem health and climate in the Southwest and other dryland areas. "The discovery that climate change impacts on biocrusts could feedback to future climate is a critical factor that hasn't been considered in the past," said Austin Rutherford, lead author of the new USGS study. "This information is an important step in understanding climate, and may be helpful in developing future global climate models." USGS scientists created outdoor testing plots located on the Colorado Plateau, where large squares of biocrusts were exposed to different warming and precipitation factors over time. Researchers not only looked at how the biocrusts responded, but also measured the amount of energy that the different biocrust communities reflected back into the atmosphere relative to how much energy came in from the sun. This effect is known as albedo. On the Colorado Plateau, mature biocrusts are bumpy and dark-colored due to the presence of lichens, mosses, and high densities of cyanobacteria and other organisms. These organisms perform critical functions, such as fertilizing soils and increasing soil stability, therefore reducing dust. Credit: Jennifer LaVista, USGSPublic domain Warming and watering treatments had large impacts on biocrust communities, transforming them from the dark to light-colored communities, and causing energy that was previously absorbed by the dark surfaces to reflect back into the atmosphere. These factors led to large increases in albedo and may represent a previously unidentified effect on future climate by slowing how fast the earth warms. The replacement of biocrust mosses and lichens with light-colored cyanobacteria may also result in increased soil erosion, decreased soil fertility and decreased removal of the greenhouse gas carbon dioxide from the air. Biocrusts provide soil stability and prevent erosion, and could help prevent the large dust storms that move through big southwestern cities such as Phoenix. Dust storms are a human health issue, as airborne particles can cause lung cancer, asthma and other respiratory problems. USGS scientist Sasha Reed studies sites where different climate conditions are being mimicked to determine effect on biocrusts. Credit: Jennifer LaVista, USGSPublic domain Many human activities can be unintentionally harmful to biological crusts. The biocrusts are no match for the compressional stress caused by footprints of livestock or people or the tracks from vehicles. "Our study shows that effects of human activity may not only alter soil stability and fertility, but also the way energy is exchanged between the planet and its atmosphere," Rutherford said. <|im_end|>

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2,052

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Agaricomycetes, or mushrooms, are familiar, conspicuous and morphologically diverse Fungi. Most Agaricomycete fruiting bodies are ephemeral, and their fossil record is limited. Here we report diverse gilled mushrooms (Agaricales) and mycophagous rove beetles (Staphylinidae) from mid-Cretaceous Burmese amber, the latter belonging to Oxyporinae, modern members of which exhibit an obligate association with soft-textured mushrooms. The discovery of four mushroom forms, most with a complete intact cap containing distinct gills and a stalk, suggests evolutionary stasis of body form for ∼ 99 Myr and highlights the palaeodiversity of Agaricomycetes. The mouthparts of early oxyporines, including enlarged mandibles and greatly enlarged apical labial palpomeres with dense specialized sensory organs, match those of modern taxa and suggest that they had a mushroom feeding biology. Diverse and morphologically specialized oxyporines from the Early Cretaceous suggests the existence of diverse Agaricomycetes and a specialized trophic interaction and ecological community structure by this early date. Introduction Agaricomycetes is the most conspicuous and morphologically diverse group of Fungi 1 . Most agaricomycete fruiting bodies are ephemeral 2 , and so their fossils are extremely sparse 2 , 3 , 4 , 5 , 6 . Evidence indicating the origin and early diversification of Agaricomycetes is very limited. A Jurassic fossil that had been interpreted as a bracket fungus 7 was shown to be the outer bark of a conifer 8 . To date, five definitive species of agarics (gilled mushrooms) have been known exclusively from amber. Among them, two different forms are from the Mesozoic, including the earliest mushrooms, Palaeoagaracites antiquus from mid-Cretaceous Burmese amber 3 ( ∼ 99 Myr old), and the slightly younger Archaeomarasmius leggetti from New Jersey amber 2 , 4 ( ∼ 90 Myr old). The remaining three species, Aureofungus yaniguaensis 5 , Coprinites dominicana 6 and Protomycena electra 4 , are known from early Miocene Dominican amber, some 20 Myr old. All known fossil agarics are very small in size. Here we report four new forms of modern-looking gilled mushrooms (Agaricales) and diverse mycophagous rove beetles (Coleoptera, Staphylinidae) from mid-Cretaceous Burmese amber, the latter belonging to Oxyporinae, modern members that exhibit an obligate association with mature soft-textured mushrooms 9 , 10 , 11 . The specialized mouthpart morphology of these beetles sheds light on the early evolution of insect–fungal associations. More importantly, diverse and morphologically specialized oxyporines from the Early Cretaceous 12 , 13 suggest a probable occurrence of diverse large-sized Agaricomycetes by that period. Results Studied material The material includes fossil mushrooms and beetles: five mushrooms of four distinctive forms (Taxa A–D) in Burmese amber ( ∼ 99 Myr old) from Hukawng Valley, northern Myanmar, and five species and four genera of oxyporine beetles. The beetles consist of two new Oxyporus species (Taxa 1 and 2) and a new genus (Taxon 3) from Burmese amber, and two monotypic genera ( Protoxyporus and Cretoxyporus ) from the Lower Cretaceous Yixian Formation ( ∼ 125 Myr old) of northeastern China. These fossils are extremely rare among the 111,000 Burmese amber inclusions and in our collections of the Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences. Diverse gilled mushrooms from Burmese amber The mid-Cretaceous fossil mushrooms ( Fig. 1 ; Supplementary Fig. 1 ) are clearly Agaricomycetes, a derived group of fungi that plays significant ecological roles as decomposers, pathogens, and symbionts in terrestrial ecosystems and that includes most edible mushrooms. Three of the four mushrooms ( Fig. 1a,c,e ; Supplementary Figs 2a,c and 3a,b ) are nearly complete, with an intact cap (pileus), gills (lamellae) and stalk. All are minute, with caps ranging from 2.6 to 3.9 mm in diameter. The caps ( Fig. 1a,c–e ; Supplementary Figs 2a,c and 3a–c ) range from strongly to slightly plano-convex and are mostly radially sulcate. Lamellae ( Fig. 1b ; Supplementary Figs 2b,d and 3e ) are mostly sub-distant and comparatively close in one form. Macromorphological features of these fossils resemble extant mushrooms. In particular, two of four forms (Taxon A and B; Fig. 1a,c ; Supplementary Fig. 2a,c ) are similar to the extant genera Marasmius, Marasmiellus or Crinipellis , and the fossil Archaeomarasmius from late-Cretaceous New Jersey amber, suggesting that they belong to the family Marasmiaceae (Agaricales). The other two forms are difficult to place in extant families due to the lack of micromorphological features and inadequate preservation. Taxon C ( Fig. 1d ; Supplementary Fig. 3c ) has a slightly convex pileus ( Fig. 1d ), close lamellae ( Supplementary Fig. 3e ) and a sub-marginal stalk ( Supplementary Fig. 3d ), a combination of features that is not easy to compare with modern agarics. Taxon D ( Fig. 1e ; Supplementary Fig. 3a,b ) has a plicate-pectinate cap margin, which is similar to that of the Miocene Coprinites from Dominican amber. However, the former differs from Coprinites by the short, stout and sub-marginal stalk ( Supplementary Fig. 3b ). The discovery of four mushroom forms from Burmese amber, together with the known Palaeoagaracites antiquus from the same deposit, highlights the palaeodiversity of Agaricomycetes in the mid-Cretaceous. Like their modern counterparts in Marasmiaceae, these mushrooms (Taxa A and B) were probably decayers of leaf litter and wood in ancient ecosystems. Detailed descriptions of the fossil mushrooms are given in Supplementary Note 1 . Figure 1: Diverse mushrooms in mid-Cretaceous amber from northern Myanmar. ( a ) General habitus of Taxon A, FXBA10101, ventral view. ( b ) Enlargement of a , showing details of lamellae and top portion of stalk. ( c ) Lateral view of two individuals of Taxon B, NIGP164521 (left) and NIGP164522 (right). ( d ) Ventral view of Taxon C, NIGP164523, showing sub-marginally inserted stalk. ( e ) Lateral view of Taxon D, NIGP164524. Abbreviations: ca, cap; st, stalk. Scale bars, 1 mm ( a , c , d ); 500 μm (others). Full size image Mycophagy and mycophagous oxyporine rove beetles Mycophagy, or fungus-feeding, is widespread in Coleoptera 14 , 15 , 16 and the occurrence of this feeding habit in older clades of", "role": "user" }, { "content": "Mushrooms are common, conspicuous and morphologically diverse fungi. Most agaricomycete fruiting bodies are ephemeral, so they are extremely rare in fossils. Up to now, all described species of gilled mushrooms, or agaricales, have been known exclusively from amber. Two forms are from the Mesozoic, including the earliest mushrooms, Palaeoagaracites antiquus from 99-million-year-old Burmese amber, and the slightly younger Archaeomarasmius leggetti from New Jersey amber (about 90 million year old). The remaining three species are known from 20-million-year-old early Miocene Dominican amber. Evidence indicating the origin and early diversification of Agaricomycetes is very limited. Recently, a research team led by Prof. HUANG Diying from Nanjing Institute of Geology and Palaeontology (NIGPAS) of the Chinese Academy of Sciences reported a diversity of gilled mushrooms and mycophagous rove beetles from Burmese amber, the latter belonging to Oxyporinae, modern members of which exhibit an obligate association with soft-textured mushrooms. The results were published in Nature Communications on 16th March, 2017. All the mushrooms they studied are very well preserved and can be grouped in four forms. A stalk and a complete intact cap containing distinct gills are visible in most of these amber mushrooms. The new discovery suggests a long-term evolutionary stasis of body form for at least 99 million years and highlights the palaeodiversity of mushrooms, pushing back the presence of agarics by at least 25 million years. More interestingly, the mouthparts of these early oxyporine rove beetles, including enlarged mandibles and greatly enlarged apical labial palpomeres with dense specialized sensory organs, match those of modern taxa and indicate a mushroom feeding habit. The diverse and morphologically specialized oxyporine beetles had also appeared by the Early Cretaceous, some 125 million years ago. Their finding displays an ancient ecological community assembling diverse mushrooms and beetles and established on specialized trophic interaction by this early date. Diverse mycophagous oxyporine rove beetles. Credit: Cai et al. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Agaricomycetes, or mushrooms, are familiar, conspicuous and morphologically diverse Fungi. Most Agaricomycete fruiting bodies are ephemeral, and their fossil record is limited. Here we report diverse gilled mushrooms (Agaricales) and mycophagous rove beetles (Staphylinidae) from mid-Cretaceous Burmese amber, the latter belonging to Oxyporinae, modern members of which exhibit an obligate association with soft-textured mushrooms. The discovery of four mushroom forms, most with a complete intact cap containing distinct gills and a stalk, suggests evolutionary stasis of body form for ∼ 99 Myr and highlights the palaeodiversity of Agaricomycetes. The mouthparts of early oxyporines, including enlarged mandibles and greatly enlarged apical labial palpomeres with dense specialized sensory organs, match those of modern taxa and suggest that they had a mushroom feeding biology. Diverse and morphologically specialized oxyporines from the Early Cretaceous suggests the existence of diverse Agaricomycetes and a specialized trophic interaction and ecological community structure by this early date. Introduction Agaricomycetes is the most conspicuous and morphologically diverse group of Fungi 1 . Most agaricomycete fruiting bodies are ephemeral 2 , and so their fossils are extremely sparse 2 , 3 , 4 , 5 , 6 . Evidence indicating the origin and early diversification of Agaricomycetes is very limited. A Jurassic fossil that had been interpreted as a bracket fungus 7 was shown to be the outer bark of a conifer 8 . To date, five definitive species of agarics (gilled mushrooms) have been known exclusively from amber. Among them, two different forms are from the Mesozoic, including the earliest mushrooms, Palaeoagaracites antiquus from mid-Cretaceous Burmese amber 3 ( ∼ 99 Myr old), and the slightly younger Archaeomarasmius leggetti from New Jersey amber 2 , 4 ( ∼ 90 Myr old). The remaining three species, Aureofungus yaniguaensis 5 , Coprinites dominicana 6 and Protomycena electra 4 , are known from early Miocene Dominican amber, some 20 Myr old. All known fossil agarics are very small in size. Here we report four new forms of modern-looking gilled mushrooms (Agaricales) and diverse mycophagous rove beetles (Coleoptera, Staphylinidae) from mid-Cretaceous Burmese amber, the latter belonging to Oxyporinae, modern members that exhibit an obligate association with mature soft-textured mushrooms 9 , 10 , 11 . The specialized mouthpart morphology of these beetles sheds light on the early evolution of insect–fungal associations. More importantly, diverse and morphologically specialized oxyporines from the Early Cretaceous 12 , 13 suggest a probable occurrence of diverse large-sized Agaricomycetes by that period. Results Studied material The material includes fossil mushrooms and beetles: five mushrooms of four distinctive forms (Taxa A–D) in Burmese amber ( ∼ 99 Myr old) from Hukawng Valley, northern Myanmar, and five species and four genera of oxyporine beetles. The beetles consist of two new Oxyporus species (Taxa 1 and 2) and a new genus (Taxon 3) from Burmese amber, and two monotypic genera ( Protoxyporus and Cretoxyporus ) from the Lower Cretaceous Yixian Formation ( ∼ 125 Myr old) of northeastern China. These fossils are extremely rare among the 111,000 Burmese amber inclusions and in our collections of the Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences. Diverse gilled mushrooms from Burmese amber The mid-Cretaceous fossil mushrooms ( Fig. 1 ; Supplementary Fig. 1 ) are clearly Agaricomycetes, a derived group of fungi that plays significant ecological roles as decomposers, pathogens, and symbionts in terrestrial ecosystems and that includes most edible mushrooms. Three of the four mushrooms ( Fig. 1a,c,e ; Supplementary Figs 2a,c and 3a,b ) are nearly complete, with an intact cap (pileus), gills (lamellae) and stalk. All are minute, with caps ranging from 2.6 to 3.9 mm in diameter. The caps ( Fig. 1a,c–e ; Supplementary Figs 2a,c and 3a–c ) range from strongly to slightly plano-convex and are mostly radially sulcate. Lamellae ( Fig. 1b ; Supplementary Figs 2b,d and 3e ) are mostly sub-distant and comparatively close in one form. Macromorphological features of these fossils resemble extant mushrooms. In particular, two of four forms (Taxon A and B; Fig. 1a,c ; Supplementary Fig. 2a,c ) are similar to the extant genera Marasmius, Marasmiellus or Crinipellis , and the fossil Archaeomarasmius from late-Cretaceous New Jersey amber, suggesting that they belong to the family Marasmiaceae (Agaricales). The other two forms are difficult to place in extant families due to the lack of micromorphological features and inadequate preservation. Taxon C ( Fig. 1d ; Supplementary Fig. 3c ) has a slightly convex pileus ( Fig. 1d ), close lamellae ( Supplementary Fig. 3e ) and a sub-marginal stalk ( Supplementary Fig. 3d ), a combination of features that is not easy to compare with modern agarics. Taxon D ( Fig. 1e ; Supplementary Fig. 3a,b ) has a plicate-pectinate cap margin, which is similar to that of the Miocene Coprinites from Dominican amber. However, the former differs from Coprinites by the short, stout and sub-marginal stalk ( Supplementary Fig. 3b ). The discovery of four mushroom forms from Burmese amber, together with the known Palaeoagaracites antiquus from the same deposit, highlights the palaeodiversity of Agaricomycetes in the mid-Cretaceous. Like their modern counterparts in Marasmiaceae, these mushrooms (Taxa A and B) were probably decayers of leaf litter and wood in ancient ecosystems. Detailed descriptions of the fossil mushrooms are given in Supplementary Note 1 . Figure 1: Diverse mushrooms in mid-Cretaceous amber from northern Myanmar. ( a ) General habitus of Taxon A, FXBA10101, ventral view. ( b ) Enlargement of a , showing details of lamellae and top portion of stalk. ( c ) Lateral view of two individuals of Taxon B, NIGP164521 (left) and NIGP164522 (right). ( d ) Ventral view of Taxon C, NIGP164523, showing sub-marginally inserted stalk. ( e ) Lateral view of Taxon D, NIGP164524. Abbreviations: ca, cap; st, stalk. Scale bars, 1 mm ( a , c , d ); 500 μm (others). Full size image Mycophagy and mycophagous oxyporine rove beetles Mycophagy, or fungus-feeding, is widespread in Coleoptera 14 , 15 , 16 and the occurrence of this feeding habit in older clades of<|im_end|> <|im_start|>assistant Mushrooms are common, conspicuous and morphologically diverse fungi. Most agaricomycete fruiting bodies are ephemeral, so they are extremely rare in fossils. Up to now, all described species of gilled mushrooms, or agaricales, have been known exclusively from amber. Two forms are from the Mesozoic, including the earliest mushrooms, Palaeoagaracites antiquus from 99-million-year-old Burmese amber, and the slightly younger Archaeomarasmius leggetti from New Jersey amber (about 90 million year old). The remaining three species are known from 20-million-year-old early Miocene Dominican amber. Evidence indicating the origin and early diversification of Agaricomycetes is very limited. Recently, a research team led by Prof. HUANG Diying from Nanjing Institute of Geology and Palaeontology (NIGPAS) of the Chinese Academy of Sciences reported a diversity of gilled mushrooms and mycophagous rove beetles from Burmese amber, the latter belonging to Oxyporinae, modern members of which exhibit an obligate association with soft-textured mushrooms. The results were published in Nature Communications on 16th March, 2017. All the mushrooms they studied are very well preserved and can be grouped in four forms. A stalk and a complete intact cap containing distinct gills are visible in most of these amber mushrooms. The new discovery suggests a long-term evolutionary stasis of body form for at least 99 million years and highlights the palaeodiversity of mushrooms, pushing back the presence of agarics by at least 25 million years. More interestingly, the mouthparts of these early oxyporine rove beetles, including enlarged mandibles and greatly enlarged apical labial palpomeres with dense specialized sensory organs, match those of modern taxa and indicate a mushroom feeding habit. The diverse and morphologically specialized oxyporine beetles had also appeared by the Early Cretaceous, some 125 million years ago. Their finding displays an ancient ecological community assembling diverse mushrooms and beetles and established on specialized trophic interaction by this early date. Diverse mycophagous oxyporine rove beetles. Credit: Cai et al. <|im_end|>

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578, 502, 18841, 13533, 264, 1317, 9860, 41993, 357, 10949, 315, 2547, 1376, 369, 520, 3325, 220, 1484, 3610, 1667, 323, 22020, 279, 11091, 6043, 347, 3050, 315, 48251, 11, 17919, 1203, 279, 9546, 315, 70479, 1233, 555, 520, 3325, 220, 914, 3610, 1667, 13, 4497, 7185, 398, 11, 279, 11013, 18753, 315, 1521, 4216, 19488, 1100, 269, 483, 938, 588, 49112, 645, 11, 2737, 74117, 11837, 21041, 323, 19407, 74117, 1469, 950, 10278, 532, 75649, 316, 13213, 449, 29050, 28175, 49069, 36853, 11, 2489, 1884, 315, 6617, 77314, 323, 13519, 264, 58466, 26040, 14464, 13, 578, 17226, 323, 27448, 30450, 28175, 19488, 1100, 269, 483, 49112, 645, 1047, 1101, 9922, 555, 279, 23591, 356, 2171, 77140, 11, 1063, 220, 6549, 3610, 1667, 4227, 13, 11205, 9455, 19207, 459, 14154, 50953, 4029, 81759, 17226, 48251, 323, 49112, 645, 323, 9749, 389, 28175, 8348, 764, 292, 16628, 555, 420, 4216, 2457, 13, 423, 8194, 856, 66, 5237, 351, 788, 19488, 1100, 269, 483, 938, 588, 49112, 645, 13, 16666, 25, 356, 2192, 1880, 453, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chromatin-binding proteins are critical regulators of cell state in haematopoiesis 1 , 2 . Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene ( KMT2A r) or mutation of the nucleophosmin gene ( NPM1 ) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs 3 , 4 , 5 . In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin–MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2A r or mutated NPM1 (ref. 6 ). Here we identified somatic mutations in MEN1 at the revumenib–menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor–menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug–target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance. Main Menin is a chromatin adaptor protein that is critical for the formation and stability of highly conserved multiprotein complexes on chromatin, including MLL1 (also known as KMT2A ) and MLL2 (also known as KMT2B ) histone methyltransferase complexes and the JUND transcription factor complex 4 , 7 , 8 . Menin is critical for the development and maintenance of acute leukaemias driven by KMT2A r or NPM1 mutations 3 , 5 . A series of small-molecule inhibitors that disrupt the menin–MLL1 protein–protein interaction have been developed 9 , 10 , 11 , 12 , 13 , 14 and demonstrate potent activity in preclinical models, including the ability to eradicate disease 5 , 10 , 14 . On the basis of this, several menin inhibitors recently entered phase 1 clinical trials ( NCT04065399 , NCT04067336 , NCT04811560 , NCT05388903 , NCT04988555 and NCT05153330 ). The menin inhibitor revumenib (also known as SNDX-5613) has been reported to be safe and effective in patients with relapsed or refractory acute leukaemia with an KMT2A r or NPM1 mutation. In the ongoing phase 1/2 first-in-human study (AUGMENT-101) of revumenib, patients with KMT2A r or NPM1 c-mutant leukaemia had an overall response rate of 53%, with 30% of treated patients achieving a complete remission or complete remission with partial haematological recovery 6 . Here we identified and characterized somatic mutations within the MEN1 gene that arise during menin inhibitor treatment and mediate therapeutic resistance in model systems and in patients enrolled in the AUGMENT-101 trial ( NCT04065399 ). MEN1 mutations in resistant leukaemias Despite significant single-agent activity of revumenib in a heavily pretreated patient population with KMT2A r and NPM1 -mutant leukaemia, we identified patients who were treated on the AUGMENT-101 phase 1 study and subsequently developed acquired resistance following an initial response (Fig. 1a ). Patients 1 and 4 with relapsed KMT2A r acute myeloid leukaemia (AML) achieved morphological leukaemia-free states after one cycle of treatment, followed by relapse despite continued exposure to the study drug. Patient 2 with NPM1 -mutant AML had a reduction in circulating blast counts after two cycles of revumenib followed by disease progression, whereas patient 3 with KMT2A r AML achieved a complete remission with incomplete count recovery and then progressed despite continued treatment with the menin inhibitor (Fig. 1a ). Next-generation targeted sequencing of bone marrow specimens from these patients at diagnosis revealed a largely stable landscape of well-characterized leukaemia drivers, but somatic mutations within the MEN1 gene were detected at time of relapse on revumenib (Extended Data Fig. 1a–c ). In three out of four patients, the M327 residue was affected (M327V or M327I), and T349M, G331R and S160T were detected in each one of the three patients at the end of treatment, respectively (Fig. 1a ). Mutation allele frequencies ranged from 5.9% to 28.2% (Extended Data Fig. 1a–c ), owing to expected dilution effects from normal leukocytes. To quantitatively assess the frequency of these novel somatic mutations within the population of patients with KMT2A r and the NPM1 mutation who had been exposed to revumenib, we performed droplet digital PCR (ddPCR) for MEN1 M327V , MEN1 M327I , MEN1 G331R , MEN1 G331D and MEN1 T349M on DNA samples collected during the AUGMENT-101 trial at different study centres. We identified 31 patients, inclusive of responders and non-responders, who were treated with revumenib for more than two cycles of treatment (more than 56 days) and had DNA material available for analysis. Among these patients, 12 individuals (38.7%) carried one or more MEN1 mutations (Fig. 1b and Extended Data Fig. 1d ). Of note, these mutations were not detected in the pretreatment samples by ddPCR, suggesting that they were either not present or present in very low abundance until menin inhibition established a selective fitness advantage (Fig. 1c ). Due to the sensitivity of the ddPCR assay, the patients found to harbor MEN1 mutations were not necessarily in overt relapse at time of detection. Longitudinal assessment of the detected mutations in single patients confirmed clonal outgrowth during drug treatment and suggested that selection for MEN1 -mutant leukaemia cells occurs after approximately two cycles of therapy (Fig. 1d and Extended Data Fig. 1e ). Fig. 1: Menin inhibitor resistance is associated with the emergence of MEN1 mutations. a , Graphical depiction of the percentage of leukaemic blasts in the peripheral blood of patients during revumenib treatment in the AUGMENT-101 clinical trial. Clinical events are marked with arrows and labelled. CRi, complete remission with incomplete count recovery; HU, hydroxyurea; MLFS, morphologic leukaemia-free state; PD, progressive disease. b , Schematic showing the fraction of patients from AUGMENT-101 in which MEN1 M327I , MEN1 M327V , MEN1 G331R , MEN1 G331D or MEN1 T349M were detected", "role": "user" }, { "content": "A new targeted drug has not only sparked remissions in patients with a common form of leukemia but also induced the cancer cells to reveal one of their schemes for resisting the drug, investigators at Dana-Farber Cancer Institute and other research centers report in a new pair of studies in the journal Nature. One of the papers presents results of a clinical trial in which approximately 40% of patients with acute leukemia subtypes had a complete response—a disappearance of all signs of cancer—to treatment with the drug revumenib. The other paper uncovers a molecular countermove by which leukemia cells come to sidestep the drug and reassert their growth. The papers point to the promise of the targeted approach to acute leukemia treatment exemplified by revumenib and to the potential to extend its benefits with drugs that trip up the resistance mechanism, researchers say. \"The two genetic subtypes of acute leukemia involved in this research account for approximately 40% of all cases of acute myeloid leukemia (AML) in children and adults,\" says Scott Armstrong, MD, Ph.D., president of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and co-senior author of the paper on revumenib resistance. \"They're driven by a rearrangement of the MLL1 gene or a mutation in the NPM1 gene. Both types depend on a protein called menin to sustain their growth.\" The first of the new Nature studies reports on a phase I/II clinical trial of the drug revumenib, which targets menin, in 68 patients with acute leukemia that wasn't responding other therapies. The trial, dubbed the AUGMENT-101 study, found that of 60 patients who could be evaluated, 53% responded to the drug and 30% had a complete response. \"For patients with acute leukemia who have undergone several previous treatments, this is a very encouraging result,\" Armstrong says. \"However, after the second cycle of treatment, some patients did develop resistance to revumenib.\" In their follow-up study, Armstrong and his associates sought a source of that resistance. Menin is a critical part of the cell's \"epigenetic\" mechanism for switching gene activity on and off. It binds to chromatin—the braid of DNA and protein packaging within the nucleus—and summons large protein complexes to join it. The complexes tighten or loosen the coils of DNA, changing the activity level of the genes at that site. One of the key proteins within these complexes is MLL1, the product of the MLL1 gene. \"Revumenib contains a small molecule that inhibits the interaction of menin and MLL1,\" Armstrong says. \"The AUGMENT trial shows it can produce remissions in a high percentage of patients.\" When Armstrong and his colleagues analyzed bone marrow samples from some of the patients who became resistant to revumenib, they found that many had developed mutations in MEN1, the gene that gives rise to the menin protein. The mutation leads to a deformed version of menin that doesn't bind well to revumenib but attaches as firmly as ever to MLL1. As menin and MLL1 renew their interaction, leukemia cell growth restarts. The finding provides \"formal proof in patients that menin itself is a valid target for therapy in both genetic subtypes of AML,\" Armstrong relates. In a sense, revumenib acts as a kind of truth-telling serum on leukemia cells: by placing the cells under pressure, it prompts them to divulge one of their strategies for survival. \"The fact that the cell has gone through so much trouble to mutate MEN1 in order to survive is a strong indication that we're hitting a target the cell truly relies on,\" Armstrong states. The ability of revumenib to stress leukemia cells to the point where they develop a mutation to remain alive is testament to the drug's effectiveness, he continues. \"This is the first time a drug targeting a chromatin-binding protein complex has been shown to put that degree of pressure on cancer in a human patient.\" By tracking the development of mutations in MEN1 and other genes in patients with acute leukemia, doctors may be able to identify patients at high risk of relapsing, Armstrong relates. Such patients might then benefit from further treatment. The discovery of MEN1 mutation as a resistance mechanism suggests that new drugs that specifically target menin or other chromatin-associated proteins could prevent or delay revumenib resistance or treat patients who have become resistant to the drug. \"Seeing Dr. Armstrong's work translated elegantly into the clinic where patients—including some at Dana-Farber, who had dramatic responses in dire situations—was highly gratifying personally and professionally,\" says Dana-Farber's Richard Stone, MD, a co-author of both Nature studies. \"We are now ready to magnify the impact of these results by conducting clinical trials combining revumenib with standard chemotherapy as well as with novel agents, also based on preclinical work done in great part by Dr. Armstrong.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chromatin-binding proteins are critical regulators of cell state in haematopoiesis 1 , 2 . Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene ( KMT2A r) or mutation of the nucleophosmin gene ( NPM1 ) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs 3 , 4 , 5 . In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin–MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2A r or mutated NPM1 (ref. 6 ). Here we identified somatic mutations in MEN1 at the revumenib–menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor–menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug–target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance. Main Menin is a chromatin adaptor protein that is critical for the formation and stability of highly conserved multiprotein complexes on chromatin, including MLL1 (also known as KMT2A ) and MLL2 (also known as KMT2B ) histone methyltransferase complexes and the JUND transcription factor complex 4 , 7 , 8 . Menin is critical for the development and maintenance of acute leukaemias driven by KMT2A r or NPM1 mutations 3 , 5 . A series of small-molecule inhibitors that disrupt the menin–MLL1 protein–protein interaction have been developed 9 , 10 , 11 , 12 , 13 , 14 and demonstrate potent activity in preclinical models, including the ability to eradicate disease 5 , 10 , 14 . On the basis of this, several menin inhibitors recently entered phase 1 clinical trials ( NCT04065399 , NCT04067336 , NCT04811560 , NCT05388903 , NCT04988555 and NCT05153330 ). The menin inhibitor revumenib (also known as SNDX-5613) has been reported to be safe and effective in patients with relapsed or refractory acute leukaemia with an KMT2A r or NPM1 mutation. In the ongoing phase 1/2 first-in-human study (AUGMENT-101) of revumenib, patients with KMT2A r or NPM1 c-mutant leukaemia had an overall response rate of 53%, with 30% of treated patients achieving a complete remission or complete remission with partial haematological recovery 6 . Here we identified and characterized somatic mutations within the MEN1 gene that arise during menin inhibitor treatment and mediate therapeutic resistance in model systems and in patients enrolled in the AUGMENT-101 trial ( NCT04065399 ). MEN1 mutations in resistant leukaemias Despite significant single-agent activity of revumenib in a heavily pretreated patient population with KMT2A r and NPM1 -mutant leukaemia, we identified patients who were treated on the AUGMENT-101 phase 1 study and subsequently developed acquired resistance following an initial response (Fig. 1a ). Patients 1 and 4 with relapsed KMT2A r acute myeloid leukaemia (AML) achieved morphological leukaemia-free states after one cycle of treatment, followed by relapse despite continued exposure to the study drug. Patient 2 with NPM1 -mutant AML had a reduction in circulating blast counts after two cycles of revumenib followed by disease progression, whereas patient 3 with KMT2A r AML achieved a complete remission with incomplete count recovery and then progressed despite continued treatment with the menin inhibitor (Fig. 1a ). Next-generation targeted sequencing of bone marrow specimens from these patients at diagnosis revealed a largely stable landscape of well-characterized leukaemia drivers, but somatic mutations within the MEN1 gene were detected at time of relapse on revumenib (Extended Data Fig. 1a–c ). In three out of four patients, the M327 residue was affected (M327V or M327I), and T349M, G331R and S160T were detected in each one of the three patients at the end of treatment, respectively (Fig. 1a ). Mutation allele frequencies ranged from 5.9% to 28.2% (Extended Data Fig. 1a–c ), owing to expected dilution effects from normal leukocytes. To quantitatively assess the frequency of these novel somatic mutations within the population of patients with KMT2A r and the NPM1 mutation who had been exposed to revumenib, we performed droplet digital PCR (ddPCR) for MEN1 M327V , MEN1 M327I , MEN1 G331R , MEN1 G331D and MEN1 T349M on DNA samples collected during the AUGMENT-101 trial at different study centres. We identified 31 patients, inclusive of responders and non-responders, who were treated with revumenib for more than two cycles of treatment (more than 56 days) and had DNA material available for analysis. Among these patients, 12 individuals (38.7%) carried one or more MEN1 mutations (Fig. 1b and Extended Data Fig. 1d ). Of note, these mutations were not detected in the pretreatment samples by ddPCR, suggesting that they were either not present or present in very low abundance until menin inhibition established a selective fitness advantage (Fig. 1c ). Due to the sensitivity of the ddPCR assay, the patients found to harbor MEN1 mutations were not necessarily in overt relapse at time of detection. Longitudinal assessment of the detected mutations in single patients confirmed clonal outgrowth during drug treatment and suggested that selection for MEN1 -mutant leukaemia cells occurs after approximately two cycles of therapy (Fig. 1d and Extended Data Fig. 1e ). Fig. 1: Menin inhibitor resistance is associated with the emergence of MEN1 mutations. a , Graphical depiction of the percentage of leukaemic blasts in the peripheral blood of patients during revumenib treatment in the AUGMENT-101 clinical trial. Clinical events are marked with arrows and labelled. CRi, complete remission with incomplete count recovery; HU, hydroxyurea; MLFS, morphologic leukaemia-free state; PD, progressive disease. b , Schematic showing the fraction of patients from AUGMENT-101 in which MEN1 M327I , MEN1 M327V , MEN1 G331R , MEN1 G331D or MEN1 T349M were detected<|im_end|> <|im_start|>assistant A new targeted drug has not only sparked remissions in patients with a common form of leukemia but also induced the cancer cells to reveal one of their schemes for resisting the drug, investigators at Dana-Farber Cancer Institute and other research centers report in a new pair of studies in the journal Nature. One of the papers presents results of a clinical trial in which approximately 40% of patients with acute leukemia subtypes had a complete response—a disappearance of all signs of cancer—to treatment with the drug revumenib. The other paper uncovers a molecular countermove by which leukemia cells come to sidestep the drug and reassert their growth. The papers point to the promise of the targeted approach to acute leukemia treatment exemplified by revumenib and to the potential to extend its benefits with drugs that trip up the resistance mechanism, researchers say. "The two genetic subtypes of acute leukemia involved in this research account for approximately 40% of all cases of acute myeloid leukemia (AML) in children and adults," says Scott Armstrong, MD, Ph.D., president of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and co-senior author of the paper on revumenib resistance. "They're driven by a rearrangement of the MLL1 gene or a mutation in the NPM1 gene. Both types depend on a protein called menin to sustain their growth." The first of the new Nature studies reports on a phase I/II clinical trial of the drug revumenib, which targets menin, in 68 patients with acute leukemia that wasn't responding other therapies. The trial, dubbed the AUGMENT-101 study, found that of 60 patients who could be evaluated, 53% responded to the drug and 30% had a complete response. "For patients with acute leukemia who have undergone several previous treatments, this is a very encouraging result," Armstrong says. "However, after the second cycle of treatment, some patients did develop resistance to revumenib." In their follow-up study, Armstrong and his associates sought a source of that resistance. Menin is a critical part of the cell's "epigenetic" mechanism for switching gene activity on and off. It binds to chromatin—the braid of DNA and protein packaging within the nucleus—and summons large protein complexes to join it. The complexes tighten or loosen the coils of DNA, changing the activity level of the genes at that site. One of the key proteins within these complexes is MLL1, the product of the MLL1 gene. "Revumenib contains a small molecule that inhibits the interaction of menin and MLL1," Armstrong says. "The AUGMENT trial shows it can produce remissions in a high percentage of patients." When Armstrong and his colleagues analyzed bone marrow samples from some of the patients who became resistant to revumenib, they found that many had developed mutations in MEN1, the gene that gives rise to the menin protein. The mutation leads to a deformed version of menin that doesn't bind well to revumenib but attaches as firmly as ever to MLL1. As menin and MLL1 renew their interaction, leukemia cell growth restarts. The finding provides "formal proof in patients that menin itself is a valid target for therapy in both genetic subtypes of AML," Armstrong relates. In a sense, revumenib acts as a kind of truth-telling serum on leukemia cells: by placing the cells under pressure, it prompts them to divulge one of their strategies for survival. "The fact that the cell has gone through so much trouble to mutate MEN1 in order to survive is a strong indication that we're hitting a target the cell truly relies on," Armstrong states. The ability of revumenib to stress leukemia cells to the point where they develop a mutation to remain alive is testament to the drug's effectiveness, he continues. "This is the first time a drug targeting a chromatin-binding protein complex has been shown to put that degree of pressure on cancer in a human patient." By tracking the development of mutations in MEN1 and other genes in patients with acute leukemia, doctors may be able to identify patients at high risk of relapsing, Armstrong relates. Such patients might then benefit from further treatment. The discovery of MEN1 mutation as a resistance mechanism suggests that new drugs that specifically target menin or other chromatin-associated proteins could prevent or delay revumenib resistance or treat patients who have become resistant to the drug. "Seeing Dr. Armstrong's work translated elegantly into the clinic where patients—including some at Dana-Farber, who had dramatic responses in dire situations—was highly gratifying personally and professionally," says Dana-Farber's Richard Stone, MD, a co-author of both Nature studies. "We are now ready to magnify the impact of these results by conducting clinical trials combining revumenib with standard chemotherapy as well as with novel agents, also based on preclinical work done in great part by Dr. Armstrong." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The 7-nitroindolinyl family of caging chromophores has received much attention in the past two decades. However, its uncaging mechanism is still not clearly understood. In this study, we performed state-of-the-art density functional theory calculations to unravel the photo-uncaging mechanism in its entirety, and we compared the probabilities of all plausible pathways. We found competition between a classical cyclization and an acyl migration pathway, and here we explain the electronic and steric reasons behind such competition. The migration mechanism possesses the characteristics of a combined Norrish type I and a 1,6-nitro-acyl variation of a Norrish type II mechanism, which is reported here for the first time. We also found negligible energetic differences in the uncaging mechanisms of the 4-methoxy-5,7-dinitroindolinyl (MDNI) cages and their mononitro analogues (MNI). We traced the experimentally observed improved quantum yields of MDNI to a higher population of the reactants in the triplet surface. This fact is supported by a more favorable intersystem crossing due to the availability of a higher number of triplet excited states with the correct symmetry in MDNI than in MNI. Our findings may pave the way for improved cage designs that possess higher quantum yields and a more efficient agonist release. Introduction The ability to deliver or activate a compound to a specific site with precise timing is of extreme value. This is widely referred to as spatio-temporal control 1 , 2 , 3 , 4 . Techniques that possess spatio-temporal advantages have found numerous applications ranging from medicinal chemistry fields with photo targeted therapeutics 1 , 3 , such as cancer treatments 5 , 6 , 7 , 8 or photoinitiated catalysis 8 , and to the neuroscience where it becomes critical to activate selected neurons to study specific pathways 1 , 9 , 10 , 11 , 12 . In the emerging field of optogenetics, light-sensitive channel rhodopsin receptors are genetically engineered in selected neurons rendering them light responsive 3 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Additional methods of firing specific neurons employed a diverse array of photocleavable protecting groups attached to critically active moieties of agonists 20 , 21 , 22 , 23 . These photocleavable protecting groups acquired the term photocages, or simply cages, as their attachment to an agonist necessarily incapacitates it, much like caging a ferocious animal. Caged molecules are inert, and they need an external agent—such as a physical, chemical, or mechanical force 8 , 24 , 25 , 26 , 27 —to induce the release of the biologically active compound they are protecting. Light represents the most advantageous activator because it offers the ability to control the precise time and the location of the release 1 , 2 , 3 , 4 . Although there are numerous classes of photocleavable groups, they share a common feature of absorbing light of specific wavelengths that leads to excitation from the singlet ground state (S 0 ) to an excited singlet state (S 1,2,3… ). Subsequently, the molecules relax to the lowest excited singlet (S 1 ) via internal conversion 28 , and some systems undergo intersystem crossing (ISC) to the triplet state manifold, and consequential fast relaxation to the lowest triplet state (T 1 ) 21 , 29 . This leads to cleavage of the protecting group at the most labile bond, which is critically positioned for such release (displayed by the red bond of 4-methoxy-5,7-dinitroindolinyl glutamate ( 1 , MDNI-Glu), shown in Fig. 1 below). These mechanisms depend on the class of protecting groups employed, but some are not clearly understood, as mechanisms in excited states may not resemble the familiar mechanistic pathways commonly accepted for ground states 21 . Figure 1 Different proposed mechanisms for the uncaging of MDNI-Glu (R=CH 2 CH 2 CH(NH 2 )COOH): Migration Pathway (MP)—computational mechanism reported by Pálfi et al. 39 ; Cyclization Pathway (CP)—mechanism presumed by Ellis-Davies et al. 34 , based on Morrison’s experimental data 40 . Full size image 7-Nitroindolinyl cages have gained popularity at the turn of the century due to their optimal quantum yields and efficient release of agonists 30 , 31 , 32 . Improvements in such cage systems led to the installation of a second nitro group at the 5 position that resulted in improved quantum yields and efficiency of the release 33 , 34 . Although the second nitro at the C-5 is not directly participating in the mechanism, as we will show later, its presence results in an improved quantum yield by at least fivefold according to experimental data 35 , 36 , 37 . The mechanism of uncaging for the 7-indolinyl system was studied by at least three groups using kinetic, fast pulse IR, and computation 33 , 38 , 39 . However, the most recently reported computational mechanisms of uncaging do not explain the difference in quantum yield, which is an important parameter, especially for consideration in future improved designs. We herein report a thorough computational analysis highlighting the electronic effects behind the better quantum yields of dinitroindolinyl systems and clarifying the mechanism with respect to the traditionally accepted formation of a cyclic intermediate. The first mechanism for the light-initiated uncaging of MDNI-Glu ( 1 in Fig. 1 ) has been proposed by Ellis-Davies and coworkers in 2005 34 , and is based on kinetic data collected by Morrison et al. 40 for another member of the 7-nitroindoline family. We will refer to this mechanism as the cyclization pathway (CP) from here on for simplicity. According to their proposed mechanism, after irradiation, the reaction proceeds on the triplet surface via a cyclic intermediate ( 5 ). Subsequently, the system is deprotonated ( 3 ), and finally, it delivers the free glutamate ( 7 ) to the reaction medium. According to the CP mechanism, the increased reactivity of MDNI is due to the influence of the nitro group in position 5 on the overall electronic structure of the indoline scaffold 34 . A subsequent computational study by Pálfi", "role": "user" }, { "content": "Human brains have an average of 86 billion neurons. These nerve cells are interconnected at junctions known as synapses, and some neurons have as many as 10,000 such synapses. A key to understanding brain function is to have a better grasp of how this non-logical arrangement of complex neurons leads to specific behaviors and cognitive function, including memory storage. Recent advances that combined chemical applications with neurobiological techniques enabled the use of light as a trigger to turn on specific neurons by activating selected synapses. Chemical groups that effectively leashed active molecules like glutamate (a key molecule in learning and memory) helped control nerve signals by keeping them in an off state. On-demand, targeted light can unleash the active molecules that lead to turning on neurons, and thus pathways of interest. The key to the success of this procedure is intricately dependent on the efficacy of light at breaking molecular bonds. Previously, there was little known on the precise mechanism by which light can induce the unleashing of certain class of molecules referred to as NitroIndolinyl (NI), which represent some of the most efficient light-responsive molecules. The research groups of Nasri Nesnas and Roberto Peverati at Florida Tech have now been able to conduct accurate computational studies that revealed important details of how bonds break to release active molecules. This is extremely valuable to enable future designs of other molecules that can modulate brain signals. This broader understanding of light's ability to induce this type of chemical bond cleavage will lead to building systems that are far more sensitive to light, requiring smaller amounts of such agents and thereby minimizing any interference with other, neighboring neurons. The collaborative study was recently published in Scientific Reports. Different proposed mechanisms for the uncaging of MDNI-Glu (R=CH2CH2CH(NH2)COOH): Migration Pathway (MP)—computational mechanism reported by Pálfi et al.39; Cyclization Pathway (CP)—mechanism presumed by Ellis-Davies et al.34, based on Morrison’s experimental data40. Credit: Scientific Reports (2021). DOI: 10.1038/s41598-020-79701-4 Florida Tech's Pierpaolo Morgante, first author of the paper, was excited to learn that there are two pathways by which such process can occur. \"I was surprised when I saw that there was some confusion in previous literature about this pathway, and I became interested in really understanding these mechanisms. I found out something really unusual.\" Peverati, who is one of the developers of the reliable computational methodology that is at the heart of these new results, added: \"Our method and its associated software have the ability to reliably predict the energies of the molecules that are involved in this pathway by simulating the behavior of every single electron contained in them. Our program has allowed us to clarify a mechanism that was the source of much debate in the specialized literature. The predictions obtained from our software match the results of Dr. Nesnas's experiments, which further validate the reliability of our approach. These results give us confidence that we can use this computer software to predict new molecules that are more responsive to light that can be used to study neurons.\" Nesnas, whose group prepares these compounds, was pleased with the outcome of the study. \"Light emerged in recent years as a powerful tool in neuroscience,\" he said. \"We noted that there was an unusual path that combined two well-known photochemical processes that have never been observed to occur simultaneously before, until this study. This is an exciting finding in the world of photochemistry.\" Being able to understand the complex brain network helps clarify possible reasons behind elusive brain disorders such as Alzheimer's disease, epilepsy, depression and other brain conditions. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The 7-nitroindolinyl family of caging chromophores has received much attention in the past two decades. However, its uncaging mechanism is still not clearly understood. In this study, we performed state-of-the-art density functional theory calculations to unravel the photo-uncaging mechanism in its entirety, and we compared the probabilities of all plausible pathways. We found competition between a classical cyclization and an acyl migration pathway, and here we explain the electronic and steric reasons behind such competition. The migration mechanism possesses the characteristics of a combined Norrish type I and a 1,6-nitro-acyl variation of a Norrish type II mechanism, which is reported here for the first time. We also found negligible energetic differences in the uncaging mechanisms of the 4-methoxy-5,7-dinitroindolinyl (MDNI) cages and their mononitro analogues (MNI). We traced the experimentally observed improved quantum yields of MDNI to a higher population of the reactants in the triplet surface. This fact is supported by a more favorable intersystem crossing due to the availability of a higher number of triplet excited states with the correct symmetry in MDNI than in MNI. Our findings may pave the way for improved cage designs that possess higher quantum yields and a more efficient agonist release. Introduction The ability to deliver or activate a compound to a specific site with precise timing is of extreme value. This is widely referred to as spatio-temporal control 1 , 2 , 3 , 4 . Techniques that possess spatio-temporal advantages have found numerous applications ranging from medicinal chemistry fields with photo targeted therapeutics 1 , 3 , such as cancer treatments 5 , 6 , 7 , 8 or photoinitiated catalysis 8 , and to the neuroscience where it becomes critical to activate selected neurons to study specific pathways 1 , 9 , 10 , 11 , 12 . In the emerging field of optogenetics, light-sensitive channel rhodopsin receptors are genetically engineered in selected neurons rendering them light responsive 3 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Additional methods of firing specific neurons employed a diverse array of photocleavable protecting groups attached to critically active moieties of agonists 20 , 21 , 22 , 23 . These photocleavable protecting groups acquired the term photocages, or simply cages, as their attachment to an agonist necessarily incapacitates it, much like caging a ferocious animal. Caged molecules are inert, and they need an external agent—such as a physical, chemical, or mechanical force 8 , 24 , 25 , 26 , 27 —to induce the release of the biologically active compound they are protecting. Light represents the most advantageous activator because it offers the ability to control the precise time and the location of the release 1 , 2 , 3 , 4 . Although there are numerous classes of photocleavable groups, they share a common feature of absorbing light of specific wavelengths that leads to excitation from the singlet ground state (S 0 ) to an excited singlet state (S 1,2,3… ). Subsequently, the molecules relax to the lowest excited singlet (S 1 ) via internal conversion 28 , and some systems undergo intersystem crossing (ISC) to the triplet state manifold, and consequential fast relaxation to the lowest triplet state (T 1 ) 21 , 29 . This leads to cleavage of the protecting group at the most labile bond, which is critically positioned for such release (displayed by the red bond of 4-methoxy-5,7-dinitroindolinyl glutamate ( 1 , MDNI-Glu), shown in Fig. 1 below). These mechanisms depend on the class of protecting groups employed, but some are not clearly understood, as mechanisms in excited states may not resemble the familiar mechanistic pathways commonly accepted for ground states 21 . Figure 1 Different proposed mechanisms for the uncaging of MDNI-Glu (R=CH 2 CH 2 CH(NH 2 )COOH): Migration Pathway (MP)—computational mechanism reported by Pálfi et al. 39 ; Cyclization Pathway (CP)—mechanism presumed by Ellis-Davies et al. 34 , based on Morrison’s experimental data 40 . Full size image 7-Nitroindolinyl cages have gained popularity at the turn of the century due to their optimal quantum yields and efficient release of agonists 30 , 31 , 32 . Improvements in such cage systems led to the installation of a second nitro group at the 5 position that resulted in improved quantum yields and efficiency of the release 33 , 34 . Although the second nitro at the C-5 is not directly participating in the mechanism, as we will show later, its presence results in an improved quantum yield by at least fivefold according to experimental data 35 , 36 , 37 . The mechanism of uncaging for the 7-indolinyl system was studied by at least three groups using kinetic, fast pulse IR, and computation 33 , 38 , 39 . However, the most recently reported computational mechanisms of uncaging do not explain the difference in quantum yield, which is an important parameter, especially for consideration in future improved designs. We herein report a thorough computational analysis highlighting the electronic effects behind the better quantum yields of dinitroindolinyl systems and clarifying the mechanism with respect to the traditionally accepted formation of a cyclic intermediate. The first mechanism for the light-initiated uncaging of MDNI-Glu ( 1 in Fig. 1 ) has been proposed by Ellis-Davies and coworkers in 2005 34 , and is based on kinetic data collected by Morrison et al. 40 for another member of the 7-nitroindoline family. We will refer to this mechanism as the cyclization pathway (CP) from here on for simplicity. According to their proposed mechanism, after irradiation, the reaction proceeds on the triplet surface via a cyclic intermediate ( 5 ). Subsequently, the system is deprotonated ( 3 ), and finally, it delivers the free glutamate ( 7 ) to the reaction medium. According to the CP mechanism, the increased reactivity of MDNI is due to the influence of the nitro group in position 5 on the overall electronic structure of the indoline scaffold 34 . A subsequent computational study by Pálfi<|im_end|> <|im_start|>assistant Human brains have an average of 86 billion neurons. These nerve cells are interconnected at junctions known as synapses, and some neurons have as many as 10,000 such synapses. A key to understanding brain function is to have a better grasp of how this non-logical arrangement of complex neurons leads to specific behaviors and cognitive function, including memory storage. Recent advances that combined chemical applications with neurobiological techniques enabled the use of light as a trigger to turn on specific neurons by activating selected synapses. Chemical groups that effectively leashed active molecules like glutamate (a key molecule in learning and memory) helped control nerve signals by keeping them in an off state. On-demand, targeted light can unleash the active molecules that lead to turning on neurons, and thus pathways of interest. The key to the success of this procedure is intricately dependent on the efficacy of light at breaking molecular bonds. Previously, there was little known on the precise mechanism by which light can induce the unleashing of certain class of molecules referred to as NitroIndolinyl (NI), which represent some of the most efficient light-responsive molecules. The research groups of Nasri Nesnas and Roberto Peverati at Florida Tech have now been able to conduct accurate computational studies that revealed important details of how bonds break to release active molecules. This is extremely valuable to enable future designs of other molecules that can modulate brain signals. This broader understanding of light's ability to induce this type of chemical bond cleavage will lead to building systems that are far more sensitive to light, requiring smaller amounts of such agents and thereby minimizing any interference with other, neighboring neurons. The collaborative study was recently published in Scientific Reports. Different proposed mechanisms for the uncaging of MDNI-Glu (R=CH2CH2CH(NH2)COOH): Migration Pathway (MP)—computational mechanism reported by Pálfi et al.39; Cyclization Pathway (CP)—mechanism presumed by Ellis-Davies et al.34, based on Morrison’s experimental data40. Credit: Scientific Reports (2021). DOI: 10.1038/s41598-020-79701-4 Florida Tech's Pierpaolo Morgante, first author of the paper, was excited to learn that there are two pathways by which such process can occur. "I was surprised when I saw that there was some confusion in previous literature about this pathway, and I became interested in really understanding these mechanisms. I found out something really unusual." Peverati, who is one of the developers of the reliable computational methodology that is at the heart of these new results, added: "Our method and its associated software have the ability to reliably predict the energies of the molecules that are involved in this pathway by simulating the behavior of every single electron contained in them. Our program has allowed us to clarify a mechanism that was the source of much debate in the specialized literature. The predictions obtained from our software match the results of Dr. Nesnas's experiments, which further validate the reliability of our approach. These results give us confidence that we can use this computer software to predict new molecules that are more responsive to light that can be used to study neurons." Nesnas, whose group prepares these compounds, was pleased with the outcome of the study. "Light emerged in recent years as a powerful tool in neuroscience," he said. "We noted that there was an unusual path that combined two well-known photochemical processes that have never been observed to occur simultaneously before, until this study. This is an exciting finding in the world of photochemistry." Being able to understand the complex brain network helps clarify possible reasons behind elusive brain disorders such as Alzheimer's disease, epilepsy, depression and other brain conditions. <|im_end|>

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439, 584, 690, 1501, 3010, 11, 1202, 9546, 3135, 304, 459, 13241, 31228, 7692, 555, 520, 3325, 4330, 20557, 4184, 311, 22772, 828, 220, 1758, 1174, 220, 1927, 1174, 220, 1806, 662, 578, 17383, 315, 21482, 4210, 369, 279, 220, 22, 18251, 37737, 4010, 1887, 574, 20041, 555, 520, 3325, 2380, 5315, 1701, 71423, 11, 5043, 28334, 16646, 11, 323, 35547, 220, 1644, 1174, 220, 1987, 1174, 220, 2137, 662, 4452, 11, 279, 1455, 6051, 5068, 55580, 24717, 315, 21482, 4210, 656, 539, 10552, 279, 6811, 304, 31228, 7692, 11, 902, 374, 459, 3062, 5852, 11, 5423, 369, 18361, 304, 3938, 13241, 14769, 13, 1226, 36881, 1934, 264, 17879, 55580, 6492, 39686, 279, 14683, 6372, 4920, 279, 2731, 31228, 36508, 315, 294, 2381, 299, 485, 37737, 4010, 6067, 323, 20064, 7922, 279, 17383, 449, 5201, 311, 279, 36342, 11928, 18488, 315, 264, 77102, 29539, 13, 578, 1176, 17383, 369, 279, 3177, 55873, 10234, 21482, 4210, 315, 14306, 15259, 12279, 10036, 320, 220, 16, 304, 23966, 13, 220, 16, 883, 706, 1027, 11223, 555, 44707, 9607, 402, 552, 323, 84055, 304, 220, 1049, 20, 220, 1958, 1174, 323, 374, 3196, 389, 71423, 828, 14890, 555, 50054, 1880, 453, 13, 220, 1272, 369, 2500, 4562, 315, 279, 220, 22, 5392, 275, 299, 485, 22671, 3070, 13, 1226, 690, 8464, 311, 420, 17383, 439, 279, 32343, 2065, 38970, 320, 7269, 8, 505, 1618, 389, 369, 40075, 13, 10771, 311, 872, 11223, 17383, 11, 1306, 76327, 367, 11, 279, 13010, 34555, 389, 279, 99809, 7479, 4669, 264, 77102, 29539, 320, 220, 20, 7609, 3804, 39742, 11, 279, 1887, 374, 409, 782, 783, 660, 320, 220, 18, 7026, 323, 5616, 11, 433, 28421, 279, 1949, 35169, 92166, 320, 220, 22, 883, 311, 279, 13010, 11298, 13, 10771, 311, 279, 15643, 17383, 11, 279, 7319, 312, 7323, 315, 14306, 15259, 374, 4245, 311, 279, 10383, 315, 279, 25719, 299, 1912, 304, 2361, 220, 20, 389, 279, 8244, 14683, 6070, 315, 279, 1280, 22671, 85552, 220, 1958, 662, 362, 17876, 55580, 4007, 555, 393, 19540, 10188, 128257, 198, 128256, 78191, 198, 35075, 35202, 617, 459, 5578, 315, 220, 4218, 7239, 34313, 13, 4314, 32015, 7917, 527, 83416, 520, 49341, 82, 3967, 439, 6925, 79390, 11, 323, 1063, 34313, 617, 439, 1690, 439, 220, 605, 11, 931, 1778, 6925, 79390, 13, 362, 1401, 311, 8830, 8271, 734, 374, 311, 617, 264, 2731, 34477, 315, 1268, 420, 2536, 12, 31356, 27204, 315, 6485, 34313, 11767, 311, 3230, 28198, 323, 25702, 734, 11, 2737, 5044, 5942, 13, 35390, 31003, 430, 11093, 11742, 8522, 449, 18247, 8385, 5848, 12823, 9147, 279, 1005, 315, 3177, 439, 264, 8346, 311, 2543, 389, 3230, 34313, 555, 72192, 4183, 6925, 79390, 13, 36424, 5315, 430, 13750, 514, 13883, 4642, 35715, 1093, 35169, 92166, 320, 64, 1401, 43030, 304, 6975, 323, 5044, 8, 9087, 2585, 32015, 17738, 555, 10494, 1124, 304, 459, 1022, 1614, 13, 1952, 57364, 11, 17550, 3177, 649, 78535, 279, 4642, 35715, 430, 3063, 311, 13353, 389, 34313, 11, 323, 8617, 44014, 315, 2802, 13, 578, 1401, 311, 279, 2450, 315, 420, 10537, 374, 94603, 2718, 18222, 389, 279, 41265, 315, 3177, 520, 15061, 31206, 27460, 13, 59787, 11, 1070, 574, 2697, 3967, 389, 279, 24473, 17383, 555, 902, 3177, 649, 49853, 279, 38826, 19587, 315, 3738, 538, 315, 35715, 14183, 311, 439, 50616, 299, 1451, 37737, 4010, 320, 15259, 705, 902, 4097, 1063, 315, 279, 1455, 11297, 3177, 21638, 35715, 13, 578, 3495, 5315, 315, 39322, 462, 92508, 46523, 323, 55183, 393, 2099, 9491, 520, 9784, 17829, 617, 1457, 1027, 3025, 311, 6929, 13687, 55580, 7978, 430, 10675, 3062, 3649, 315, 1268, 27460, 1464, 311, 4984, 4642, 35715, 13, 1115, 374, 9193, 15525, 311, 7431, 3938, 14769, 315, 1023, 35715, 430, 649, 1491, 6468, 8271, 17738, 13, 1115, 27927, 8830, 315, 3177, 596, 5845, 311, 49853, 420, 955, 315, 11742, 11049, 11551, 68256, 690, 3063, 311, 4857, 6067, 430, 527, 3117, 810, 16614, 311, 3177, 11, 23537, 9333, 15055, 315, 1778, 13307, 323, 28592, 77391, 904, 32317, 449, 1023, 11, 42617, 34313, 13, 578, 40806, 4007, 574, 6051, 4756, 304, 38130, 29140, 13, 34496, 11223, 24717, 369, 279, 21482, 4210, 315, 14306, 15259, 12279, 10036, 320, 49, 28, 2198, 17, 2198, 17, 2198, 8368, 39, 17, 8, 8445, 47861, 1680, 21943, 8092, 3195, 320, 5901, 68850, 66047, 1697, 17383, 5068, 555, 393, 19540, 10188, 1880, 453, 13, 2137, 26, 72545, 2065, 8092, 3195, 320, 7269, 68850, 2727, 5776, 2191, 62357, 555, 44707, 9607, 402, 552, 1880, 453, 13, 1958, 11, 3196, 389, 50054, 753, 22772, 828, 1272, 13, 16666, 25, 38130, 29140, 320, 2366, 16, 570, 59670, 25, 220, 605, 13, 6889, 23, 2754, 18136, 3264, 12, 11139, 12, 25314, 1721, 12, 19, 9784, 17829, 596, 21377, 6733, 10216, 79160, 5048, 11, 1176, 3229, 315, 279, 5684, 11, 574, 12304, 311, 4048, 430, 1070, 527, 1403, 44014, 555, 902, 1778, 1920, 649, 12446, 13, 330, 40, 574, 14792, 994, 358, 5602, 430, 1070, 574, 1063, 22047, 304, 3766, 17649, 922, 420, 38970, 11, 323, 358, 6244, 8173, 304, 2216, 8830, 1521, 24717, 13, 358, 1766, 704, 2555, 2216, 19018, 1210, 393, 2099, 9491, 11, 889, 374, 832, 315, 279, 13707, 315, 279, 15062, 55580, 38152, 430, 374, 520, 279, 4851, 315, 1521, 502, 3135, 11, 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25291, 1603, 11, 3156, 420, 4007, 13, 1115, 374, 459, 13548, 9455, 304, 279, 1917, 315, 6685, 52755, 1210, 21347, 3025, 311, 3619, 279, 6485, 8271, 4009, 8779, 38263, 3284, 8125, 4920, 66684, 8271, 24673, 1778, 439, 44531, 596, 8624, 11, 70655, 11, 18710, 323, 1023, 8271, 4787, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genetics (i.e., mutations) has been assumed to be the major factor in rheumatoid arthritis (RA) etiology, but accounts for a minority of the variance in disease risk for RA. In contrast to genetics, the environment can have dramatic impacts on epigenetics that associate with disease etiology. The current study used buccal cells and purified blood monocytes from two different clinical cohorts involving Caucasian or African American female populations with or without arthritis. The differential DNA methylation regions (DMRs) between the control and RA populations were identified with an epigenome-wide association study. The DMRs (i.e., epimutations) identified in the buccal cells and monocytes were found to be distinct. The DMR associated genes were identified and many have previously been shown to be associated with arthritis. Observations demonstrate DNA methylation epimutation RA biomarkers are cell type specific and similar findings were observed with the two racial background populations. Rheumatoid arthritis susceptibility epigenetic diagnosis appears feasible and may improve the clinical management of RA and allowpreventative medicine considerations. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease predominant in females with a worldwide prevalence of 0.5–1.0% 1 . The frequency of RA has increased in the past few decades, and is proportionally higher in North American populations 1 , 2 . RA is characterized by synovial hyperplasia and joint destruction 3 . RA impacts both African American and Caucasian populations, but does have higher comorbidity 4 prevalence in African American populations. Coronary heart disease is more common in rheumatoid arthritis populations 4 , as in other chronic inflammatory diseases. Inflammatory lung disease is a common extra-articular manifestation 5 , along with rheumatoid nodules, secondary Sjogrens from endocrine gland inflammation, and more rarely rheumatoid vasculitis in this multisystem autoimmune disease. Correlations between RA and neurodegeneration have also been observed 6 . Environment and lifestyle have been shown to influence the risk of RA 7 . Smoking and nutrition are two of the major factors linked to RA risk 8 , 9 . Nutrition and dieting habits also have a role in RA risk and progression 10 . Environmental toxicant exposures have been shown to be involved in the etiology of rheumatoid arthritis 11 , 12 . In addition to environmental toxicants, alcohol consumption is a risk factor for the incidence of RA 13 . Similar observations have been shown in various worldwide populations and ethnic backgrounds 14 , 15 , 16 . Therefore, environmental factors and lifestyle have a significant impact on the etiology and progression of rheumatoid arthritis. Genetics has been assumed to be a major factor in rheumatoid arthritis etiology. Initially, gene associations were identified that involved a number of cellular pathways and immune related processes, such as the major histocompatibility complex (MHC), in particular the HLA-DRB1 and closely related genes 17 . These types of genetic mutation gene associations have been estimated to explain a minority of the variance in disease risk for RA 18 , 19 . A number of genome-wide association studies (GWAS) have been performed and identified hundreds of single-nucleotide polymorphisms (SNPs) that are associated with RA and speculated to impact a large number of biological processes 20 . Potential secondary gene associations suggest genetics can potentially explain 30% of familial disease cases 18 . Although these GWAS and similar gene impact studies have helped to better understand the molecular basis of RA, an alternate molecular process involving epigenetics is now assumed to be equally important and a significant factor in the etiology of RA 21 . Since environmental factors generally cannot directly change DNA sequence to alter genetic processes, the environmental impacts on RA etiology observed involve epigenetics. Epigenetics provides the molecular process for environmental factors such as nutrition and toxicants to impact genetics 22 . Therefore, an integration of environment, epigenetics and genetics is now thought to be involved in the etiology and progression of rheumatoid arthritis 21 , 23 , 24 . Epigenetics is defined as “molecular factors and processes around DNA that regulate genome activity independent of DNA sequence, and are mitotically stable” 22 . Epigenetic factors include DNA methylation, histone modifications, non-coding RNA (ncRNA), chromatin structure and RNA methylation 22 . Although all these processes will be involved in RA, DNA methylation at 5-methylcytosine has been the primary epigenetic process investigated in rheumatoid arthritis 21 , 25 , 26 . Epigenome-wide association studies (EWAS) have been used to identify specific immune gene associations 21 , 27 , as have genome-wide investigations 21 . Some studies have investigated blood 28 , which contains over 20 different cell types. In contrast to genetics, where the DNA sequence is the same between different cell types, each individual cell type has a unique epigenome to give the cell type its specificity. Therefore, mixed cell type (e.g., blood or mixed T cell lymphocytes) analysis can be misleading and reflect changes in cell populations instead of epigenetic change. A number of RA studies have investigated purified cell populations to provide insights into rheumatoid arthritis etiology including B lymphocytes 29 , monocytes 30 , and synoviocytes 31 , 32 , 33 , 34 , which have distinct roles in RA etiology. Therefore, epigenetic analysis has provided insight into the pathology of rheumatoid arthritis 21 , 35 . The potential role of inheritance of RA has been demonstrated through familial clusters and parental transmission of arthritis susceptibility 36 , 37 , 38 . A non-genetic form of inheritance has been previously described that involves epigenetic alterations in the germline (sperm and egg) and the inheritance to subsequent generations, termed epigenetic transgenerational inheritance 22 , 39 . When the germ cell transmits the altered epigenetics to the developing embryo stem cells, all subsequent somatic cells developed will have altered epigenomes and transcriptomes. Those cell types sensitive to the shift in epigenetics will have a susceptibility to develop disease later in life 22 . Therefore, various somatic cell populations could be used as surrogate biomarker cell types to identify disease susceptibility and disease conditions. The role of epigenetic biomarkers in autoimmune", "role": "user" }, { "content": "Cells from a cheek swab revealed biomarkers for rheumatoid arthritis that could lead to a way to diagnose and begin treatment before the disease develops, according to a study published in Scientific Reports. In the study, researchers from Washington State University and Arthritis Northwest in Spokane, Washington identified a set of epimutations in cells from women who had rheumatoid arthritis that were distinct from those without the joint-damaging autoimmune disease. Epimutations are molecular factors and processes around DNA that regulate genome activity, independent of DNA sequence. The discovery could advance treatment for rheumatoid arthritis, said Michael Skinner, the senior author on the paper. \"If we can identify these patients ten years earlier before the disease develops, it opens up a whole arena of preventative medicine that we did not have access to before,\" said Skinner, a professor in WSU's School of Biological Sciences. Rheumatoid arthritis affects about 200,000 people in the U.S. each year with a higher prevalence in women than in men. While current drug treatments have limited efficacy in many patients who have already developed the disease, some studies have shown that treatments begun in early stages of the disease can cause remission of symptoms. Having biomarkers could allow treatment to begin even earlier before the first signs of it start, Skinner said. For the study, researchers collected buccal, or cheek, cells using a swab from two cohorts of women: a group of 26 Caucasian women from Spokane and a group of 23 African-American women from Los Angeles. In each group, about half of the women had rheumatoid arthritis with the other half serving as a control. Even though they are taken from the cheek, buccal cells allowed the researchers to conduct an epigenome-wide analysis. Translating literally as \"above\" the genome, an epigenome consists of chemical factors that can modify the genome and change its behavior. While not part of DNA itself, epimutations can still be passed down to subsequent generations. In this study, the researchers found epimutations in areas called DNA methylation regions, among the women in both groups who had rheumatoid arthritis. The study was designed to see if there were differences between racial groups since African Americans have shown some signs of increased prevalence of rheumatoid arthritis. However, while some differences were noted, the researchers found a large overlap in epimutations among women with rheumatoid arthritis of both races, meaning the identified biomarkers hold a strong signal for the disease. \"Surprisingly, most of the DNA methylation sites we found that were consistent among patients with the disease were associated with genes previously known to be involved in rheumatoid arthritis,\" said Skinner. The findings add evidence that the disease is likely systemic, Skinner said, meaning it was found not just in immune system cells involved in rheumatoid arthritis development but in many different cells throughout the body. The research team also tested an immune-related monocyte cell type in blood samples from a portion of the women, but the buccal cells showed the epimutations as well, indicating that a relatively non-invasive diagnostic cheek swab test could be developed to screen for the disease. This study was supported by Epigenesys Inc. and the John Templeton Foundation. In addition to Skinner, the research team included Gary Craig and Howard Kenney of Arthritis Northwest who are also clinical faculty at the WSU Elson S. Floyd College of Medicine in Spokane as well as Eric Nilsson, Ingrid Sadler-Riggleman and Daniel Beck from WSU's School of Biological Sciences. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Genetics (i.e., mutations) has been assumed to be the major factor in rheumatoid arthritis (RA) etiology, but accounts for a minority of the variance in disease risk for RA. In contrast to genetics, the environment can have dramatic impacts on epigenetics that associate with disease etiology. The current study used buccal cells and purified blood monocytes from two different clinical cohorts involving Caucasian or African American female populations with or without arthritis. The differential DNA methylation regions (DMRs) between the control and RA populations were identified with an epigenome-wide association study. The DMRs (i.e., epimutations) identified in the buccal cells and monocytes were found to be distinct. The DMR associated genes were identified and many have previously been shown to be associated with arthritis. Observations demonstrate DNA methylation epimutation RA biomarkers are cell type specific and similar findings were observed with the two racial background populations. Rheumatoid arthritis susceptibility epigenetic diagnosis appears feasible and may improve the clinical management of RA and allowpreventative medicine considerations. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease predominant in females with a worldwide prevalence of 0.5–1.0% 1 . The frequency of RA has increased in the past few decades, and is proportionally higher in North American populations 1 , 2 . RA is characterized by synovial hyperplasia and joint destruction 3 . RA impacts both African American and Caucasian populations, but does have higher comorbidity 4 prevalence in African American populations. Coronary heart disease is more common in rheumatoid arthritis populations 4 , as in other chronic inflammatory diseases. Inflammatory lung disease is a common extra-articular manifestation 5 , along with rheumatoid nodules, secondary Sjogrens from endocrine gland inflammation, and more rarely rheumatoid vasculitis in this multisystem autoimmune disease. Correlations between RA and neurodegeneration have also been observed 6 . Environment and lifestyle have been shown to influence the risk of RA 7 . Smoking and nutrition are two of the major factors linked to RA risk 8 , 9 . Nutrition and dieting habits also have a role in RA risk and progression 10 . Environmental toxicant exposures have been shown to be involved in the etiology of rheumatoid arthritis 11 , 12 . In addition to environmental toxicants, alcohol consumption is a risk factor for the incidence of RA 13 . Similar observations have been shown in various worldwide populations and ethnic backgrounds 14 , 15 , 16 . Therefore, environmental factors and lifestyle have a significant impact on the etiology and progression of rheumatoid arthritis. Genetics has been assumed to be a major factor in rheumatoid arthritis etiology. Initially, gene associations were identified that involved a number of cellular pathways and immune related processes, such as the major histocompatibility complex (MHC), in particular the HLA-DRB1 and closely related genes 17 . These types of genetic mutation gene associations have been estimated to explain a minority of the variance in disease risk for RA 18 , 19 . A number of genome-wide association studies (GWAS) have been performed and identified hundreds of single-nucleotide polymorphisms (SNPs) that are associated with RA and speculated to impact a large number of biological processes 20 . Potential secondary gene associations suggest genetics can potentially explain 30% of familial disease cases 18 . Although these GWAS and similar gene impact studies have helped to better understand the molecular basis of RA, an alternate molecular process involving epigenetics is now assumed to be equally important and a significant factor in the etiology of RA 21 . Since environmental factors generally cannot directly change DNA sequence to alter genetic processes, the environmental impacts on RA etiology observed involve epigenetics. Epigenetics provides the molecular process for environmental factors such as nutrition and toxicants to impact genetics 22 . Therefore, an integration of environment, epigenetics and genetics is now thought to be involved in the etiology and progression of rheumatoid arthritis 21 , 23 , 24 . Epigenetics is defined as “molecular factors and processes around DNA that regulate genome activity independent of DNA sequence, and are mitotically stable” 22 . Epigenetic factors include DNA methylation, histone modifications, non-coding RNA (ncRNA), chromatin structure and RNA methylation 22 . Although all these processes will be involved in RA, DNA methylation at 5-methylcytosine has been the primary epigenetic process investigated in rheumatoid arthritis 21 , 25 , 26 . Epigenome-wide association studies (EWAS) have been used to identify specific immune gene associations 21 , 27 , as have genome-wide investigations 21 . Some studies have investigated blood 28 , which contains over 20 different cell types. In contrast to genetics, where the DNA sequence is the same between different cell types, each individual cell type has a unique epigenome to give the cell type its specificity. Therefore, mixed cell type (e.g., blood or mixed T cell lymphocytes) analysis can be misleading and reflect changes in cell populations instead of epigenetic change. A number of RA studies have investigated purified cell populations to provide insights into rheumatoid arthritis etiology including B lymphocytes 29 , monocytes 30 , and synoviocytes 31 , 32 , 33 , 34 , which have distinct roles in RA etiology. Therefore, epigenetic analysis has provided insight into the pathology of rheumatoid arthritis 21 , 35 . The potential role of inheritance of RA has been demonstrated through familial clusters and parental transmission of arthritis susceptibility 36 , 37 , 38 . A non-genetic form of inheritance has been previously described that involves epigenetic alterations in the germline (sperm and egg) and the inheritance to subsequent generations, termed epigenetic transgenerational inheritance 22 , 39 . When the germ cell transmits the altered epigenetics to the developing embryo stem cells, all subsequent somatic cells developed will have altered epigenomes and transcriptomes. Those cell types sensitive to the shift in epigenetics will have a susceptibility to develop disease later in life 22 . Therefore, various somatic cell populations could be used as surrogate biomarker cell types to identify disease susceptibility and disease conditions. The role of epigenetic biomarkers in autoimmune<|im_end|> <|im_start|>assistant Cells from a cheek swab revealed biomarkers for rheumatoid arthritis that could lead to a way to diagnose and begin treatment before the disease develops, according to a study published in Scientific Reports. In the study, researchers from Washington State University and Arthritis Northwest in Spokane, Washington identified a set of epimutations in cells from women who had rheumatoid arthritis that were distinct from those without the joint-damaging autoimmune disease. Epimutations are molecular factors and processes around DNA that regulate genome activity, independent of DNA sequence. The discovery could advance treatment for rheumatoid arthritis, said Michael Skinner, the senior author on the paper. "If we can identify these patients ten years earlier before the disease develops, it opens up a whole arena of preventative medicine that we did not have access to before," said Skinner, a professor in WSU's School of Biological Sciences. Rheumatoid arthritis affects about 200,000 people in the U.S. each year with a higher prevalence in women than in men. While current drug treatments have limited efficacy in many patients who have already developed the disease, some studies have shown that treatments begun in early stages of the disease can cause remission of symptoms. Having biomarkers could allow treatment to begin even earlier before the first signs of it start, Skinner said. For the study, researchers collected buccal, or cheek, cells using a swab from two cohorts of women: a group of 26 Caucasian women from Spokane and a group of 23 African-American women from Los Angeles. In each group, about half of the women had rheumatoid arthritis with the other half serving as a control. Even though they are taken from the cheek, buccal cells allowed the researchers to conduct an epigenome-wide analysis. Translating literally as "above" the genome, an epigenome consists of chemical factors that can modify the genome and change its behavior. While not part of DNA itself, epimutations can still be passed down to subsequent generations. In this study, the researchers found epimutations in areas called DNA methylation regions, among the women in both groups who had rheumatoid arthritis. The study was designed to see if there were differences between racial groups since African Americans have shown some signs of increased prevalence of rheumatoid arthritis. However, while some differences were noted, the researchers found a large overlap in epimutations among women with rheumatoid arthritis of both races, meaning the identified biomarkers hold a strong signal for the disease. "Surprisingly, most of the DNA methylation sites we found that were consistent among patients with the disease were associated with genes previously known to be involved in rheumatoid arthritis," said Skinner. The findings add evidence that the disease is likely systemic, Skinner said, meaning it was found not just in immune system cells involved in rheumatoid arthritis development but in many different cells throughout the body. The research team also tested an immune-related monocyte cell type in blood samples from a portion of the women, but the buccal cells showed the epimutations as well, indicating that a relatively non-invasive diagnostic cheek swab test could be developed to screen for the disease. This study was supported by Epigenesys Inc. and the John Templeton Foundation. In addition to Skinner, the research team included Gary Craig and Howard Kenney of Arthritis Northwest who are also clinical faculty at the WSU Elson S. Floyd College of Medicine in Spokane as well as Eric Nilsson, Ingrid Sadler-Riggleman and Daniel Beck from WSU's School of Biological Sciences. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Prime editing is a recently reported genome editing tool using a nickase-cas9 fused to a reverse transcriptase that directly synthesizes the desired edit at the target site. Here, we explore the use of prime editing in human organoids. Common TP53 mutations can be correctly modeled in human adult stem cell–derived colonic organoids with efficiencies up to 25% and up to 97% in hepatocyte organoids. Next, we functionally repaired the cystic fibrosis CFTR-F508del mutation and compared prime editing to CRISPR/Cas9–mediated homology-directed repair and adenine base editing on the CFTR-R785* mutation. Whole-genome sequencing of prime editing–repaired organoids revealed no detectable off-target effects. Despite encountering varying editing efficiencies and undesired mutations at the target site, these results underline the broad applicability of prime editing for modeling oncogenic mutations and showcase the potential clinical application of this technique, pending further optimization. Introduction The field of genome engineering has been revolutionized by the development of the efficient genome editing tool CRISPR/Cas9. In CRISPR/Cas9–mediated genome engineering, the effector protein cas9 is guided towards the target site in the genome by an RNA guide ( Jinek et al, 2012 ). Upon target recognition, cas9 generates a double stranded break (DSB) that can be exploited for a variety of genome engineering strategies ( Cong et al, 2013 ; Mali et al, 2013 ). Because of the easy reprogrammability and high efficiency of CRISPR/Cas9, the technology is widely used for gene modification and is considered to be the most promising tool for clinical gene editing. However, the repair of DSBs is often error-prone and can result in unwanted DNA damage at the target site as well as at off-target sites that closely resemble the guide-RNA ( Fu et al, 2013 ; Pattanayak et al, 2013 ; Cho et al, 2014 ; Kosicki et al, 2018 ). These issues have been circumvented by the development of Cas9 fusion proteins, called base editors. In base editing, a partially nuclease-inactive nickase-cas9 (nCas9) protein is fused to either the cytidine deaminase APOBEC1A to enable C-G to T-A base pair changes or to an evolved TadA heterodimer to facilitate the opposite reaction, turning A-T base pairs into G-C base pairs ( Komor et al, 2016 ; Gaudelli et al, 2017 ). Base editors show high efficiency and infrequent unwanted DNA changes in a variety of model systems but are strictly limited to transition DNA substitutions ( Pavlov et al, 2019 ; Zuo et al, 2019 ; Geurts et al, 2020 ). To overcome these limitations, prime editing has been developed to enable both transition and transversion reactions as well as insertions and deletions of up to 80 nucleotides in length without the need to generate DSBs ( Anzalone et al, 2019 ). In prime editing, an nCas9 is fused to an engineered reverse transcriptase (RT) that is used to generate complementary DNA from an RNA template (PE2) ( Fig 1 ). This fusion protein is combined with a prime editing guide-RNA (pegRNA) that guides the nCas9 to its target and contains the RNA template that encodes the desired edit. Upon target recognition the protospacer adjacent motif (PAM)–containing strand is nicked and the pegRNA extension binds to the nicked strand at the primer-binding site (PBS). The RT domain then uses the remainder (RT template) of the pegRNA to synthesize a 3′-DNA-flap containing the edit of interest. This DNA-flap is resolved by cellular DNA repair processes that can be further enhanced by inducing a proximal second nick in the opposing DNA strand, guided by a second (PE3) guide-RNA ( Anzalone et al, 2019 ) ( Fig 1 ). Prime editing holds great promise, as it can—in theory—repair 89% of all disease-causing variants ( Anzalone et al, 2019 ). Here, we apply this approach in human organoids to introduce cancer mutations and to repair mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel that cause cystic fibrosis (CF), a Mendelian disorder with high prevalence in European ancestry. Download figure Open in new tab Download PowerPoint Figure 1. Principles of prime editing adapted from Anzalone et al (2019) . Principles of prime editing: The pegRNA complexes with the nCas9 (H840A)–reverse transcriptase (RT) prime-editing fusion protein and binds to the target DNA. Upon protospacer adjacent motif strand cleavage by nCas9, the primer-binding site of the pegRNA extension binds the single-stranded DNA upon which the RT synthesizes a 3′-DNA flap containing the edit of interest. This 3′-flap is resolved by cellular DNA processes which can be further enhanced by introducing a proximal second nick in the opposing DNA strand, guided by a second (PE3) guide-RNA. Red scissors indicate nick site of the nCas9. RT = Reverse Transcriptase. Results Modeling common mutations in cancer in colon and hepatocyte organoids We first characterized and optimized prime-editing efficacy in adult human stem cell–derived organoids by targeting TP53 , a gene that is often mutated in cancer. Previously, we have shown that TP53 -mutant organoids can be selected by adding nutlin-3, a molecule that inhibits the interaction between TP53 and MDM2, to the organoid culture medium ( Drost et al, 2015 ; Matano et al, 2015 ). By co-transfecting plasmids containing genome-editing components targeting TP53 with plasmids encoding a PiggyBac system conveying hygromycin resistance to transfected organoids, we can simultaneously functionally detect TP53 mutants by nutlin-3 resistance and determine editing efficiency by Sanger sequencing of hygromycin-resistant clones ( Fig 2A ). Using the pegFinder online software tool, we designed a single pegRNA and PE3-guide pair to introduce the R175H mutation, the most common mutation found in TP53 according to the Catalogue Of Somatic Mutations in Cancer ( Forbes et al, 2017 ; Chow & Chen, 2020 Preprint ). The pegRNAs were designed to integrate a PAM-disrupting mutation to block re-binding of Cas9 after the correct editing event has occurred. We co-transfected PE2 plasmids, the pegRNA/PE3-guide pair and hygromycin resistance PiggyBac plasmids in colonic organoids by electroporation. Clonally selected organoids appeared after 2 wk of nutlin-3 selection whereas control organoids, transfected with PE2 plasmids and a non-targeting scrambled sgRNA did not grow out", "role": "user" }, { "content": "Researchers from the group of Hans Clevers (Hubrecht Institute) corrected mutations that cause cystic fibrosis in cultured human stem cells. In collaboration with the UMC Utrecht and Oncode Institute, they used a technique called prime editing to replace the 'faulty' piece of DNA with a healthy piece. The study, published in Life Science Alliance on August 9, shows that prime editing is safer than the conventional CRISPR/Cas9 technique. \"We have for the first time demonstrated that this technique really works and can be safely applied in human stem cells to correct cystic fibrosis.\" Cystic fibrosis (CF) is one of the most prevalent genetic diseases worldwide and has grave consequences for the patient. The mucus in the lungs, throat and intestines is sticky and thick, which causes blockages in organs. Although treatments are available to dilute the mucus and prevent inflammations, CF is not yet curable. However, a new study from the group of Hans Clevers (Hubrecht Institute) in collaboration with the UMC Utrecht and Oncode Institute offers new hope. Correcting CF mutations The researchers succeeded in correcting the mutations that cause CF in human intestinal organoids. These organoids, also called mini-organs, are tiny 3-D structures that mimic the intestinal function of patients with CF. They were previously developed by the same research group from stem cells of patients with CF and stored in a biobank in Utrecht. For the study, published in Life Science Alliance, a technique named prime editing was used to replace the piece of mutated DNA that causes CF with a healthy piece of DNA in these organoids. Safer than CRISPR/Cas9 Prime editing is a newer version of the better-known gene editing technique CRISPR/Cas9. CRISPR/Cas9 cuts the DNA before correcting it. Although this corrects the mutated piece of DNA, it also causes damage in other regions in the genome. \"In our study, prime editing proves to be a safer technique than the conventional CRISPR/Cas9. It can build in a new piece of DNA without causing damage elsewhere in the DNA. That makes the technique promising for application in patients,\" says Maarten Geurts, first author on the publication. Swelling The mutations that cause CF are localized in the CFTR channel, which is present in the cells of various organs including the lungs. Due to the mutations, the channel does not function properly, leaving the layer of mucus that covers the cells with too little water: the mucus becomes sticky. The addition of a substance called forskolin causes healthy organoids to swell, but this does not happen in organoids with mutations in the CFTR channel. \"We applied prime editing to the mutations, after which the treated organoids demonstrated the same response as the healthy organoids: they became swollen. That provided us with proof that our technique worked and replaced the mutated DNA,\" Geurts explains. Cystic Fibrosis patient derived organoids do not show a swelling response. The swelling response is regained after prime-editing mediated repair of the CFTR channel. Credit: Eyleen de Poel and Maarten Geurts, UMC Utrecht and Hubrecht Institute Curing genetic diseases Now that the researchers showed that the mutations that cause CF can be safely corrected, applications in the clinic come one step closer. \"New variants of CRISPR/Cas9, such as prime editing, can safely correct mutations without causing damage in other regions of the DNA. This will hopefully enable us to cure or even prevent genetic diseases in the future.\" But before that, some challenges still lie ahead for the researchers. The technique for example still needs to be adapted for safe use in humans. \"But this is a great step towards successfully applying prime editing in the clinic,\" Geurts concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Prime editing is a recently reported genome editing tool using a nickase-cas9 fused to a reverse transcriptase that directly synthesizes the desired edit at the target site. Here, we explore the use of prime editing in human organoids. Common TP53 mutations can be correctly modeled in human adult stem cell–derived colonic organoids with efficiencies up to 25% and up to 97% in hepatocyte organoids. Next, we functionally repaired the cystic fibrosis CFTR-F508del mutation and compared prime editing to CRISPR/Cas9–mediated homology-directed repair and adenine base editing on the CFTR-R785* mutation. Whole-genome sequencing of prime editing–repaired organoids revealed no detectable off-target effects. Despite encountering varying editing efficiencies and undesired mutations at the target site, these results underline the broad applicability of prime editing for modeling oncogenic mutations and showcase the potential clinical application of this technique, pending further optimization. Introduction The field of genome engineering has been revolutionized by the development of the efficient genome editing tool CRISPR/Cas9. In CRISPR/Cas9–mediated genome engineering, the effector protein cas9 is guided towards the target site in the genome by an RNA guide ( Jinek et al, 2012 ). Upon target recognition, cas9 generates a double stranded break (DSB) that can be exploited for a variety of genome engineering strategies ( Cong et al, 2013 ; Mali et al, 2013 ). Because of the easy reprogrammability and high efficiency of CRISPR/Cas9, the technology is widely used for gene modification and is considered to be the most promising tool for clinical gene editing. However, the repair of DSBs is often error-prone and can result in unwanted DNA damage at the target site as well as at off-target sites that closely resemble the guide-RNA ( Fu et al, 2013 ; Pattanayak et al, 2013 ; Cho et al, 2014 ; Kosicki et al, 2018 ). These issues have been circumvented by the development of Cas9 fusion proteins, called base editors. In base editing, a partially nuclease-inactive nickase-cas9 (nCas9) protein is fused to either the cytidine deaminase APOBEC1A to enable C-G to T-A base pair changes or to an evolved TadA heterodimer to facilitate the opposite reaction, turning A-T base pairs into G-C base pairs ( Komor et al, 2016 ; Gaudelli et al, 2017 ). Base editors show high efficiency and infrequent unwanted DNA changes in a variety of model systems but are strictly limited to transition DNA substitutions ( Pavlov et al, 2019 ; Zuo et al, 2019 ; Geurts et al, 2020 ). To overcome these limitations, prime editing has been developed to enable both transition and transversion reactions as well as insertions and deletions of up to 80 nucleotides in length without the need to generate DSBs ( Anzalone et al, 2019 ). In prime editing, an nCas9 is fused to an engineered reverse transcriptase (RT) that is used to generate complementary DNA from an RNA template (PE2) ( Fig 1 ). This fusion protein is combined with a prime editing guide-RNA (pegRNA) that guides the nCas9 to its target and contains the RNA template that encodes the desired edit. Upon target recognition the protospacer adjacent motif (PAM)–containing strand is nicked and the pegRNA extension binds to the nicked strand at the primer-binding site (PBS). The RT domain then uses the remainder (RT template) of the pegRNA to synthesize a 3′-DNA-flap containing the edit of interest. This DNA-flap is resolved by cellular DNA repair processes that can be further enhanced by inducing a proximal second nick in the opposing DNA strand, guided by a second (PE3) guide-RNA ( Anzalone et al, 2019 ) ( Fig 1 ). Prime editing holds great promise, as it can—in theory—repair 89% of all disease-causing variants ( Anzalone et al, 2019 ). Here, we apply this approach in human organoids to introduce cancer mutations and to repair mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel that cause cystic fibrosis (CF), a Mendelian disorder with high prevalence in European ancestry. Download figure Open in new tab Download PowerPoint Figure 1. Principles of prime editing adapted from Anzalone et al (2019) . Principles of prime editing: The pegRNA complexes with the nCas9 (H840A)–reverse transcriptase (RT) prime-editing fusion protein and binds to the target DNA. Upon protospacer adjacent motif strand cleavage by nCas9, the primer-binding site of the pegRNA extension binds the single-stranded DNA upon which the RT synthesizes a 3′-DNA flap containing the edit of interest. This 3′-flap is resolved by cellular DNA processes which can be further enhanced by introducing a proximal second nick in the opposing DNA strand, guided by a second (PE3) guide-RNA. Red scissors indicate nick site of the nCas9. RT = Reverse Transcriptase. Results Modeling common mutations in cancer in colon and hepatocyte organoids We first characterized and optimized prime-editing efficacy in adult human stem cell–derived organoids by targeting TP53 , a gene that is often mutated in cancer. Previously, we have shown that TP53 -mutant organoids can be selected by adding nutlin-3, a molecule that inhibits the interaction between TP53 and MDM2, to the organoid culture medium ( Drost et al, 2015 ; Matano et al, 2015 ). By co-transfecting plasmids containing genome-editing components targeting TP53 with plasmids encoding a PiggyBac system conveying hygromycin resistance to transfected organoids, we can simultaneously functionally detect TP53 mutants by nutlin-3 resistance and determine editing efficiency by Sanger sequencing of hygromycin-resistant clones ( Fig 2A ). Using the pegFinder online software tool, we designed a single pegRNA and PE3-guide pair to introduce the R175H mutation, the most common mutation found in TP53 according to the Catalogue Of Somatic Mutations in Cancer ( Forbes et al, 2017 ; Chow & Chen, 2020 Preprint ). The pegRNAs were designed to integrate a PAM-disrupting mutation to block re-binding of Cas9 after the correct editing event has occurred. We co-transfected PE2 plasmids, the pegRNA/PE3-guide pair and hygromycin resistance PiggyBac plasmids in colonic organoids by electroporation. Clonally selected organoids appeared after 2 wk of nutlin-3 selection whereas control organoids, transfected with PE2 plasmids and a non-targeting scrambled sgRNA did not grow out<|im_end|> <|im_start|>assistant Researchers from the group of Hans Clevers (Hubrecht Institute) corrected mutations that cause cystic fibrosis in cultured human stem cells. In collaboration with the UMC Utrecht and Oncode Institute, they used a technique called prime editing to replace the 'faulty' piece of DNA with a healthy piece. The study, published in Life Science Alliance on August 9, shows that prime editing is safer than the conventional CRISPR/Cas9 technique. "We have for the first time demonstrated that this technique really works and can be safely applied in human stem cells to correct cystic fibrosis." Cystic fibrosis (CF) is one of the most prevalent genetic diseases worldwide and has grave consequences for the patient. The mucus in the lungs, throat and intestines is sticky and thick, which causes blockages in organs. Although treatments are available to dilute the mucus and prevent inflammations, CF is not yet curable. However, a new study from the group of Hans Clevers (Hubrecht Institute) in collaboration with the UMC Utrecht and Oncode Institute offers new hope. Correcting CF mutations The researchers succeeded in correcting the mutations that cause CF in human intestinal organoids. These organoids, also called mini-organs, are tiny 3-D structures that mimic the intestinal function of patients with CF. They were previously developed by the same research group from stem cells of patients with CF and stored in a biobank in Utrecht. For the study, published in Life Science Alliance, a technique named prime editing was used to replace the piece of mutated DNA that causes CF with a healthy piece of DNA in these organoids. Safer than CRISPR/Cas9 Prime editing is a newer version of the better-known gene editing technique CRISPR/Cas9. CRISPR/Cas9 cuts the DNA before correcting it. Although this corrects the mutated piece of DNA, it also causes damage in other regions in the genome. "In our study, prime editing proves to be a safer technique than the conventional CRISPR/Cas9. It can build in a new piece of DNA without causing damage elsewhere in the DNA. That makes the technique promising for application in patients," says Maarten Geurts, first author on the publication. Swelling The mutations that cause CF are localized in the CFTR channel, which is present in the cells of various organs including the lungs. Due to the mutations, the channel does not function properly, leaving the layer of mucus that covers the cells with too little water: the mucus becomes sticky. The addition of a substance called forskolin causes healthy organoids to swell, but this does not happen in organoids with mutations in the CFTR channel. "We applied prime editing to the mutations, after which the treated organoids demonstrated the same response as the healthy organoids: they became swollen. That provided us with proof that our technique worked and replaced the mutated DNA," Geurts explains. Cystic Fibrosis patient derived organoids do not show a swelling response. The swelling response is regained after prime-editing mediated repair of the CFTR channel. Credit: Eyleen de Poel and Maarten Geurts, UMC Utrecht and Hubrecht Institute Curing genetic diseases Now that the researchers showed that the mutations that cause CF can be safely corrected, applications in the clinic come one step closer. "New variants of CRISPR/Cas9, such as prime editing, can safely correct mutations without causing damage in other regions of the DNA. This will hopefully enable us to cure or even prevent genetic diseases in the future." But before that, some challenges still lie ahead for the researchers. The technique for example still needs to be adapted for safe use in humans. "But this is a great step towards successfully applying prime editing in the clinic," Geurts concludes. <|im_end|>

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2,302

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Immune Checkpoint Inhibitor (ICI) therapy has revolutionized treatment for advanced melanoma; however, only a subset of patients benefit from this treatment. Despite considerable efforts, the Tumor Mutation Burden (TMB) is the only FDA-approved biomarker in melanoma. However, the mechanisms underlying TMB association with prolonged ICI survival are not entirely understood and may depend on numerous confounding factors. To identify more interpretable ICI response biomarkers based on tumor mutations, we train classifiers using mutations within distinct biological processes. We evaluate a variety of feature selection and classification methods and identify key mutated biological processes that provide improved predictive capability compared to the TMB. The top mutated processes we identify are leukocyte and T-cell proliferation regulation, which demonstrate stable predictive performance across different data cohorts of melanoma patients treated with ICI. This study provides biologically interpretable genomic predictors of ICI response with substantially improved predictive performance over the TMB. Introduction Melanoma is a highly aggressive disease and the deadliest form of skin cancer. Deaths from melanoma account for ~60% of skin cancer mortality 1 , 2 . Prognosis greatly depends on the stage at which the cancer is discovered. Whereas almost all patients diagnosed with localized melanoma survive for at least five years, less than a third of patients diagnosed with distant metastasized melanoma survive over the same period 3 . The majority of patients with metastatic melanoma do not benefit from surgery, chemotherapy and radiation alone 4 , 5 . Targeted therapies such as BRAF and MEK inhibitors have dramatically improved the prognosis of patients with metastatic melanoma that harbor specific mutations 6 , 7 , 8 . However, only a subset of the patients can benefit from these treatments, and the majority of those develop resistance over time 9 , 10 . In recent years, Immune Checkpoint Inhibitor (ICI) therapy has been approved for patients with advanced disease, demonstrating durable remission in up to half of the patients 5 , 9 , 11 . The first antibody developed for clinical ICI treatment targets the cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 is a T-cell surface protein which binds to B7-1 and B7-2 expressed by antigen-presenting cells (APC) 12 , resulting in suppression of immune response by the T cells. Ipilimumab, a human monoclonal antibody targeting CTLA-4, was the first ICI agent to demonstrate increased progression-free survival (PFS) and overall survival (OS) compared to more traditional cancer treatment methods 12 , 13 , 14 . Subsequently, clinical targeting of the programmed cell death receptor 1 (PD1), which binds to its ligand-receptor PD-L1 to elicit tumor immune escape, has markedly improved the treatment of melanoma and demonstrated durable responses in other types of cancer 15 , 16 . Several potential new ICI antibodies are currently being explored, such as those targeting the regulatory surface glycoprotein TIM-3 17 . While 40–60% of patients with advanced melanoma experience benefit from ICI, a substantial fraction of patients do not benefit from this treatment, which can incur severe autoimmune adverse events 13 , 14 , 18 , 19 . Therefore, it is critical to uncover tumor characteristics that predict response to ICI. Numerous biomarkers have been proposed for the prediction of ICI response, but most have not been validated for clinical use. Gene expression biomarkers include PDL-1 20 , CD38 21 , TIM-3 22 , and CXCL9 23 expression, cytolytic activity 24 , as well as machine learning-derived signatures such as IPRES 25 , TIDE 26 , IMPRES 27 , Immonophenoscores 28 , and others 29 , 30 . However, a recent meta-analysis evaluated the reproducibility of ICI biomarkers and found that only a subset of these maintained any predictive performance 31 . To date, gene expression signatures predicting ICI response have not been incorporated into clinical use, likely due to limited reproducibility and lack of benchmarking standards, among other factors 32 . Genomic biomarkers of ICI benefit have met more success in terms of clinical use. In 2017, the U.S. Food and Drug Administration (FDA) approved the first biomarker for anti-PD1 efficacy based on high levels of microsatellite instability (MSI-H) 33 . However, MSI-H is only found in a subset of gastrointestinal and endometrial tumors. In 2020, the high tumor mutation burden (TMB-H), quantifying the number of mutations in a tumor, has been approved by the FDA as a marker for anti-PD1 efficacy 34 . While TMB-H has been associated with ICI benefit across different cancer types, there are several challenges for its utility. For example, TMB is tumor type-specific; moreover, TMB-H status does not preclude tumor progression, and low TMB does not preclude response 35 , 36 . In addition, the mechanism underlying the clinical utility of the TMB is unclear. Therefore, there is a need for additional genomic ICI response biomarkers with improved predictive performance that are more biologically interpretable. Recent studies have examined the mechanistic link between anti-PD1 response or resistance and mutated biological processes such as interferon signaling, MHC presentation, and beta-catenin 37 , 38 , prompting a need for process-level ICI response biomarkers. Here, we use tumor mutation data in the context of biological processes to predict patient response to anti-PD1 treatment. We first investigate whether the mutation burden in genes that belong to different biological processes correlate with anti-PD1 benefit. We then apply feature selection methods to distinct processes to identify subsets of genes in which the mutational count predicts anti-PD1 response. This revealed sets of mutated genes in several biological processes with a comparable predictive ability of anti-PD1 response to TMB. Employing nonlinear classification methods further enhanced the predictive performance of classifiers based on mutated genes in specific biological processes. The advantage of these methods is that they can capture intricate relations between the mutated genes in a process and anti-PD1 responses, simultaneously weighing mutations that contribute to either response or resistance. Evaluating decision-tree algorithms and neural network architectures, we found that random forest maintains the most robust performance across different datasets, accurately predicting response and overall survival in independent datasets spanning over 500 melanoma patients in total.", "role": "user" }, { "content": "Immune checkpoint inhibitor (ICI) therapy is a type of treatment for melanoma, the deadliest form of skin cancer, which blocks proteins on tumor or immune cells that prevent the immune system from killing cancer cells. While this treatment has shown some clinical success in patients with advanced stages of melanoma, its efficacy depends on reliable predictors of a patient's response to the therapy. Currently, the only FDA approved biomarker for ICI melanoma treatment is the tumor mutation burden assay, but the mechanisms linking it to ICI remain unclear. However, new research now provides evidence of novel, reliable biomarkers that predict therapy response using advanced computer technology. In a paper published in Nature Communications, Noam Auslander, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program of Wistar's Ellen and Ronald Caplan Cancer Center, and Andrew Patterson, graduate student in the Auslander lab, identify novel predictors of ICI therapy for melanoma. In particular, mutations in the processes of leukocyte and T-cell proliferation regulation show potential as biomarkers with reliable and stable prediction of ICI therapy response across multiple different datasets of melanoma patients. \"This work aims to identify better and more biologically interpretable genomic predictors for immunotherapy responses,\" notes Auslander. \"We need better biomarkers to help select patients that are more likely to respond to ICI therapy and understand what factors can help to enhance responses and increase those numbers.\" Using machine learning and publicly available de-identified clinical data, researchers investigated why some melanoma patients responded to ICI therapy and others did not. Patterson, first author on the paper, details that their research process involved training machine learning models on a dataset to predict whether a patient responds to ICI therapy, and then confirming that the model was able to continually predict response or resistance to this treatment over multiple other datasets. The team found that leukocyte and T-cell proliferation regulation processes have some mutated genes that contribute to ICI treatment response and resistance. This knowledge could be used to identify targets to enhance responses or mitigate resistance in patients with melanoma. \"We were able to better predict if a patient would respond to ICI therapy than the current clinical standard method as well as extract biological information that could help in further understanding the mechanisms behind ICI therapy response and resistance,\" Patterson explains. The scientists intend to continue this work with the goals of increasing prediction accuracy, further understanding biological mechanisms underpinning patient resistance or responsiveness to ICI therapy, and determining whether the processes distinguished in the paper can also serve as predictors of ICI treatment response for other cancer types. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Immune Checkpoint Inhibitor (ICI) therapy has revolutionized treatment for advanced melanoma; however, only a subset of patients benefit from this treatment. Despite considerable efforts, the Tumor Mutation Burden (TMB) is the only FDA-approved biomarker in melanoma. However, the mechanisms underlying TMB association with prolonged ICI survival are not entirely understood and may depend on numerous confounding factors. To identify more interpretable ICI response biomarkers based on tumor mutations, we train classifiers using mutations within distinct biological processes. We evaluate a variety of feature selection and classification methods and identify key mutated biological processes that provide improved predictive capability compared to the TMB. The top mutated processes we identify are leukocyte and T-cell proliferation regulation, which demonstrate stable predictive performance across different data cohorts of melanoma patients treated with ICI. This study provides biologically interpretable genomic predictors of ICI response with substantially improved predictive performance over the TMB. Introduction Melanoma is a highly aggressive disease and the deadliest form of skin cancer. Deaths from melanoma account for ~60% of skin cancer mortality 1 , 2 . Prognosis greatly depends on the stage at which the cancer is discovered. Whereas almost all patients diagnosed with localized melanoma survive for at least five years, less than a third of patients diagnosed with distant metastasized melanoma survive over the same period 3 . The majority of patients with metastatic melanoma do not benefit from surgery, chemotherapy and radiation alone 4 , 5 . Targeted therapies such as BRAF and MEK inhibitors have dramatically improved the prognosis of patients with metastatic melanoma that harbor specific mutations 6 , 7 , 8 . However, only a subset of the patients can benefit from these treatments, and the majority of those develop resistance over time 9 , 10 . In recent years, Immune Checkpoint Inhibitor (ICI) therapy has been approved for patients with advanced disease, demonstrating durable remission in up to half of the patients 5 , 9 , 11 . The first antibody developed for clinical ICI treatment targets the cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 is a T-cell surface protein which binds to B7-1 and B7-2 expressed by antigen-presenting cells (APC) 12 , resulting in suppression of immune response by the T cells. Ipilimumab, a human monoclonal antibody targeting CTLA-4, was the first ICI agent to demonstrate increased progression-free survival (PFS) and overall survival (OS) compared to more traditional cancer treatment methods 12 , 13 , 14 . Subsequently, clinical targeting of the programmed cell death receptor 1 (PD1), which binds to its ligand-receptor PD-L1 to elicit tumor immune escape, has markedly improved the treatment of melanoma and demonstrated durable responses in other types of cancer 15 , 16 . Several potential new ICI antibodies are currently being explored, such as those targeting the regulatory surface glycoprotein TIM-3 17 . While 40–60% of patients with advanced melanoma experience benefit from ICI, a substantial fraction of patients do not benefit from this treatment, which can incur severe autoimmune adverse events 13 , 14 , 18 , 19 . Therefore, it is critical to uncover tumor characteristics that predict response to ICI. Numerous biomarkers have been proposed for the prediction of ICI response, but most have not been validated for clinical use. Gene expression biomarkers include PDL-1 20 , CD38 21 , TIM-3 22 , and CXCL9 23 expression, cytolytic activity 24 , as well as machine learning-derived signatures such as IPRES 25 , TIDE 26 , IMPRES 27 , Immonophenoscores 28 , and others 29 , 30 . However, a recent meta-analysis evaluated the reproducibility of ICI biomarkers and found that only a subset of these maintained any predictive performance 31 . To date, gene expression signatures predicting ICI response have not been incorporated into clinical use, likely due to limited reproducibility and lack of benchmarking standards, among other factors 32 . Genomic biomarkers of ICI benefit have met more success in terms of clinical use. In 2017, the U.S. Food and Drug Administration (FDA) approved the first biomarker for anti-PD1 efficacy based on high levels of microsatellite instability (MSI-H) 33 . However, MSI-H is only found in a subset of gastrointestinal and endometrial tumors. In 2020, the high tumor mutation burden (TMB-H), quantifying the number of mutations in a tumor, has been approved by the FDA as a marker for anti-PD1 efficacy 34 . While TMB-H has been associated with ICI benefit across different cancer types, there are several challenges for its utility. For example, TMB is tumor type-specific; moreover, TMB-H status does not preclude tumor progression, and low TMB does not preclude response 35 , 36 . In addition, the mechanism underlying the clinical utility of the TMB is unclear. Therefore, there is a need for additional genomic ICI response biomarkers with improved predictive performance that are more biologically interpretable. Recent studies have examined the mechanistic link between anti-PD1 response or resistance and mutated biological processes such as interferon signaling, MHC presentation, and beta-catenin 37 , 38 , prompting a need for process-level ICI response biomarkers. Here, we use tumor mutation data in the context of biological processes to predict patient response to anti-PD1 treatment. We first investigate whether the mutation burden in genes that belong to different biological processes correlate with anti-PD1 benefit. We then apply feature selection methods to distinct processes to identify subsets of genes in which the mutational count predicts anti-PD1 response. This revealed sets of mutated genes in several biological processes with a comparable predictive ability of anti-PD1 response to TMB. Employing nonlinear classification methods further enhanced the predictive performance of classifiers based on mutated genes in specific biological processes. The advantage of these methods is that they can capture intricate relations between the mutated genes in a process and anti-PD1 responses, simultaneously weighing mutations that contribute to either response or resistance. Evaluating decision-tree algorithms and neural network architectures, we found that random forest maintains the most robust performance across different datasets, accurately predicting response and overall survival in independent datasets spanning over 500 melanoma patients in total.<|im_end|> <|im_start|>assistant Immune checkpoint inhibitor (ICI) therapy is a type of treatment for melanoma, the deadliest form of skin cancer, which blocks proteins on tumor or immune cells that prevent the immune system from killing cancer cells. While this treatment has shown some clinical success in patients with advanced stages of melanoma, its efficacy depends on reliable predictors of a patient's response to the therapy. Currently, the only FDA approved biomarker for ICI melanoma treatment is the tumor mutation burden assay, but the mechanisms linking it to ICI remain unclear. However, new research now provides evidence of novel, reliable biomarkers that predict therapy response using advanced computer technology. In a paper published in Nature Communications, Noam Auslander, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program of Wistar's Ellen and Ronald Caplan Cancer Center, and Andrew Patterson, graduate student in the Auslander lab, identify novel predictors of ICI therapy for melanoma. In particular, mutations in the processes of leukocyte and T-cell proliferation regulation show potential as biomarkers with reliable and stable prediction of ICI therapy response across multiple different datasets of melanoma patients. "This work aims to identify better and more biologically interpretable genomic predictors for immunotherapy responses," notes Auslander. "We need better biomarkers to help select patients that are more likely to respond to ICI therapy and understand what factors can help to enhance responses and increase those numbers." Using machine learning and publicly available de-identified clinical data, researchers investigated why some melanoma patients responded to ICI therapy and others did not. Patterson, first author on the paper, details that their research process involved training machine learning models on a dataset to predict whether a patient responds to ICI therapy, and then confirming that the model was able to continually predict response or resistance to this treatment over multiple other datasets. The team found that leukocyte and T-cell proliferation regulation processes have some mutated genes that contribute to ICI treatment response and resistance. This knowledge could be used to identify targets to enhance responses or mitigate resistance in patients with melanoma. "We were able to better predict if a patient would respond to ICI therapy than the current clinical standard method as well as extract biological information that could help in further understanding the mechanisms behind ICI therapy response and resistance," Patterson explains. The scientists intend to continue this work with the goals of increasing prediction accuracy, further understanding biological mechanisms underpinning patient resistance or responsiveness to ICI therapy, and determining whether the processes distinguished in the paper can also serve as predictors of ICI treatment response for other cancer types. <|im_end|>

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1,902

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract DNA-encoded library technologies enable the screening of synthetic molecules but have thus far not tapped into the power of Darwinian selection with iterative cycles of selection, amplification and diversification. Here we report a simple strategy to rapidly assemble libraries of conformationally constrained peptides that are paired in a combinatorial fashion (suprabodies). We demonstrate that the pairing can be shuffled after each amplification cycle in a process similar to DNA shuffling or mating to regenerate diversity. Using simulations, we show the benefits of this recombination in yielding a more accurate correlation of selection fitness with affinity after multiple rounds of selection, particularly if the starting library is heterogeneous in the concentration of its members. The method was validated with selections against streptavidin and applied to the discovery of PD-L1 binders. We further demonstrate that the binding of self-assembled suprabodies can be recapitulated by smaller ( ∼ 7 kDa) synthetic products that maintain the conformational constraint of the peptides. Main The discovery of ligands that interact and modulate the function of biomolecules is a central challenge in chemistry and biology, and often a rate-limiting step in biomedical research. DNA-encoded library (DEL) technologies dramatically simplify and accelerate this process by linking the function of a synthetic molecule (phenotype) to an amplifiable nucleic acid tag (genotype) 1 , 2 . The advent of DNA sequencing makes affinity-based screens operationally simple to decode. While the idea of encoding chemical libraries with DNA was set forth at the onset of combinatorial chemistry in the 1990s 3 , its practical implementation required innovative solutions to access DELs of meaningful molecular diversity. Breakthroughs in this area were enabled by a range of technologies, including DNA-templated synthesis 4 , 5 , peptide nucleic acid (PNA)-encoded synthesis (hybridized to a complementary DNA for decoding—DNA display) 6 , 7 , DNA routing 8 , 9 , self-assembling libraries 10 , primer extension 11 or enzymatic ligation 12 , to introduce the DNA tag. Although all these technologies facilitate the screening by providing a fast and simple decoding of hits, only a few allow regeneration of the subset of the selected molecules following the amplification of DNA for iterative screening (Fig. 1 ) 4 , 8 , 13 , 14 , 15 , 16 . However, none of the technologies makes it possible to truly tap into Darwinian selection by allowing molecular diversity to be regenerated after every cycle of selection. Several studies have demonstrated an important step: translating the genetic information into small molecules or synthetic polymers 4 , 5 , 8 , 9 , 13 , 15 , 17 , 18 , 19 , 20 , 21 ; thus the molecules selected can be regenerated (amplification) but there is no mechanism to introduce molecular diversity. The use of error-prone polymerase chain reaction (PCR) may appear to be a simple solution; however, it is not applicable to the existing technologies because the codon design of DELs does not (and cannot) use the entire repertoire of sequence permutation, and hence point mutations would lead to non-coding sequences. Reagent hybridization in DNA-templated synthesis, or fragment hybridization in DNA display, or library segregation in DNA routing requires a sequence-specific hybridization that would be compromised with codons that differ by a single nucleobase and that are not matched in melting temperature (the GC content of codons must be balanced across the codon repertoire excluding the use of full sequence space). Taking cues from the advent of de novo evolution in proteins, an important breakthrough was the development of DNA shuffling 22 , 23 (termed ‘sexual’ PCR 24 ). This DNA shuffling method, which is akin to homologous recombination and lineage crossing of sexual reproduction, was experimentally shown to be far superior to cassette mutagenesis and error-prone PCR (which are intrinsically not combinatorial). This is due to the low probability that a given change (mutation) is beneficial and the exponentially lower probability of multiple beneficial mutations. Recombination mechanisms and lineage mixing enable beneficial mutations from different library members to be combined, thus augmenting the chance of acquiring multiple beneficial mutations (Fig. 1c ). Evolution has also selected for recombination mechanisms to generate antibody diversity; antibody repertoire diversification being one of the most powerful examples of combinatorial biomolecular diversity. In analogy, hybridization has been used to combinatorially pair small molecules in DELs 10 , 13 , 14 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , however, the reported designs do not allow cycles of amplification with diversification which is essential to realize the full power of Darwinian evolution. Fig. 1: Darwinian evolution by selection/amplification/diversification, D suprabody and P suprabody assemblies, and a general selection-protocol scheme. a , DNA-encoded libraries allow identification of the fittest member, b , The power of Darwinian evolution requires a diversification mechanism. c , Lineage crossing accelerates evolution by increasing the probability that beneficial changes are combined. d , Schematic representation of a D suprabody assembly and a P suprabody. Same colour PNA and DNA in D suprabody denotes complementarity. e , Schematic representation of the full protocol for the generation of a 10 8 D suprabody library followed by several rounds of selection. Full size image We envisioned that libraries of macrocyclic-like structures could be accessed by hybridization of a peptidic library flanked by PNA tags to a DNA template (Fig. 1d ). It is well established that the restrained conformational profile of a macrocycle benefits affinity and specificity in the interactions with a target protein 33 , 34 and these properties have stimulated the use of macrocycles in DEL 16 , 35 . It has also been shown that the conformation of a peptide can be constrained by hybridization of flanking nucleic acid tags, resulting in enhanced function 36 , 37 . In analogy to antibodies, which achieve selective target recognition with several hypervariable loops, we also envisioned that a library of higher complexity could be obtained by combining two constrained peptide loops through hybridization of the DNA template (Fig. 1d", "role": "user" }, { "content": "The body must constantly defend itself against bacteria and viruses. It generates millions of different antibodies, which are selected to recognize the enemy and trigger the best possible immune response. Scientists use these antibodies for therapeutic purposes to target proteins and disrupt their harmful effects. However, identifying small molecules that will form the basis of drugs is a long and tedious process. Chemists at the University of Geneva (UNIGE), Switzerland, have developed a technique inspired by the theory of Darwinian evolution: Amplifying the best combinations and generating diversity that allows biology to find solutions to new problems. They have created a new methodology that rapidly generates millions of combinations of small molecules through programmed assembly using DNA-pairing processes, finding the best possible combination to counter a target protein within two weeks. These results, published in the journal Nature Chemistry, will open up a new and untapped space for drug development. The way drugs work is based on the molecular recognition of a target protein involved in a disease, and then disarming it. To do this, scientists use high-throughput screening to identify which molecule could become a drug, specifically targeting the protein of interest. Over the last ten years, the technique has been improved by encoding small molecules with DNA tags that simplify their identification, as DNA is easy to decode. Drawing inspiration from Darwinian evolutionary forces to find efficient assemblies \"Biology always finds a solution to a problem, explains Nicolas Winssinger, professor in the Department of Organic Chemistry at the Faculty of Science, UNIGE, and the corresponding author of the study. This is the principle of natural evolution, which consists of amplifying the best individuals, while generating diversity to adapt and survive changing conditions. That's what we've set up for small molecules.\" Indeed, the scientists have developed a technology that generates diversity by creating more than 100 million assemblies of molecules via their DNA, from which they then select to best match a particular protein. \"We were inspired by the characteristics of antibodies that recognize target proteins and sought to mimic them in the form of simpler molecules to allow them to be assembled in different combinations, directed by DNA sequences,\" explains Nicolas Winssinger. These combinations are then selected and amplified several times to find the best possible match with the protein to be targeted, all in one to two weeks, compared with months or even a year for traditional high-throughput screening. A proven, easily reproducible and inexpensive technique To validate the effectiveness of this methodology, the Geneva team focused on the PD-L1 protein, which protects cancer cells by diverting the immune system. \"Thanks to our methodology, we quickly identified an assembly that specifically targets PD-L1, confirming that it works effectively,\" says Nicolas Winssinger. This technique, which is easy to reproduce in any laboratory in the world, costs only a few thousand francs, compared with millions for high-throughput screening. \"By exploiting the evolutionary forces highlighted by Darwin, we can now improve our molecular assemblies and open up a new space of possible combinations that has not yet been exploited, in order to create new, more effective drugs,\" concludes the Geneva researcher. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract DNA-encoded library technologies enable the screening of synthetic molecules but have thus far not tapped into the power of Darwinian selection with iterative cycles of selection, amplification and diversification. Here we report a simple strategy to rapidly assemble libraries of conformationally constrained peptides that are paired in a combinatorial fashion (suprabodies). We demonstrate that the pairing can be shuffled after each amplification cycle in a process similar to DNA shuffling or mating to regenerate diversity. Using simulations, we show the benefits of this recombination in yielding a more accurate correlation of selection fitness with affinity after multiple rounds of selection, particularly if the starting library is heterogeneous in the concentration of its members. The method was validated with selections against streptavidin and applied to the discovery of PD-L1 binders. We further demonstrate that the binding of self-assembled suprabodies can be recapitulated by smaller ( ∼ 7 kDa) synthetic products that maintain the conformational constraint of the peptides. Main The discovery of ligands that interact and modulate the function of biomolecules is a central challenge in chemistry and biology, and often a rate-limiting step in biomedical research. DNA-encoded library (DEL) technologies dramatically simplify and accelerate this process by linking the function of a synthetic molecule (phenotype) to an amplifiable nucleic acid tag (genotype) 1 , 2 . The advent of DNA sequencing makes affinity-based screens operationally simple to decode. While the idea of encoding chemical libraries with DNA was set forth at the onset of combinatorial chemistry in the 1990s 3 , its practical implementation required innovative solutions to access DELs of meaningful molecular diversity. Breakthroughs in this area were enabled by a range of technologies, including DNA-templated synthesis 4 , 5 , peptide nucleic acid (PNA)-encoded synthesis (hybridized to a complementary DNA for decoding—DNA display) 6 , 7 , DNA routing 8 , 9 , self-assembling libraries 10 , primer extension 11 or enzymatic ligation 12 , to introduce the DNA tag. Although all these technologies facilitate the screening by providing a fast and simple decoding of hits, only a few allow regeneration of the subset of the selected molecules following the amplification of DNA for iterative screening (Fig. 1 ) 4 , 8 , 13 , 14 , 15 , 16 . However, none of the technologies makes it possible to truly tap into Darwinian selection by allowing molecular diversity to be regenerated after every cycle of selection. Several studies have demonstrated an important step: translating the genetic information into small molecules or synthetic polymers 4 , 5 , 8 , 9 , 13 , 15 , 17 , 18 , 19 , 20 , 21 ; thus the molecules selected can be regenerated (amplification) but there is no mechanism to introduce molecular diversity. The use of error-prone polymerase chain reaction (PCR) may appear to be a simple solution; however, it is not applicable to the existing technologies because the codon design of DELs does not (and cannot) use the entire repertoire of sequence permutation, and hence point mutations would lead to non-coding sequences. Reagent hybridization in DNA-templated synthesis, or fragment hybridization in DNA display, or library segregation in DNA routing requires a sequence-specific hybridization that would be compromised with codons that differ by a single nucleobase and that are not matched in melting temperature (the GC content of codons must be balanced across the codon repertoire excluding the use of full sequence space). Taking cues from the advent of de novo evolution in proteins, an important breakthrough was the development of DNA shuffling 22 , 23 (termed ‘sexual’ PCR 24 ). This DNA shuffling method, which is akin to homologous recombination and lineage crossing of sexual reproduction, was experimentally shown to be far superior to cassette mutagenesis and error-prone PCR (which are intrinsically not combinatorial). This is due to the low probability that a given change (mutation) is beneficial and the exponentially lower probability of multiple beneficial mutations. Recombination mechanisms and lineage mixing enable beneficial mutations from different library members to be combined, thus augmenting the chance of acquiring multiple beneficial mutations (Fig. 1c ). Evolution has also selected for recombination mechanisms to generate antibody diversity; antibody repertoire diversification being one of the most powerful examples of combinatorial biomolecular diversity. In analogy, hybridization has been used to combinatorially pair small molecules in DELs 10 , 13 , 14 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , however, the reported designs do not allow cycles of amplification with diversification which is essential to realize the full power of Darwinian evolution. Fig. 1: Darwinian evolution by selection/amplification/diversification, D suprabody and P suprabody assemblies, and a general selection-protocol scheme. a , DNA-encoded libraries allow identification of the fittest member, b , The power of Darwinian evolution requires a diversification mechanism. c , Lineage crossing accelerates evolution by increasing the probability that beneficial changes are combined. d , Schematic representation of a D suprabody assembly and a P suprabody. Same colour PNA and DNA in D suprabody denotes complementarity. e , Schematic representation of the full protocol for the generation of a 10 8 D suprabody library followed by several rounds of selection. Full size image We envisioned that libraries of macrocyclic-like structures could be accessed by hybridization of a peptidic library flanked by PNA tags to a DNA template (Fig. 1d ). It is well established that the restrained conformational profile of a macrocycle benefits affinity and specificity in the interactions with a target protein 33 , 34 and these properties have stimulated the use of macrocycles in DEL 16 , 35 . It has also been shown that the conformation of a peptide can be constrained by hybridization of flanking nucleic acid tags, resulting in enhanced function 36 , 37 . In analogy to antibodies, which achieve selective target recognition with several hypervariable loops, we also envisioned that a library of higher complexity could be obtained by combining two constrained peptide loops through hybridization of the DNA template (Fig. 1d<|im_end|> <|im_start|>assistant The body must constantly defend itself against bacteria and viruses. It generates millions of different antibodies, which are selected to recognize the enemy and trigger the best possible immune response. Scientists use these antibodies for therapeutic purposes to target proteins and disrupt their harmful effects. However, identifying small molecules that will form the basis of drugs is a long and tedious process. Chemists at the University of Geneva (UNIGE), Switzerland, have developed a technique inspired by the theory of Darwinian evolution: Amplifying the best combinations and generating diversity that allows biology to find solutions to new problems. They have created a new methodology that rapidly generates millions of combinations of small molecules through programmed assembly using DNA-pairing processes, finding the best possible combination to counter a target protein within two weeks. These results, published in the journal Nature Chemistry, will open up a new and untapped space for drug development. The way drugs work is based on the molecular recognition of a target protein involved in a disease, and then disarming it. To do this, scientists use high-throughput screening to identify which molecule could become a drug, specifically targeting the protein of interest. Over the last ten years, the technique has been improved by encoding small molecules with DNA tags that simplify their identification, as DNA is easy to decode. Drawing inspiration from Darwinian evolutionary forces to find efficient assemblies "Biology always finds a solution to a problem, explains Nicolas Winssinger, professor in the Department of Organic Chemistry at the Faculty of Science, UNIGE, and the corresponding author of the study. This is the principle of natural evolution, which consists of amplifying the best individuals, while generating diversity to adapt and survive changing conditions. That's what we've set up for small molecules." Indeed, the scientists have developed a technology that generates diversity by creating more than 100 million assemblies of molecules via their DNA, from which they then select to best match a particular protein. "We were inspired by the characteristics of antibodies that recognize target proteins and sought to mimic them in the form of simpler molecules to allow them to be assembled in different combinations, directed by DNA sequences," explains Nicolas Winssinger. These combinations are then selected and amplified several times to find the best possible match with the protein to be targeted, all in one to two weeks, compared with months or even a year for traditional high-throughput screening. A proven, easily reproducible and inexpensive technique To validate the effectiveness of this methodology, the Geneva team focused on the PD-L1 protein, which protects cancer cells by diverting the immune system. "Thanks to our methodology, we quickly identified an assembly that specifically targets PD-L1, confirming that it works effectively," says Nicolas Winssinger. This technique, which is easy to reproduce in any laboratory in the world, costs only a few thousand francs, compared with millions for high-throughput screening. "By exploiting the evolutionary forces highlighted by Darwin, we can now improve our molecular assemblies and open up a new space of possible combinations that has not yet been exploited, in order to create new, more effective drugs," concludes the Geneva researcher. <|im_end|>

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1,977

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Trace-level plutonium in the environment often comprises local and global contributions, and is usually anthropogenic in origin. Here, we report estimates of local and global contributions to trace-level plutonium in soil from a former, fast-breeder reactor site. The measured 240 Pu/ 239 Pu ratio is anomalously low, as per the reduced 240 Pu yield expected in plutonium bred with fast neutrons. Anomalies in plutonium concentration and isotopic ratio suggest forensic insight into specific activities on site, such as clean-up or structural change. Local and global 239 Pu contributions on-site are estimated at (34 ± 1)% and (66 ± 3)%, respectively, with mass concentrations of (183 ± 6) fg g −1 and (362 ± 13) fg g −1 . The latter is consistent with levels at undisturbed and distant sites, (384 ± 44) fg g −1 , where no local contribution is expected. The 240 Pu/ 239 Pu ratio for site-derived material is estimated at 0.05 ± 0.04. Our study demonstrates the multi-faceted potential of trace plutonium assay to inform clean-up strategies of fast breeder legacies. Introduction Minute quantities of plutonium occur naturally in the terrestrial environment 1 from neutron capture on 238 U in uranium-rich deposits. Anthropogenic contributions occur local to their source of production, for example, from nuclear plant effluents, reactor accidents, accidents involving nuclear weapons and plutonium-powered space probes etc., and also globally from fallout. Following the measurements Seaborg et al. 1 , 2 of Canadian pitchblende (yielding a 239 Pu mass concentration of 550 fg g −1 ), Krey et al. 3 estimated the 240/239 Pu ratio due to fallout, at 0.176 ± 0.02: this has been used widely for comparison by subsequent studies. Harley 4 suggested a distribution of the oxide from weapons testing of 2 mCi km −2 (~485 fg g −1 assuming deposition in the first 5 cm and a bulk soil density of 1.33 g cm −3 ) in the north temperate zone. The depth-resolved assessment of plutonium residues in Lake Ontario sediments followed, yielding a 240 Pu/ 239 Pu ratio 5 , 6 consistent with Krey et al. Subsequently, Buesseler et al. 7 reported measurements of a dated coral record from the North Pacific of 239 Pu mass (~55 fg g −1 ) and 240/239 Pu ratio (>0.2), the latter reflecting the predominance of fallout in this environment, in agreement with the prior art 3 . Plutonium-239 abundance of the contrasting residues from the Cigar Lake natural ore body (Canada) were reported 8 , resolved with depth, in the range 17–6200 fg g −1 . Kelley et al. 9 reported on the global distribution, including a sample from Wick (Scotland), ~50 km from the site at Dounreay studied in this research, with a 240 Pu/ 239 Pu ratio of 0.182 ± 0.001. Muramatsu et al. published an analysis of samples from the Marshall islands 10 with a 240 Pu/ 239 Pu range of 0.065–0.306 and 239 Pu mass 75–500 fg g −1 . In 2013, Steier et al. 11 reported accelerator mass spectrometry (AMS) measurements of samples from Sellafield (UK) with a 240 Pu/ 239 Pu range of 0.183–0.228 (±0.001) and, in 2015, Armstrong et al. 12 reported a 10-year assessment of samples from Savannah River (USA) with 240 Pu/ 239 Pu range of 0.0757–0.3035. Terrestrial plutonium abundance, albeit deposited over decades, varies slowly with time due to the long half-lives of most plutonium isotopes and relatively slow natural transport mechanisms, in the absence of human intervention. The ability to discern local sources of plutonium from global fallout is important to inform decisions concerning nuclear legacies, particularly the clean-up of contaminated land. As Harley 4 stated, it remains ‘…desirable…to distinguish…local sources from global fallout’ for exactly this reason. Given this context, the motivation for this study is to determine whether the local contribution to trace plutonium abundance on a fast breeder site might be discerned from the global contribution, to inform the extent to which clean-up of the local component might be necessary. In addition to the variation in trace elemental plutonium, the isotopic distribution varies too. Plutonium-239 is the more probable product of activation in reactors relative to the higher-mass plutonium isotopes. Industrially, fissile Pu, in particular 239 Pu, has also been the focus of nuclear reprocessing, mixed-oxide and metal fuel manufacture, and nuclear weapons fabrication operations for ~70 years worldwide, albeit on a localised basis. Of particular relevance to this research is 239 Pu produced by breeding in the mid-to-late 20th century and the legacy of these activities. In comparison with 239 Pu, the higher-mass plutonium isotopes ( 240 Pu, 241 Pu, 242 Pu and 244 Pu) have few specific applications and have not been manufactured on a comparable scale. Since their formation is dependent on the neutron fluence and energy spectrum, estimating the extent to which they are produced can require knowledge of the associated neutron environment, in which they are made. Elemental plutonium concentration in soils is dependent on many factors, in addition to the way in which it was formed, such as geographic location, precipitation and soil composition etc. By contrast, the link between a specific isotope, considered via the isotopic ratio, and its origin often yields a more tangible association 13 , for example: a pre-detonation weapon safety test might cause 239 Pu to dominate; fallout from atmospheric detonations can comprise higher-mass isotopes through to 244 Pu (refs. 14 , 15 ), whereas a relatively low 240 Pu/ 239 Pu ratio might reflect the low proportions of 240 Pu desirable in some applications, such as that obtained by breeding. Material dispersed in fallout will often have a higher proportion of 244 Pu (ref. 16 ), whereas higher-burnup manufacture in thermal spectrum nuclear reactors, might afford an inventory effectively limited to 240 Pu and 241 Pu, generally with a higher proportion of 240 Pu; the decay of 241 Pu affords for the activation of americium products by neutrons and the formation of curium isotopes 17 , also less prominent in contributions from weapons fallout. While the", "role": "user" }, { "content": "Researchers looking at miniscule levels of plutonium pollution in our soils have made a breakthrough which could help inform future 'clean up' operations on land around nuclear power plants, saving time and money. Publishing in the journal Nature Communications, researchers show how they have measured the previously 'unmeasurable' and taken a step forward in differentiating between local and global sources of plutonium pollution in the soil. By identifying the isotopic 'fingerprint' of trace-level quantities of plutonium in the soil which matched the isotopic fingerprint of the plutonium created by an adjacent nuclear reactor, the research team was able to estimate levels of plutonium in the soil which were attributable to reactor pollution and distinguish this from plutonium from general global pollution. This is important to provide key information to those responsible for environmental assessment and clean up. Plutonium formed in the big bang decayed away long ago, but miniscule quantities can be found in the environment as a result of reactions in naturally occurring uranium in the ground, and due to human activity. The latter occur local to their source of production, for example, from nuclear plant effluents, reactor accidents, accidents involving nuclear weapons and plutonium-powered space probes. They also occur globally from fallout from atmospheric nuclear weapon tests which took place between the 1950s and 1980. In the absence of human intervention, the amount of plutonium in the earth varies very slowly with time due to the long half-lives of most plutonium isotopes and relatively slow natural transport mechanisms. The ability to differentiate between local sources of plutonium and global fallout is important to inform decisions concerning nuclear legacies, particularly the clean-up of contaminated land. Given this context, the study set out to determine whether the local contribution to trace plutonium levels on the site of a fast breeder nuclear reactor might be discerned from the global contribution. Using accelerator mass spectrometry (one of the most sensitive ways to measure plutonium), the researchers, from Lancaster University, ETH Zürich, and Dounreay Site Restoration Ltd, were able to demonstrate this was possible and say their research findings could help inform the extent to which clean-up of the local plutonium might be necessary. Professor Malcolm Joyce, of Lancaster University and Principal Investigator, said: \"Plutonium is primordially extinct but that does not mean we don't find it in the earth. Up until 1980 many nuclear weapons were tested in the atmosphere—this coupled with other forms of pollution, has resulted in trace levels of pollution. \"Our study showed we've measured what one might have assumed was 'unmeasureable', differentiating between two very different sources of trace amounts of plutonium, hence demonstrating that it is possible to measure this extraordinarily low-level indicator of human activity if we need to do so.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Trace-level plutonium in the environment often comprises local and global contributions, and is usually anthropogenic in origin. Here, we report estimates of local and global contributions to trace-level plutonium in soil from a former, fast-breeder reactor site. The measured 240 Pu/ 239 Pu ratio is anomalously low, as per the reduced 240 Pu yield expected in plutonium bred with fast neutrons. Anomalies in plutonium concentration and isotopic ratio suggest forensic insight into specific activities on site, such as clean-up or structural change. Local and global 239 Pu contributions on-site are estimated at (34 ± 1)% and (66 ± 3)%, respectively, with mass concentrations of (183 ± 6) fg g −1 and (362 ± 13) fg g −1 . The latter is consistent with levels at undisturbed and distant sites, (384 ± 44) fg g −1 , where no local contribution is expected. The 240 Pu/ 239 Pu ratio for site-derived material is estimated at 0.05 ± 0.04. Our study demonstrates the multi-faceted potential of trace plutonium assay to inform clean-up strategies of fast breeder legacies. Introduction Minute quantities of plutonium occur naturally in the terrestrial environment 1 from neutron capture on 238 U in uranium-rich deposits. Anthropogenic contributions occur local to their source of production, for example, from nuclear plant effluents, reactor accidents, accidents involving nuclear weapons and plutonium-powered space probes etc., and also globally from fallout. Following the measurements Seaborg et al. 1 , 2 of Canadian pitchblende (yielding a 239 Pu mass concentration of 550 fg g −1 ), Krey et al. 3 estimated the 240/239 Pu ratio due to fallout, at 0.176 ± 0.02: this has been used widely for comparison by subsequent studies. Harley 4 suggested a distribution of the oxide from weapons testing of 2 mCi km −2 (~485 fg g −1 assuming deposition in the first 5 cm and a bulk soil density of 1.33 g cm −3 ) in the north temperate zone. The depth-resolved assessment of plutonium residues in Lake Ontario sediments followed, yielding a 240 Pu/ 239 Pu ratio 5 , 6 consistent with Krey et al. Subsequently, Buesseler et al. 7 reported measurements of a dated coral record from the North Pacific of 239 Pu mass (~55 fg g −1 ) and 240/239 Pu ratio (>0.2), the latter reflecting the predominance of fallout in this environment, in agreement with the prior art 3 . Plutonium-239 abundance of the contrasting residues from the Cigar Lake natural ore body (Canada) were reported 8 , resolved with depth, in the range 17–6200 fg g −1 . Kelley et al. 9 reported on the global distribution, including a sample from Wick (Scotland), ~50 km from the site at Dounreay studied in this research, with a 240 Pu/ 239 Pu ratio of 0.182 ± 0.001. Muramatsu et al. published an analysis of samples from the Marshall islands 10 with a 240 Pu/ 239 Pu range of 0.065–0.306 and 239 Pu mass 75–500 fg g −1 . In 2013, Steier et al. 11 reported accelerator mass spectrometry (AMS) measurements of samples from Sellafield (UK) with a 240 Pu/ 239 Pu range of 0.183–0.228 (±0.001) and, in 2015, Armstrong et al. 12 reported a 10-year assessment of samples from Savannah River (USA) with 240 Pu/ 239 Pu range of 0.0757–0.3035. Terrestrial plutonium abundance, albeit deposited over decades, varies slowly with time due to the long half-lives of most plutonium isotopes and relatively slow natural transport mechanisms, in the absence of human intervention. The ability to discern local sources of plutonium from global fallout is important to inform decisions concerning nuclear legacies, particularly the clean-up of contaminated land. As Harley 4 stated, it remains ‘…desirable…to distinguish…local sources from global fallout’ for exactly this reason. Given this context, the motivation for this study is to determine whether the local contribution to trace plutonium abundance on a fast breeder site might be discerned from the global contribution, to inform the extent to which clean-up of the local component might be necessary. In addition to the variation in trace elemental plutonium, the isotopic distribution varies too. Plutonium-239 is the more probable product of activation in reactors relative to the higher-mass plutonium isotopes. Industrially, fissile Pu, in particular 239 Pu, has also been the focus of nuclear reprocessing, mixed-oxide and metal fuel manufacture, and nuclear weapons fabrication operations for ~70 years worldwide, albeit on a localised basis. Of particular relevance to this research is 239 Pu produced by breeding in the mid-to-late 20th century and the legacy of these activities. In comparison with 239 Pu, the higher-mass plutonium isotopes ( 240 Pu, 241 Pu, 242 Pu and 244 Pu) have few specific applications and have not been manufactured on a comparable scale. Since their formation is dependent on the neutron fluence and energy spectrum, estimating the extent to which they are produced can require knowledge of the associated neutron environment, in which they are made. Elemental plutonium concentration in soils is dependent on many factors, in addition to the way in which it was formed, such as geographic location, precipitation and soil composition etc. By contrast, the link between a specific isotope, considered via the isotopic ratio, and its origin often yields a more tangible association 13 , for example: a pre-detonation weapon safety test might cause 239 Pu to dominate; fallout from atmospheric detonations can comprise higher-mass isotopes through to 244 Pu (refs. 14 , 15 ), whereas a relatively low 240 Pu/ 239 Pu ratio might reflect the low proportions of 240 Pu desirable in some applications, such as that obtained by breeding. Material dispersed in fallout will often have a higher proportion of 244 Pu (ref. 16 ), whereas higher-burnup manufacture in thermal spectrum nuclear reactors, might afford an inventory effectively limited to 240 Pu and 241 Pu, generally with a higher proportion of 240 Pu; the decay of 241 Pu affords for the activation of americium products by neutrons and the formation of curium isotopes 17 , also less prominent in contributions from weapons fallout. While the<|im_end|> <|im_start|>assistant Researchers looking at miniscule levels of plutonium pollution in our soils have made a breakthrough which could help inform future 'clean up' operations on land around nuclear power plants, saving time and money. Publishing in the journal Nature Communications, researchers show how they have measured the previously 'unmeasurable' and taken a step forward in differentiating between local and global sources of plutonium pollution in the soil. By identifying the isotopic 'fingerprint' of trace-level quantities of plutonium in the soil which matched the isotopic fingerprint of the plutonium created by an adjacent nuclear reactor, the research team was able to estimate levels of plutonium in the soil which were attributable to reactor pollution and distinguish this from plutonium from general global pollution. This is important to provide key information to those responsible for environmental assessment and clean up. Plutonium formed in the big bang decayed away long ago, but miniscule quantities can be found in the environment as a result of reactions in naturally occurring uranium in the ground, and due to human activity. The latter occur local to their source of production, for example, from nuclear plant effluents, reactor accidents, accidents involving nuclear weapons and plutonium-powered space probes. They also occur globally from fallout from atmospheric nuclear weapon tests which took place between the 1950s and 1980. In the absence of human intervention, the amount of plutonium in the earth varies very slowly with time due to the long half-lives of most plutonium isotopes and relatively slow natural transport mechanisms. The ability to differentiate between local sources of plutonium and global fallout is important to inform decisions concerning nuclear legacies, particularly the clean-up of contaminated land. Given this context, the study set out to determine whether the local contribution to trace plutonium levels on the site of a fast breeder nuclear reactor might be discerned from the global contribution. Using accelerator mass spectrometry (one of the most sensitive ways to measure plutonium), the researchers, from Lancaster University, ETH Zürich, and Dounreay Site Restoration Ltd, were able to demonstrate this was possible and say their research findings could help inform the extent to which clean-up of the local plutonium might be necessary. Professor Malcolm Joyce, of Lancaster University and Principal Investigator, said: "Plutonium is primordially extinct but that does not mean we don't find it in the earth. Up until 1980 many nuclear weapons were tested in the atmosphere—this coupled with other forms of pollution, has resulted in trace levels of pollution. "Our study showed we've measured what one might have assumed was 'unmeasureable', differentiating between two very different sources of trace amounts of plutonium, hence demonstrating that it is possible to measure this extraordinarily low-level indicator of human activity if we need to do so." <|im_end|>

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2,014

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Using the latest sequencing and optical mapping technologies, we have produced a high-quality de novo assembly of the apple ( Malus domestica Borkh.) genome. Repeat sequences, which represented over half of the assembly, provided an unprecedented opportunity to investigate the uncharacterized regions of a tree genome; we identified a new hyper-repetitive retrotransposon sequence that was over-represented in heterochromatic regions and estimated that a major burst of different transposable elements (TEs) occurred 21 million years ago. Notably, the timing of this TE burst coincided with the uplift of the Tian Shan mountains, which is thought to be the center of the location where the apple originated, suggesting that TEs and associated processes may have contributed to the diversification of the apple ancestor and possibly to its divergence from pear. Finally, genome-wide DNA methylation data suggest that epigenetic marks may contribute to agronomically relevant aspects, such as apple fruit development. Main Accurate sequence information, genome assemblies and annotations are the foundation for genetic and genome-wide studies. The major factors that limit de novo genome assembly are heterozygosity and repetitive sequences, such as TEs, which are often collapsed to single copies in draft genomes 1 . In recent years, however, evidence supporting the importance of TEs in genome evolution, genome structure, regulation of gene expression and epigenetics has been mounting 2 , 3 , 4 , 5 . The characterization of sequences and the distribution of TEs within a genome is, therefore, of great importance. Until now, the study of epigenetically controlled characteristics in perennial plants has been hampered by the draft status of their genome sequences. In the case of apple, a draft was produced 6 but remained incomplete with inaccurate contig positions 7 ; this hindered its utility for genetic and epigenetic studies. De novo sequencing and assembly of a new genome for apple, using technologies of the third generation, had thus become a necessity. In the last few years, single-molecule sequencing and optical-mapping technologies have emerged 8 , which are well suited for assembling genomic regions that contain long repetitive elements. Recently, several high-quality genome assemblies have been published using one or both technologies 9 , 10 , 11 , 12 , 13 , 14 . The use of long-read sequencing technologies may also tackle potential assembly issues that are related to the presence of highly similar sequences resulting from whole-genome duplication events that frequently occurred in angiosperm genomes 15 . In addition to DNA sequence modifications, it has been shown that epigenetic variations contribute to genome accessibility, functionality and structure 16 , 17 . Several studies have demonstrated that local DNA methylation variants, which are represented by differential cytosine methylation at particular loci, can have major effects on the transcription of nearby genes and can be inherited over generations 18 , 19 , 20 . Apple, like most other fruit tree crops, is propagated by grafting onto rootstocks, which over time can allow the acquisition and propagation of epimutations, via variation in DNA methylation states that can influence various phenotypes, such as fruit color 21 , 22 . Thus, knowledge of the epigenetic landscape of apple cultivars could provide new tools to study somatic variants, leading to the development of epigenetic markers for marker-assisted selection. To produce a high-quality apple reference genome and methylome, we generated a de novo assembly of a 'Golden Delicious' doubled-haploid tree (GDDH13) composed of 280 assembled scaffolds and arranged into 17 pseudomolecules, which represent the 17 chromosomes of apple. This assembly resulted from a combination of short (Illumina) and long sequencing reads (PacBio), along with scaffolding based on optical maps (BioNano) and a high-density integrated genetic linkage map 23 . This chromosome-scale assembly was complemented by a detailed de novo annotation of genes based on RNA sequencing (RNA-seq) data, TE annotation and small RNA alignments. To understand the potential role of epigenetic marks on fruit development, we constructed genome-wide DNA methylation maps that compared different tissues and two isogenic apple lines that produce large or small fruits. This led to the identification of differential DNA methylation patterns that are associated with genes involved in fruit development. This work provides a solid foundation for future genetic and epigenomic studies in apple. Furthermore, our TE annotation provides novel insights into the evolutionary history of apple and may contribute to explaining its divergence from pear. Results Genome sequencing, assembly and scaffolding The doubled-haploid Golden Delicious line (GDDH13, also coded X9273) used in this study is the result of breeding efforts that were initiated at INRA in 1963 (ref. 24 ) ( Supplementary Fig. 1 and Online Methods ). Homozygosity of this line was confirmed with microsatellite markers that are distributed along the apple genome (data not shown) and by observation of the k-mer spectrum of Illumina reads derived from GDDH13 ( Fig. 1a and Supplementary Note ). Figure 1: Assembly and validation of the GDDH13 doubled-haploid apple genome. ( a ) k-mer (23 bp) spectra of the doubled-haploid GDDH13 and the heterozygous Golden Delicious 33 genomes. The x axis represents k-mer multiplicity, and the y axis represents the number of k-mers with a given multiplicity in the sequencing data. The green dashed line represents the ideal Poisson distribution fitted on the data of GDDH13. ( b ) Overview of the processing pipeline used for the assembly of the GDDH13 genome (see Supplementary Note for details). ( c ) Graphical representation of the location of SNP markers on the physical map ( x axis), as compared to their position on the integrated genetic map ( y axis), for Chr11 of the GDDH13 genome. Each marker is depicted as a circle on the plot (1,069 data points). The colors depict the chromosomes as follows: red for Chr01, light green for Chr04, pink for Chr08, blue for Chr10 and violet for Chr11. ( d ) Graphical representation of the mean local recombination rates between successive SNP markers along Chr11 (3-Mb sliding window, 1-Mb shift, threshold 4). The x axis represents the physical positions of the means on Chr11, and", "role": "user" }, { "content": "A high quality genome sequence of apple is published in this week's Nature Genetics by an international team of scientists, among which researchers of Wageningen University & Research in the Netherlands. The publication of the sequence facilitates faster and more targeted breeding of new apple varieties with increased disease resistance, improved production traits, and better fruit quality. With this the results support a more sustainable production of apple fruit, both from an environmental and a financial perspective. The genome sequence was assembled by an international consortium of research institutions from France, Italy, Germany, the Netherlands and South Africa. The high quality of the genome data, indicating over 42 thousand putative genes, is the result of the use of latest sequencing technologies, which generate long stretches of DNA sequences, a very specific apple variety, and the most informative genetic linkage map in apple developed in earlier research. The genome sequence gives new insights into the organization of the apple genome. Already 93 percent of the 42,000 putative genes have been validated through RNA sequencing. This knowledge is useful for the identification of genes that control a trait of interest and for the development of DNA-based diagnostic tests that can accelerate breeding of new varieties. The use of a so-called di-haploid apple variety was critical for the success of this study. Apple is an outcrossing species, making its genome heterozygous. Also, apple originated from a hybridization between two different species, which was coupled with a whole genome duplication. As a result, each regular apple variety has up to four variants for each of its DNA sequences. The di-haploid variety used in this study is special as it has only up to two variants of every sequence. This leads to a dramatic complexity reduction, which made it possible to generate a very high quality genome sequence. The new insights in the apple genome include a clear view on the duplication patterns among the 17 chromosomes of apple. This facilitates the identification of gene copies with similar function. Next, so called 'repetitive regions' have been assembled. These thus far uncharacterized regions of the apple genome may be involved in regulating gene expression. Finally, a new type of repeat sequence was found that may be specific for centromeres, which may lead to new insights in chromosome division and replication. The research was coordinated by Etienne Bucher of INRA-Angers. Researchers of Wageningen University & Research contributed to the genome sequencing, genome mapping and assembly, applying their experience and skills in bioinformatics and by giving early access to a high quality reference genetic linkage map in apple. Wageningen University & Research itself develops new apple varieties, which resulted in the top-variety 'Elstar', 'Santana' and the recently released 'Natyra'. The latter two are suited for biological production since these varieties have disease resistances. Additionally, 'Santana' is suitable for consumption by most individuals with a mild apple allergy. Wageningen will use the new insights in the DNA of the apple in the targeted breeding of new varieties. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Using the latest sequencing and optical mapping technologies, we have produced a high-quality de novo assembly of the apple ( Malus domestica Borkh.) genome. Repeat sequences, which represented over half of the assembly, provided an unprecedented opportunity to investigate the uncharacterized regions of a tree genome; we identified a new hyper-repetitive retrotransposon sequence that was over-represented in heterochromatic regions and estimated that a major burst of different transposable elements (TEs) occurred 21 million years ago. Notably, the timing of this TE burst coincided with the uplift of the Tian Shan mountains, which is thought to be the center of the location where the apple originated, suggesting that TEs and associated processes may have contributed to the diversification of the apple ancestor and possibly to its divergence from pear. Finally, genome-wide DNA methylation data suggest that epigenetic marks may contribute to agronomically relevant aspects, such as apple fruit development. Main Accurate sequence information, genome assemblies and annotations are the foundation for genetic and genome-wide studies. The major factors that limit de novo genome assembly are heterozygosity and repetitive sequences, such as TEs, which are often collapsed to single copies in draft genomes 1 . In recent years, however, evidence supporting the importance of TEs in genome evolution, genome structure, regulation of gene expression and epigenetics has been mounting 2 , 3 , 4 , 5 . The characterization of sequences and the distribution of TEs within a genome is, therefore, of great importance. Until now, the study of epigenetically controlled characteristics in perennial plants has been hampered by the draft status of their genome sequences. In the case of apple, a draft was produced 6 but remained incomplete with inaccurate contig positions 7 ; this hindered its utility for genetic and epigenetic studies. De novo sequencing and assembly of a new genome for apple, using technologies of the third generation, had thus become a necessity. In the last few years, single-molecule sequencing and optical-mapping technologies have emerged 8 , which are well suited for assembling genomic regions that contain long repetitive elements. Recently, several high-quality genome assemblies have been published using one or both technologies 9 , 10 , 11 , 12 , 13 , 14 . The use of long-read sequencing technologies may also tackle potential assembly issues that are related to the presence of highly similar sequences resulting from whole-genome duplication events that frequently occurred in angiosperm genomes 15 . In addition to DNA sequence modifications, it has been shown that epigenetic variations contribute to genome accessibility, functionality and structure 16 , 17 . Several studies have demonstrated that local DNA methylation variants, which are represented by differential cytosine methylation at particular loci, can have major effects on the transcription of nearby genes and can be inherited over generations 18 , 19 , 20 . Apple, like most other fruit tree crops, is propagated by grafting onto rootstocks, which over time can allow the acquisition and propagation of epimutations, via variation in DNA methylation states that can influence various phenotypes, such as fruit color 21 , 22 . Thus, knowledge of the epigenetic landscape of apple cultivars could provide new tools to study somatic variants, leading to the development of epigenetic markers for marker-assisted selection. To produce a high-quality apple reference genome and methylome, we generated a de novo assembly of a 'Golden Delicious' doubled-haploid tree (GDDH13) composed of 280 assembled scaffolds and arranged into 17 pseudomolecules, which represent the 17 chromosomes of apple. This assembly resulted from a combination of short (Illumina) and long sequencing reads (PacBio), along with scaffolding based on optical maps (BioNano) and a high-density integrated genetic linkage map 23 . This chromosome-scale assembly was complemented by a detailed de novo annotation of genes based on RNA sequencing (RNA-seq) data, TE annotation and small RNA alignments. To understand the potential role of epigenetic marks on fruit development, we constructed genome-wide DNA methylation maps that compared different tissues and two isogenic apple lines that produce large or small fruits. This led to the identification of differential DNA methylation patterns that are associated with genes involved in fruit development. This work provides a solid foundation for future genetic and epigenomic studies in apple. Furthermore, our TE annotation provides novel insights into the evolutionary history of apple and may contribute to explaining its divergence from pear. Results Genome sequencing, assembly and scaffolding The doubled-haploid Golden Delicious line (GDDH13, also coded X9273) used in this study is the result of breeding efforts that were initiated at INRA in 1963 (ref. 24 ) ( Supplementary Fig. 1 and Online Methods ). Homozygosity of this line was confirmed with microsatellite markers that are distributed along the apple genome (data not shown) and by observation of the k-mer spectrum of Illumina reads derived from GDDH13 ( Fig. 1a and Supplementary Note ). Figure 1: Assembly and validation of the GDDH13 doubled-haploid apple genome. ( a ) k-mer (23 bp) spectra of the doubled-haploid GDDH13 and the heterozygous Golden Delicious 33 genomes. The x axis represents k-mer multiplicity, and the y axis represents the number of k-mers with a given multiplicity in the sequencing data. The green dashed line represents the ideal Poisson distribution fitted on the data of GDDH13. ( b ) Overview of the processing pipeline used for the assembly of the GDDH13 genome (see Supplementary Note for details). ( c ) Graphical representation of the location of SNP markers on the physical map ( x axis), as compared to their position on the integrated genetic map ( y axis), for Chr11 of the GDDH13 genome. Each marker is depicted as a circle on the plot (1,069 data points). The colors depict the chromosomes as follows: red for Chr01, light green for Chr04, pink for Chr08, blue for Chr10 and violet for Chr11. ( d ) Graphical representation of the mean local recombination rates between successive SNP markers along Chr11 (3-Mb sliding window, 1-Mb shift, threshold 4). The x axis represents the physical positions of the means on Chr11, and<|im_end|> <|im_start|>assistant A high quality genome sequence of apple is published in this week's Nature Genetics by an international team of scientists, among which researchers of Wageningen University & Research in the Netherlands. The publication of the sequence facilitates faster and more targeted breeding of new apple varieties with increased disease resistance, improved production traits, and better fruit quality. With this the results support a more sustainable production of apple fruit, both from an environmental and a financial perspective. The genome sequence was assembled by an international consortium of research institutions from France, Italy, Germany, the Netherlands and South Africa. The high quality of the genome data, indicating over 42 thousand putative genes, is the result of the use of latest sequencing technologies, which generate long stretches of DNA sequences, a very specific apple variety, and the most informative genetic linkage map in apple developed in earlier research. The genome sequence gives new insights into the organization of the apple genome. Already 93 percent of the 42,000 putative genes have been validated through RNA sequencing. This knowledge is useful for the identification of genes that control a trait of interest and for the development of DNA-based diagnostic tests that can accelerate breeding of new varieties. The use of a so-called di-haploid apple variety was critical for the success of this study. Apple is an outcrossing species, making its genome heterozygous. Also, apple originated from a hybridization between two different species, which was coupled with a whole genome duplication. As a result, each regular apple variety has up to four variants for each of its DNA sequences. The di-haploid variety used in this study is special as it has only up to two variants of every sequence. This leads to a dramatic complexity reduction, which made it possible to generate a very high quality genome sequence. The new insights in the apple genome include a clear view on the duplication patterns among the 17 chromosomes of apple. This facilitates the identification of gene copies with similar function. Next, so called 'repetitive regions' have been assembled. These thus far uncharacterized regions of the apple genome may be involved in regulating gene expression. Finally, a new type of repeat sequence was found that may be specific for centromeres, which may lead to new insights in chromosome division and replication. The research was coordinated by Etienne Bucher of INRA-Angers. Researchers of Wageningen University & Research contributed to the genome sequencing, genome mapping and assembly, applying their experience and skills in bioinformatics and by giving early access to a high quality reference genetic linkage map in apple. Wageningen University & Research itself develops new apple varieties, which resulted in the top-variety 'Elstar', 'Santana' and the recently released 'Natyra'. The latter two are suited for biological production since these varieties have disease resistances. Additionally, 'Santana' is suitable for consumption by most individuals with a mild apple allergy. Wageningen will use the new insights in the DNA of the apple in the targeted breeding of new varieties. <|im_end|>

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1,975

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Glaciers calving icebergs into the ocean significantly contribute to sea-level rise and can trigger tsunamis, posing severe hazards for coastal regions. Computational modeling of such multiphase processes is a great challenge involving complex solid–fluid interactions. Here, a new continuum damage Material Point Method has been developed to model dynamic glacier fracture under the combined effects of gravity and buoyancy, as well as the subsequent propagation of tsunami-like waves induced by released icebergs. We reproduce the main features of tsunamis obtained in laboratory experiments as well as calving characteristics, the iceberg size, tsunami amplitude and wave speed measured at Eqip Sermia, an ocean-terminating outlet glacier of the Greenland ice sheet. Our hybrid approach constitutes important progress towards the modeling of solid–fluid interactions, and has the potential to contribute to refining empirical calving laws used in large-scale earth-system models as well as to improve hazard assessments and mitigation measures in coastal regions, which is essential in the context of climate change. Introduction Glacier calving into the ocean (Fig. 1 ) is predicted to be one of the largest contributions to sea-level rise in the future 1 , 2 , 3 . This process corresponds to ~50% of the mass loss from ice sheets in Greenland and Antarctica 4 , 5 . Glacier calving is caused by first, second, and third-order processes. First-order processes correspond to the formation of surface crevasses in the ice owing to spatial variation in flow velocity. Second and third-order processes include crack propagation owing to local stress concentrations, ice stretching in the vicinity of the ice front, and oceanic erosion and torque induced by buoyant forces 6 , 7 . Depending on the shape of the glacier outlet, this may lead to different calving scenarios 8 . Glacier calving can have dramatic consequences, as falling or capsizing icebergs can generate large tsunamis, which are a threat to coastal infrastructure, ecology, and people 9 , 10 , 11 , 12 , 13 , 14 , 15 . In high mountain proglacial lakes, calving-induced waves may further pose major hazards through triggering lake outburst floods with high destructive potential in downstream valleys 16 . Fig. 1: Calving event triggering a large tsunami. Kongsfjorden, Svalbard. [MB Photography]/[Moment] via Getty Images. Full size image Most existing numerical approaches for marine-terminating glaciers were developed to study the slow creep of ice using continuum Eulerian methods (e.g., Elmer/Ice 17 ), and the calving rate is generally evaluated using simplified and empirically based calving laws or simple analytic models 18 . In general, the validation of these models against observations remains relatively limited 19 and mostly excludes temporal scales of single calving events. Åström et al. 5 , 20 and Bassis and Jacobs 21 developed purely Lagrangian particle-based models, based on a discrete version of Newton’s equations of motion, to study the dynamics of sea ice and glacier calving. Despite several approximations, including a simplified water–ice interaction law, their simulations were able to reproduce the fractal nature of the debris size distribution 20 and diverse calving features based on glacier geometry 21 . However, the discrete nature of these models makes them computationally very expensive and therefore limited to single events. Furthermore, the water in their simulation is not explicitly modeled, which prevents the study of the tsunamigenic potential of glacier calving. More recently, Mercenier et al. 22 , 23 developed a transient multiphysics finite element model to simulate the effect of oceanic melt on ice break-off at the terminus of a marine glacier. They showed that a von Mises stress criterion led to realistic calving front geometries. Although this model successfully couples slow glacier flow with a damage-based calving criterion, it cannot simulate tsunamis induced by calving. Tsunamis generated by landslides were extensively studied 24 , 25 . Yet, only a few studies focused on tsunamis induced by calving glaciers. Lüthi and Vieli 10 reported a 45–50 m tsunami generated by the calving of a 200 m high ice cliff of the calving front of the Eqip Sermia glacier in Greenland. The wave was still 3.3 m large 4.5 km from the calving outlet and led to a 20 m run-up on the opposite shore. Recently, Heller et al. 13 performed large-scale laboratory experiments to study the characteristics of waves generated by different calving mechanisms. These authors showed that empirical equations established for landslides-induced tsunamis 25 overestimated wave amplitudes and generally fail to reproduce the physics of calving-induced tsunamis. Recently, Chen et al. 26 were able to reproduce the characteristics of waves reported in Heller et al. 13 using foam-extend and the Immersed Boundary Method. Yet, an approach to simulate fracture processes during dynamic glacier calving and tsunamis in a unified manner is still missing. Here, we report coupled glacier calving and tsunami experiments and develop a continuum damage Material Point Method (MPM) to explicitly simulate ice fracture and hydraulic interactions. This new model accurately reproduces dynamic ice fractures and generated tsunami characteristics for different calving mechanisms for laboratory and real-world scales. Results Ice and water mechanics To model the dynamic fracture of the glacier ice, we developed a non-associative elastoplastic model based on the Cohesive Cam Clay (CCC) yield surface used by Gaume et al. 27 to simulate snow and avalanche mechanics. A mixed-mode yield surface such as this was shown to adequately model brittle ice fracture based on experimental data 28 . However, the previously chosen associative flow rule was only adequate owing to the porous nature of snow, allowing for volume change (compaction hardening). Conversely, in the case of a significantly less-porous material such as ice, choosing a non-associative flow rule 29 is key owing to its natural volume-preserving qualities 30 . As such, we adopt a non-associative flow rule 31 coupled with a softening law to model the dynamic ice fracture. The mechanical behavior of water is simulated using a nearly incompressible equation of state 32 . The mass and momentum balance equations are solved numerically using the MPM 27 , 33 (see Methods for a complete model description).", "role": "user" }, { "content": "A team of scientists has developed a new model for simulating both iceberg calving and the tsunamis that are triggered as a result. Their method can help improve hazard assessment in coastal areas and refine the empirical calving models used to evaluate rising sea levels. Johan Gaume, an EPFL expert in avalanches and geomechanics, has turned his attention to ice. His goal is to better understand the correlation between the size of an iceberg and the amplitude of the tsunami that results from its calving. Gaume, along with a team of scientists from other research institutes, has just unveiled a new method for modeling these events. Their work appears in Communications Earth & Environment. These scientists are the first to simulate the phenomena of both glacier fracture and wave formation when the iceberg falls into the water. \"Our goal was to model the explicit interaction between water and ice—but that has a substantial cost in terms of computing time. We therefore decided to use a continuum model, which is very powerful numerically and which gives results that are both conclusive and consistent with much of the experimental data,\" says Gaume, who heads EPFL's Snow Avalanche Simulation Laboratory (SLAB) and is the study's corresponding author. The other institutes involved in the study are the University of Pennsylvania, the University of Zurich, the University of Nottingham, and Switzerland's WSL Institute for Snow and Avalanche Research. Improving calving laws The scientists' method can also provide insight into the specific mechanisms involved in glacial rupture. \"Researchers can use the results of our simulations to refine the calving laws incorporated into their large-scale models for predicting sea-level rises, while providing detailed information about the size of icebergs, which represent a sizeable amount of mass loss,\" says Gaume. Calving occurs when chunks of ice on the edge of a glacier break off and fall into the sea. The mechanisms behind the rupture generally depend on how high the water is. If the water level is low, the iceberg breaks off from the top of the glacier. If the water level is high, the iceberg is longer and breaks off from the bottom, before eventually floating to the surface owing to buoyancy. These different mechanisms create icebergs of different sizes—and therefore waves of different amplitudes. \"Another event that can trigger a tsunami is when an iceberg's center of gravity changes, causing the iceberg itself to rotate,\" says Gaume. \"We were able to simulate all these processes.\" In Greenland, the scientists placed a series of sensors at Eqip Sermia, a 3-km-wide outlet glacier of the Greenland ice sheet that ends in a fjord with a 200 m ice cliff. Back in 2014, an iceberg measuring some 1 million m3 (the equivalent of 300 Olympic-sized swimming pools) broke off the front of the glacier and produced a 50 m-high tsunami; the wave was still 3 m high when it reached the first populated shoreline some 4 km away. The scientists tested their modeling method on large-scale field datasets from Eqip Sermia as well as with empirical data on tsunami waves obtained in a laboratory basin at the Deltares institute in the Netherlands. Projects in the pipeline Glacier melting has become a major focus area of research today as a result of global warming. One of the University of Zurich scientists involved in the study kicked off a new research project this year with funding from the Swiss National Science Foundation. This project will investigate the dynamics of Greenland's fastest-moving glacier, Jakobshavn Isbrae, by combining data from individual field experiments in Greenland with the results of simulations run using the SLAB model. \"Our method will also be used to model chains of complex processes triggered by gravitational mass movements, such as the interaction between a rock avalanche and a mountain lake,\" says Gaume. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Glaciers calving icebergs into the ocean significantly contribute to sea-level rise and can trigger tsunamis, posing severe hazards for coastal regions. Computational modeling of such multiphase processes is a great challenge involving complex solid–fluid interactions. Here, a new continuum damage Material Point Method has been developed to model dynamic glacier fracture under the combined effects of gravity and buoyancy, as well as the subsequent propagation of tsunami-like waves induced by released icebergs. We reproduce the main features of tsunamis obtained in laboratory experiments as well as calving characteristics, the iceberg size, tsunami amplitude and wave speed measured at Eqip Sermia, an ocean-terminating outlet glacier of the Greenland ice sheet. Our hybrid approach constitutes important progress towards the modeling of solid–fluid interactions, and has the potential to contribute to refining empirical calving laws used in large-scale earth-system models as well as to improve hazard assessments and mitigation measures in coastal regions, which is essential in the context of climate change. Introduction Glacier calving into the ocean (Fig. 1 ) is predicted to be one of the largest contributions to sea-level rise in the future 1 , 2 , 3 . This process corresponds to ~50% of the mass loss from ice sheets in Greenland and Antarctica 4 , 5 . Glacier calving is caused by first, second, and third-order processes. First-order processes correspond to the formation of surface crevasses in the ice owing to spatial variation in flow velocity. Second and third-order processes include crack propagation owing to local stress concentrations, ice stretching in the vicinity of the ice front, and oceanic erosion and torque induced by buoyant forces 6 , 7 . Depending on the shape of the glacier outlet, this may lead to different calving scenarios 8 . Glacier calving can have dramatic consequences, as falling or capsizing icebergs can generate large tsunamis, which are a threat to coastal infrastructure, ecology, and people 9 , 10 , 11 , 12 , 13 , 14 , 15 . In high mountain proglacial lakes, calving-induced waves may further pose major hazards through triggering lake outburst floods with high destructive potential in downstream valleys 16 . Fig. 1: Calving event triggering a large tsunami. Kongsfjorden, Svalbard. [MB Photography]/[Moment] via Getty Images. Full size image Most existing numerical approaches for marine-terminating glaciers were developed to study the slow creep of ice using continuum Eulerian methods (e.g., Elmer/Ice 17 ), and the calving rate is generally evaluated using simplified and empirically based calving laws or simple analytic models 18 . In general, the validation of these models against observations remains relatively limited 19 and mostly excludes temporal scales of single calving events. Åström et al. 5 , 20 and Bassis and Jacobs 21 developed purely Lagrangian particle-based models, based on a discrete version of Newton’s equations of motion, to study the dynamics of sea ice and glacier calving. Despite several approximations, including a simplified water–ice interaction law, their simulations were able to reproduce the fractal nature of the debris size distribution 20 and diverse calving features based on glacier geometry 21 . However, the discrete nature of these models makes them computationally very expensive and therefore limited to single events. Furthermore, the water in their simulation is not explicitly modeled, which prevents the study of the tsunamigenic potential of glacier calving. More recently, Mercenier et al. 22 , 23 developed a transient multiphysics finite element model to simulate the effect of oceanic melt on ice break-off at the terminus of a marine glacier. They showed that a von Mises stress criterion led to realistic calving front geometries. Although this model successfully couples slow glacier flow with a damage-based calving criterion, it cannot simulate tsunamis induced by calving. Tsunamis generated by landslides were extensively studied 24 , 25 . Yet, only a few studies focused on tsunamis induced by calving glaciers. Lüthi and Vieli 10 reported a 45–50 m tsunami generated by the calving of a 200 m high ice cliff of the calving front of the Eqip Sermia glacier in Greenland. The wave was still 3.3 m large 4.5 km from the calving outlet and led to a 20 m run-up on the opposite shore. Recently, Heller et al. 13 performed large-scale laboratory experiments to study the characteristics of waves generated by different calving mechanisms. These authors showed that empirical equations established for landslides-induced tsunamis 25 overestimated wave amplitudes and generally fail to reproduce the physics of calving-induced tsunamis. Recently, Chen et al. 26 were able to reproduce the characteristics of waves reported in Heller et al. 13 using foam-extend and the Immersed Boundary Method. Yet, an approach to simulate fracture processes during dynamic glacier calving and tsunamis in a unified manner is still missing. Here, we report coupled glacier calving and tsunami experiments and develop a continuum damage Material Point Method (MPM) to explicitly simulate ice fracture and hydraulic interactions. This new model accurately reproduces dynamic ice fractures and generated tsunami characteristics for different calving mechanisms for laboratory and real-world scales. Results Ice and water mechanics To model the dynamic fracture of the glacier ice, we developed a non-associative elastoplastic model based on the Cohesive Cam Clay (CCC) yield surface used by Gaume et al. 27 to simulate snow and avalanche mechanics. A mixed-mode yield surface such as this was shown to adequately model brittle ice fracture based on experimental data 28 . However, the previously chosen associative flow rule was only adequate owing to the porous nature of snow, allowing for volume change (compaction hardening). Conversely, in the case of a significantly less-porous material such as ice, choosing a non-associative flow rule 29 is key owing to its natural volume-preserving qualities 30 . As such, we adopt a non-associative flow rule 31 coupled with a softening law to model the dynamic ice fracture. The mechanical behavior of water is simulated using a nearly incompressible equation of state 32 . The mass and momentum balance equations are solved numerically using the MPM 27 , 33 (see Methods for a complete model description).<|im_end|> <|im_start|>assistant A team of scientists has developed a new model for simulating both iceberg calving and the tsunamis that are triggered as a result. Their method can help improve hazard assessment in coastal areas and refine the empirical calving models used to evaluate rising sea levels. Johan Gaume, an EPFL expert in avalanches and geomechanics, has turned his attention to ice. His goal is to better understand the correlation between the size of an iceberg and the amplitude of the tsunami that results from its calving. Gaume, along with a team of scientists from other research institutes, has just unveiled a new method for modeling these events. Their work appears in Communications Earth & Environment. These scientists are the first to simulate the phenomena of both glacier fracture and wave formation when the iceberg falls into the water. "Our goal was to model the explicit interaction between water and ice—but that has a substantial cost in terms of computing time. We therefore decided to use a continuum model, which is very powerful numerically and which gives results that are both conclusive and consistent with much of the experimental data," says Gaume, who heads EPFL's Snow Avalanche Simulation Laboratory (SLAB) and is the study's corresponding author. The other institutes involved in the study are the University of Pennsylvania, the University of Zurich, the University of Nottingham, and Switzerland's WSL Institute for Snow and Avalanche Research. Improving calving laws The scientists' method can also provide insight into the specific mechanisms involved in glacial rupture. "Researchers can use the results of our simulations to refine the calving laws incorporated into their large-scale models for predicting sea-level rises, while providing detailed information about the size of icebergs, which represent a sizeable amount of mass loss," says Gaume. Calving occurs when chunks of ice on the edge of a glacier break off and fall into the sea. The mechanisms behind the rupture generally depend on how high the water is. If the water level is low, the iceberg breaks off from the top of the glacier. If the water level is high, the iceberg is longer and breaks off from the bottom, before eventually floating to the surface owing to buoyancy. These different mechanisms create icebergs of different sizes—and therefore waves of different amplitudes. "Another event that can trigger a tsunami is when an iceberg's center of gravity changes, causing the iceberg itself to rotate," says Gaume. "We were able to simulate all these processes." In Greenland, the scientists placed a series of sensors at Eqip Sermia, a 3-km-wide outlet glacier of the Greenland ice sheet that ends in a fjord with a 200 m ice cliff. Back in 2014, an iceberg measuring some 1 million m3 (the equivalent of 300 Olympic-sized swimming pools) broke off the front of the glacier and produced a 50 m-high tsunami; the wave was still 3 m high when it reached the first populated shoreline some 4 km away. The scientists tested their modeling method on large-scale field datasets from Eqip Sermia as well as with empirical data on tsunami waves obtained in a laboratory basin at the Deltares institute in the Netherlands. Projects in the pipeline Glacier melting has become a major focus area of research today as a result of global warming. One of the University of Zurich scientists involved in the study kicked off a new research project this year with funding from the Swiss National Science Foundation. This project will investigate the dynamics of Greenland's fastest-moving glacier, Jakobshavn Isbrae, by combining data from individual field experiments in Greenland with the results of simulations run using the SLAB model. "Our method will also be used to model chains of complex processes triggered by gravitational mass movements, such as the interaction between a rock avalanche and a mountain lake," says Gaume. <|im_end|>

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11, 1193, 264, 2478, 7978, 10968, 389, 10814, 359, 309, 285, 36572, 555, 1652, 4504, 95790, 13, 445, 2448, 339, 72, 323, 11655, 12574, 220, 605, 5068, 264, 220, 1774, 4235, 1135, 296, 72155, 8066, 555, 279, 1652, 4504, 315, 264, 220, 1049, 296, 1579, 10054, 44106, 315, 279, 1652, 4504, 4156, 315, 279, 34222, 575, 328, 4289, 689, 94867, 304, 73778, 13, 578, 12330, 574, 2103, 220, 18, 13, 18, 296, 3544, 220, 19, 13, 20, 13437, 505, 279, 1652, 4504, 27487, 323, 6197, 311, 264, 220, 508, 296, 1629, 5352, 389, 279, 14329, 31284, 13, 42096, 11, 93893, 1880, 453, 13, 220, 1032, 10887, 3544, 13230, 27692, 21896, 311, 4007, 279, 17910, 315, 17301, 8066, 555, 2204, 1652, 4504, 24717, 13, 4314, 12283, 8710, 430, 46763, 39006, 9749, 369, 12098, 75, 3422, 38973, 10814, 359, 309, 285, 220, 914, 927, 45329, 12330, 1097, 2344, 29246, 323, 8965, 3775, 311, 23645, 279, 22027, 315, 1652, 4504, 38973, 10814, 359, 309, 285, 13, 42096, 11, 25507, 1880, 453, 13, 220, 1627, 1051, 3025, 311, 23645, 279, 17910, 315, 17301, 5068, 304, 93893, 1880, 453, 13, 220, 1032, 1701, 32183, 12, 26103, 323, 279, 15695, 41019, 77516, 6872, 13, 14968, 11, 459, 5603, 311, 38553, 59904, 11618, 2391, 8915, 94867, 1652, 4504, 323, 10814, 359, 309, 285, 304, 264, 43790, 11827, 374, 2103, 7554, 13, 5810, 11, 584, 1934, 34356, 94867, 1652, 4504, 323, 72155, 21896, 323, 2274, 264, 86901, 5674, 10441, 5236, 6872, 320, 5901, 44, 8, 311, 21650, 38553, 10054, 59904, 323, 44175, 22639, 13, 1115, 502, 1646, 30357, 14843, 1634, 8915, 10054, 78332, 323, 8066, 72155, 17910, 369, 2204, 1652, 4504, 24717, 369, 27692, 323, 1972, 31184, 29505, 13, 18591, 20534, 323, 3090, 30126, 2057, 1646, 279, 8915, 59904, 315, 279, 94867, 10054, 11, 584, 8040, 264, 2536, 12, 25304, 1413, 92185, 454, 52279, 1646, 3196, 389, 279, 84675, 288, 535, 8215, 32501, 320, 54973, 8, 7692, 7479, 1511, 555, 18879, 3972, 1880, 453, 13, 220, 1544, 311, 38553, 12056, 323, 96694, 30126, 13, 362, 9709, 15331, 7692, 7479, 1778, 439, 420, 574, 6982, 311, 49672, 1646, 95749, 10054, 59904, 3196, 389, 22772, 828, 220, 1591, 662, 4452, 11, 279, 8767, 12146, 70003, 6530, 6037, 574, 1193, 26613, 56612, 311, 279, 94761, 7138, 315, 12056, 11, 10923, 369, 8286, 2349, 320, 5807, 1335, 2653, 6147, 570, 82671, 11, 304, 279, 1162, 315, 264, 12207, 2753, 2320, 20857, 3769, 1778, 439, 10054, 11, 19301, 264, 2536, 12, 25304, 1413, 6530, 6037, 220, 1682, 374, 1401, 56612, 311, 1202, 5933, 8286, 80876, 20073, 29600, 220, 966, 662, 1666, 1778, 11, 584, 11142, 264, 2536, 12, 25304, 1413, 6530, 6037, 220, 2148, 34356, 449, 264, 8579, 6147, 2383, 311, 1646, 279, 8915, 10054, 59904, 13, 578, 22936, 7865, 315, 3090, 374, 46836, 1701, 264, 7154, 304, 39460, 1260, 24524, 315, 1614, 220, 843, 662, 578, 3148, 323, 24151, 8335, 39006, 527, 29056, 8015, 2740, 1701, 279, 386, 8971, 220, 1544, 1174, 220, 1644, 320, 4151, 19331, 369, 264, 4686, 1646, 4096, 570, 128257, 198, 128256, 78191, 198, 32, 2128, 315, 14248, 706, 8040, 264, 502, 1646, 369, 1675, 15853, 2225, 89135, 1652, 4504, 323, 279, 10814, 359, 309, 285, 430, 527, 22900, 439, 264, 1121, 13, 11205, 1749, 649, 1520, 7417, 31397, 15813, 304, 35335, 5789, 323, 46464, 279, 46763, 1652, 4504, 4211, 1511, 311, 15806, 16448, 9581, 5990, 13, 89907, 18879, 3972, 11, 459, 19613, 6254, 6335, 304, 41635, 83281, 323, 3980, 638, 5776, 1233, 11, 706, 6656, 813, 6666, 311, 10054, 13, 5414, 5915, 374, 311, 2731, 3619, 279, 26670, 1990, 279, 1404, 315, 459, 89135, 323, 279, 45209, 315, 279, 72155, 430, 3135, 505, 1202, 1652, 4504, 13, 18879, 3972, 11, 3235, 449, 264, 2128, 315, 14248, 505, 1023, 3495, 94812, 11, 706, 1120, 39297, 264, 502, 1749, 369, 34579, 1521, 4455, 13, 11205, 990, 8111, 304, 26545, 9420, 612, 11847, 13, 4314, 14248, 527, 279, 1176, 311, 38553, 279, 44247, 315, 2225, 94867, 59904, 323, 12330, 18488, 994, 279, 89135, 17503, 1139, 279, 3090, 13, 330, 8140, 5915, 574, 311, 1646, 279, 11720, 16628, 1990, 3090, 323, 10054, 38542, 430, 706, 264, 12190, 2853, 304, 3878, 315, 25213, 892, 13, 1226, 9093, 6773, 311, 1005, 264, 86901, 1646, 11, 902, 374, 1633, 8147, 8015, 2740, 323, 902, 6835, 3135, 430, 527, 2225, 98586, 323, 13263, 449, 1790, 315, 279, 22772, 828, 1359, 2795, 18879, 3972, 11, 889, 14971, 19613, 6254, 596, 19435, 99807, 44220, 32184, 320, 8143, 1905, 8, 323, 374, 279, 4007, 596, 12435, 3229, 13, 578, 1023, 94812, 6532, 304, 279, 4007, 527, 279, 3907, 315, 20355, 11, 279, 3907, 315, 72826, 11, 279, 3907, 315, 67659, 11, 323, 30221, 596, 468, 8143, 10181, 369, 19435, 323, 99807, 8483, 13, 22728, 4504, 1652, 4504, 7016, 578, 14248, 6, 1749, 649, 1101, 3493, 20616, 1139, 279, 3230, 24717, 6532, 304, 2840, 33211, 89869, 13, 330, 60210, 649, 1005, 279, 3135, 315, 1057, 47590, 311, 46464, 279, 1652, 4504, 7016, 32762, 1139, 872, 3544, 13230, 4211, 369, 52997, 9581, 11852, 38268, 11, 1418, 8405, 11944, 2038, 922, 279, 1404, 315, 10054, 655, 5981, 11, 902, 4097, 264, 1404, 481, 3392, 315, 3148, 4814, 1359, 2795, 18879, 3972, 13, 3400, 4504, 13980, 994, 27855, 315, 10054, 389, 279, 6964, 315, 264, 94867, 1464, 1022, 323, 4498, 1139, 279, 9581, 13, 578, 24717, 4920, 279, 89869, 8965, 6904, 389, 1268, 1579, 279, 3090, 374, 13, 1442, 279, 3090, 2237, 374, 3428, 11, 279, 89135, 18808, 1022, 505, 279, 1948, 315, 279, 94867, 13, 1442, 279, 3090, 2237, 374, 1579, 11, 279, 89135, 374, 5129, 323, 18808, 1022, 505, 279, 5740, 11, 1603, 9778, 19596, 311, 279, 7479, 56612, 311, 75720, 6709, 13, 4314, 2204, 24717, 1893, 10054, 655, 5981, 315, 2204, 12562, 17223, 9093, 17301, 315, 2204, 1097, 2344, 29246, 13, 330, 14364, 1567, 430, 649, 8346, 264, 72155, 374, 994, 459, 89135, 596, 4219, 315, 24128, 4442, 11, 14718, 279, 89135, 5196, 311, 17348, 1359, 2795, 18879, 3972, 13, 330, 1687, 1051, 3025, 311, 38553, 682, 1521, 11618, 1210, 763, 73778, 11, 279, 14248, 9277, 264, 4101, 315, 26148, 520, 34222, 575, 328, 4289, 689, 11, 264, 220, 18, 12934, 76, 25480, 27487, 94867, 315, 279, 73778, 10054, 11071, 430, 10548, 304, 264, 76471, 541, 449, 264, 220, 1049, 296, 10054, 44106, 13, 6984, 304, 220, 679, 19, 11, 459, 89135, 30090, 1063, 220, 16, 3610, 296, 18, 320, 1820, 13890, 315, 220, 3101, 25944, 28935, 24269, 34239, 8, 14760, 1022, 279, 4156, 315, 279, 94867, 323, 9124, 264, 220, 1135, 296, 28661, 72155, 26, 279, 12330, 574, 2103, 220, 18, 296, 1579, 994, 433, 8813, 279, 1176, 35459, 99164, 1063, 220, 19, 13437, 3201, 13, 578, 14248, 12793, 872, 34579, 1749, 389, 3544, 13230, 2115, 30525, 505, 34222, 575, 328, 4289, 689, 439, 1664, 439, 449, 46763, 828, 389, 72155, 17301, 12457, 304, 264, 27692, 58309, 520, 279, 26002, 417, 44798, 304, 279, 26746, 13, 32323, 304, 279, 15660, 96486, 50684, 706, 3719, 264, 3682, 5357, 3158, 315, 3495, 3432, 439, 264, 1121, 315, 3728, 24808, 13, 3861, 315, 279, 3907, 315, 72826, 14248, 6532, 304, 279, 4007, 28219, 1022, 264, 502, 3495, 2447, 420, 1060, 449, 11006, 505, 279, 30791, 5165, 10170, 5114, 13, 1115, 2447, 690, 19874, 279, 30295, 315, 73778, 596, 26731, 86572, 94867, 11, 35934, 677, 939, 31697, 2209, 14720, 68, 11, 555, 35271, 828, 505, 3927, 2115, 21896, 304, 73778, 449, 279, 3135, 315, 47590, 1629, 1701, 279, 17216, 1905, 1646, 13, 330, 8140, 1749, 690, 1101, 387, 1511, 311, 1646, 27271, 315, 6485, 11618, 22900, 555, 71019, 3148, 19567, 11, 1778, 439, 279, 16628, 1990, 264, 7091, 96694, 323, 264, 16700, 22553, 1359, 2795, 18879, 3972, 13, 220, 128257, 198 ]

2,143

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Microfluidic chips can generate emulsions, which can be used to synthesize polymer microparticles that have superior pharmacological performance compared to particles prepared by conventional techniques. However, low production rates of microfluidics remains a challenge to successfully translate laboratory discoveries to commercial manufacturing. We present a silicon and glass device that incorporates an array of 10,260 (285 × 36) microfluidic droplet generators that uses only a single set of inlets and outlets, increasing throughput by >10,000× compared to microfluidics with a single generator. Our design breaks the tradeoff between the number of generators and the maximum throughput of individual generators by incorporating high aspect ratio flow resistors. We test these design strategies by generating hexadecane microdroplets at >1 trillion droplets per h with a coefficient of variation CV <3%. To demonstrate the synthesis of biocompatible microparticles, we generated 8–16 µm polycaprolactone particles with a CV <5% at a rate of 277 g h −1 . Introduction In 1959, Richard Feynman famously proposed the use of micrometer- and nanometer-scale particles for medicine, as well as the creation of enormous numbers of microfabricated “factories” to generate large quantities of these engineered materials 1 . In the last two decades, significant progress has been made toward accomplishing this vision. In particular, microfluidics has been used to enable precise control of multiphasic flows to generate micrometer- and nanometer-scale materials with control and uniformity not possible using conventional techniques 2 , 3 , 4 , 5 , 6 . These micro- and nano-engineered materials have generated particular enthusiasm in the pharmaceutical industry, as well as the food and cosmetics industries, where they have created new opportunities to generate novel drug formulations that offer unprecedented spatial and temporal control of drug delivery within the body 7 , 8 , 9 . In comparison to conventional particle formation techniques, such as spray drying or ball milling 10 , microfluidic-generated formulations have demonstrated increased particle monodispersity, more uniform composition of drug within the particles, increased drug yield, longer lasting formulations that are still injectable, and reduced burst release of drug 2 , 6 , 11 . The low production rate of microfluidic devices for the generation of microparticles (<10 mL h −1 for the dispersed phase, <100 mg h −1 of particles) has remained a key challenge to successfully translate the many promising laboratory-scale results of microfluidics to commercial-scale production of microfluidic-generated materials. In previous work, architectures have been developed that make it possible to operate many microfluidic droplet generators in parallel 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . While great progress has been made in these approaches, current chips with parallelized devices are limited to production rates ϕ max ⪍ 1 L h −1 , have droplet homogeneities set by three-dimensional (3D) soft-lithography fabrication 15 , are limited to low temperature and pressure operation, can only be used with the solvents compatible with the device’s polymer construction, or are unable to be adapted to produce higher-order emulsions and particles that require multi-step processing 23 , 24 , 25 . To address these challenges, we present the all silicon and glass very large scale droplet integration (VLSDI), in which we incorporate an array of 10,260 (285 × 36) microfluidic droplet generators onto a 3D-etched single silicon wafer that is operated using only a single set of inlets and outlets. The monolithic construction from a single silicon wafer obviates the alignment and bonding challenges of prior multilayer approaches and allows high pressure use. To demonstrate the power of this approach, we generate polycaprolactone (PCL) solid microparticles, a biodegradable material approved by the United States Food and Drug Administration (US FDA), with a coefficient of variation CV <5%, and an emulsion production rate that results in 277 g h −1 particle production (2.09 L h −1 dispersed phase, 328 billion particles per h). Key to achieving this throughput lies in a design strategy that breaks the tradeoff between the number of integrated droplet generators N max and the maximum throughput of each droplet generator ϕ i max . Our design includes a high aspect ratio flow resistor into each droplet generator, which decouples the design of the individual droplet generator from the high fluidic resistance requirement necessary for parallelization. Moreover, because of the VLSDI’s all silicon and glass construction, it can operate at high pressure ( P max > 1000 PSI (pounds per square inch)) and high temperature ( T max > 500 °C), use solvents prevalent in the pharmaceutical industry but that are incompatible with polymer devices, and achieve a uniformity not possible using soft-lithography based devices (CV <3%). Because of the VLSDI’s 3D fabrication strategy, it can be scaled to the 10,000 droplet generators that we demonstrate in this study and beyond using conventional semiconductor fabrication, in contrast to prior approaches that have used either two-dimensional microfluidic or two-dimensional microfluidics attached to macroscopically defined manifolds. Because our device allows arbitrary microfluidic droplet generators to be parallelized, it can produce higher-order emulsions and particles that require multi-step processing. Results Very large scale droplet integration fabrication We fabricate the VLSDI using a single microfabricated 500 µm thick 4″ Si wafer encapsulated in glass, resulting in a robust, monolithic construction.(Supplementary Fig. 2 for step by step fabrication) (Fig. 1a, b ) This design enables the production of highly monodispersed PCL solid microparticles (CV <5%), >1000× faster than previously reported parallelized microfluidic approaches (Fig. 1c, d ). Fig. 1 All silicon and glass VLSDI for high-throughput microparticle production. a A photograph of the VLSDI chip, which consists of 10,260 (285 × 36) flow-focusing droplet generators (FFGs). b An optical micrograph of two individual droplet generators producing droplets. Scale bar: 140 µm. c Organic phase in water emulsion (3.5 L) generated from VLSDI in 30 min on a chip operated at a dispersed flow rate Φ d = 2.09 L h −1 (10 wt% polycaprolactone in dichloromethane) and a continuous flow rate Φ c = 5", "role": "user" }, { "content": "Pharmaceuticals owe their effects mostly to their chemical composition, but the packaging of these drugs into specific physical formulations also need to be done to exact specifications. For example, many drugs are encapsulated in solid microparticles, the size and shape of which determine the timing of the drug's release and its delivery to specific parts of the body. When engineering these drug microparticles, consistency is key, but common drug manufacturing techniques, such as spray drying and ball milling, produce uneven results. The ideal method involves microfluidics, a kind of liquid assembly line that drips out perfectly sized microparticles, one at a time. University of Pennsylvania engineers have now developed a microfluidic system where more than ten thousand of these devices run in parallel, all on a silicon-and-glass chip that can fit into a shirt pocket. Scaling up microfluidic systems has been a major challenge, as they depend on a tightly controlled flow rates to produce particles of a consistent size. The Penn team's innovation is new fluidic architecture, built with the technology used to manufacture computer chips, resulting in a system that can manufacture these drug particles a thousand times faster than ever before. The team, led by David Issadore, assistant professor in the School of Engineering and Applied Science's Department of Bioengineering, and Sagar Yadavali, a postdoctoral researcher in his lab, outlined the design of their system in the journal Nature Communications. Daeyeon Lee, professor in the Department of Chemical and Biomolecular Engineering, and Heon-Ho Jeong, then graduate student in his lab, contributed to the study. The Penn team is currently testing their system with David Lai, a research investigator at GlaxoSmithKline. Current pharmaceutical microparticle manufacturing techniques involve spraying them in liquid form from a nozzle and letting them dry, or milling larger solid particles down in a tumbler. However, since the microparticles are being made en masse, there can be significant variations in their size and shape. Extended-release drugs rely on microparticles of consistent size and shape so they dissolve at a predictable rate. University of Pennsylvania engineers have now developed a microfluidic system where more than ten thousand microparticle generators run in parallel, making more than 300 billion an hour, all on a silicon-and-glass chip that can fit into a shirt pocket. Credit: University of Pennsylvania \"These manufacturing problems mean that an enormous amount of time and money is spent on size reductions,\" Yadavali said. \"That leads to higher costs.\" Microfluidics provides a potential solution to these problems. By synthesizing the drugs in a network of microscopic channels and chambers, surface tension and drag forces can be finely tuned to generate particles of a consistent size and shape. However, there are intrinsic limitations to how fast these microscale devices can work. \"The bottleneck for increasing the throughput of microfluidics is a fundamental physics problem,\" Issadore said. \"We cannot run the individual microfluidic devices faster than any other lab, because the microfluidic phenomenon that enables the drug microparticles to be precisely fabricated stops working above a critical flow rate?—?they go from making bubbles to making unstable jets.\" Typical flow rates are a milliliter-per-hour, far too slow to be of use in an industrial setting. Since increasing the flow rate is not an option, the only way to scale up production is to increase the number of devices. Previous attempts at large-scale parallelization struggled with another trade-off. In order to distribute flow evenly to all of the devices on the chip, each individual device must have a large pressure drop across it relative to the pressure drop along the delivery channels that feed it. This results in each device running slower than they would if they were fed individually. The Penn researchers solved this problem by separating the devices into two, one component that provides the required pressure drop and another downstream that makes the particles. This allows many devices to be incorporated in parallel without having an effect on the throughput of each one. \"By incorporating high-aspect-ratio flow resistors upstream of each device,\" Yadavali said, \"we can decouple individual droplet design from the system-level design. which allows us to incorporate any type of microfluidic particle generator we want, and as many as we can fit onto a chip.\" Using lithography to simultaneously etch 10,260 devices into a four-inch silicon wafer, sandwiching it between two glass plates to make hollow channels, and hooking up its single sets of inlets and outlets, the Penn team's system produces an effective flow rate than is more than ten thousand times faster than what can be typically achieved in a microfluidic device. Credit: University of Pennsylvania Using lithography to simultaneously etch 10,260 devices into a four-inch silicon wafer, sandwiching it between two glass plates to make hollow channels, and hooking up its single sets of inlets and outlets, the Penn team's system produces an effective flow rate than is more than ten thousand times faster than what can be typically achieved in a microfluidic device. The Penn team first tested their system by making simple oil-in-water droplets, at a rate of more than 1 trillion droplets per hour. To demonstrate it with materials more relevant to drug manufacturing, they also made biocompatible microparticles out of polycaprolactone, at a rate of about 328 billion particles per hour. \"Drugs can be mixed into polycaprolactone microparticles, so that controlled amounts of drug can be gradually released as the particle dissolves,\" Sagar said. \"The rate that the drug leaves the particle is dependent on the particle size, which is why having a consistent size is so important.\" The researchers only mixed the polycaprolactone with water; testing on a real drug would have been prohibitively expensive given their system's rate of production. \"We at GSK are delighted to be part of a research collaboration with Daeyeon and David's research groups. Congratulations on an exquisite and impactful publication,\" said Lai. The researcher's microfluidic system is currently capable of this kind of simple drug packaging, but other, more complicated manufacturing techniques are possible. \"We are now working to implement additional microfluidic operations onto our chip, including miniaturized versions of solvent extraction, crystallization, and other traditional chemical engineering processes,\" Issadore said. \"By bringing more of the operations necessary to formulate the drug onto our chip, precise 'designer' microparticle drug formulations can be produced at an industrial scale.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Microfluidic chips can generate emulsions, which can be used to synthesize polymer microparticles that have superior pharmacological performance compared to particles prepared by conventional techniques. However, low production rates of microfluidics remains a challenge to successfully translate laboratory discoveries to commercial manufacturing. We present a silicon and glass device that incorporates an array of 10,260 (285 × 36) microfluidic droplet generators that uses only a single set of inlets and outlets, increasing throughput by >10,000× compared to microfluidics with a single generator. Our design breaks the tradeoff between the number of generators and the maximum throughput of individual generators by incorporating high aspect ratio flow resistors. We test these design strategies by generating hexadecane microdroplets at >1 trillion droplets per h with a coefficient of variation CV <3%. To demonstrate the synthesis of biocompatible microparticles, we generated 8–16 µm polycaprolactone particles with a CV <5% at a rate of 277 g h −1 . Introduction In 1959, Richard Feynman famously proposed the use of micrometer- and nanometer-scale particles for medicine, as well as the creation of enormous numbers of microfabricated “factories” to generate large quantities of these engineered materials 1 . In the last two decades, significant progress has been made toward accomplishing this vision. In particular, microfluidics has been used to enable precise control of multiphasic flows to generate micrometer- and nanometer-scale materials with control and uniformity not possible using conventional techniques 2 , 3 , 4 , 5 , 6 . These micro- and nano-engineered materials have generated particular enthusiasm in the pharmaceutical industry, as well as the food and cosmetics industries, where they have created new opportunities to generate novel drug formulations that offer unprecedented spatial and temporal control of drug delivery within the body 7 , 8 , 9 . In comparison to conventional particle formation techniques, such as spray drying or ball milling 10 , microfluidic-generated formulations have demonstrated increased particle monodispersity, more uniform composition of drug within the particles, increased drug yield, longer lasting formulations that are still injectable, and reduced burst release of drug 2 , 6 , 11 . The low production rate of microfluidic devices for the generation of microparticles (<10 mL h −1 for the dispersed phase, <100 mg h −1 of particles) has remained a key challenge to successfully translate the many promising laboratory-scale results of microfluidics to commercial-scale production of microfluidic-generated materials. In previous work, architectures have been developed that make it possible to operate many microfluidic droplet generators in parallel 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . While great progress has been made in these approaches, current chips with parallelized devices are limited to production rates ϕ max ⪍ 1 L h −1 , have droplet homogeneities set by three-dimensional (3D) soft-lithography fabrication 15 , are limited to low temperature and pressure operation, can only be used with the solvents compatible with the device’s polymer construction, or are unable to be adapted to produce higher-order emulsions and particles that require multi-step processing 23 , 24 , 25 . To address these challenges, we present the all silicon and glass very large scale droplet integration (VLSDI), in which we incorporate an array of 10,260 (285 × 36) microfluidic droplet generators onto a 3D-etched single silicon wafer that is operated using only a single set of inlets and outlets. The monolithic construction from a single silicon wafer obviates the alignment and bonding challenges of prior multilayer approaches and allows high pressure use. To demonstrate the power of this approach, we generate polycaprolactone (PCL) solid microparticles, a biodegradable material approved by the United States Food and Drug Administration (US FDA), with a coefficient of variation CV <5%, and an emulsion production rate that results in 277 g h −1 particle production (2.09 L h −1 dispersed phase, 328 billion particles per h). Key to achieving this throughput lies in a design strategy that breaks the tradeoff between the number of integrated droplet generators N max and the maximum throughput of each droplet generator ϕ i max . Our design includes a high aspect ratio flow resistor into each droplet generator, which decouples the design of the individual droplet generator from the high fluidic resistance requirement necessary for parallelization. Moreover, because of the VLSDI’s all silicon and glass construction, it can operate at high pressure ( P max > 1000 PSI (pounds per square inch)) and high temperature ( T max > 500 °C), use solvents prevalent in the pharmaceutical industry but that are incompatible with polymer devices, and achieve a uniformity not possible using soft-lithography based devices (CV <3%). Because of the VLSDI’s 3D fabrication strategy, it can be scaled to the 10,000 droplet generators that we demonstrate in this study and beyond using conventional semiconductor fabrication, in contrast to prior approaches that have used either two-dimensional microfluidic or two-dimensional microfluidics attached to macroscopically defined manifolds. Because our device allows arbitrary microfluidic droplet generators to be parallelized, it can produce higher-order emulsions and particles that require multi-step processing. Results Very large scale droplet integration fabrication We fabricate the VLSDI using a single microfabricated 500 µm thick 4″ Si wafer encapsulated in glass, resulting in a robust, monolithic construction.(Supplementary Fig. 2 for step by step fabrication) (Fig. 1a, b ) This design enables the production of highly monodispersed PCL solid microparticles (CV <5%), >1000× faster than previously reported parallelized microfluidic approaches (Fig. 1c, d ). Fig. 1 All silicon and glass VLSDI for high-throughput microparticle production. a A photograph of the VLSDI chip, which consists of 10,260 (285 × 36) flow-focusing droplet generators (FFGs). b An optical micrograph of two individual droplet generators producing droplets. Scale bar: 140 µm. c Organic phase in water emulsion (3.5 L) generated from VLSDI in 30 min on a chip operated at a dispersed flow rate Φ d = 2.09 L h −1 (10 wt% polycaprolactone in dichloromethane) and a continuous flow rate Φ c = 5<|im_end|> <|im_start|>assistant Pharmaceuticals owe their effects mostly to their chemical composition, but the packaging of these drugs into specific physical formulations also need to be done to exact specifications. For example, many drugs are encapsulated in solid microparticles, the size and shape of which determine the timing of the drug's release and its delivery to specific parts of the body. When engineering these drug microparticles, consistency is key, but common drug manufacturing techniques, such as spray drying and ball milling, produce uneven results. The ideal method involves microfluidics, a kind of liquid assembly line that drips out perfectly sized microparticles, one at a time. University of Pennsylvania engineers have now developed a microfluidic system where more than ten thousand of these devices run in parallel, all on a silicon-and-glass chip that can fit into a shirt pocket. Scaling up microfluidic systems has been a major challenge, as they depend on a tightly controlled flow rates to produce particles of a consistent size. The Penn team's innovation is new fluidic architecture, built with the technology used to manufacture computer chips, resulting in a system that can manufacture these drug particles a thousand times faster than ever before. The team, led by David Issadore, assistant professor in the School of Engineering and Applied Science's Department of Bioengineering, and Sagar Yadavali, a postdoctoral researcher in his lab, outlined the design of their system in the journal Nature Communications. Daeyeon Lee, professor in the Department of Chemical and Biomolecular Engineering, and Heon-Ho Jeong, then graduate student in his lab, contributed to the study. The Penn team is currently testing their system with David Lai, a research investigator at GlaxoSmithKline. Current pharmaceutical microparticle manufacturing techniques involve spraying them in liquid form from a nozzle and letting them dry, or milling larger solid particles down in a tumbler. However, since the microparticles are being made en masse, there can be significant variations in their size and shape. Extended-release drugs rely on microparticles of consistent size and shape so they dissolve at a predictable rate. University of Pennsylvania engineers have now developed a microfluidic system where more than ten thousand microparticle generators run in parallel, making more than 300 billion an hour, all on a silicon-and-glass chip that can fit into a shirt pocket. Credit: University of Pennsylvania "These manufacturing problems mean that an enormous amount of time and money is spent on size reductions," Yadavali said. "That leads to higher costs." Microfluidics provides a potential solution to these problems. By synthesizing the drugs in a network of microscopic channels and chambers, surface tension and drag forces can be finely tuned to generate particles of a consistent size and shape. However, there are intrinsic limitations to how fast these microscale devices can work. "The bottleneck for increasing the throughput of microfluidics is a fundamental physics problem," Issadore said. "We cannot run the individual microfluidic devices faster than any other lab, because the microfluidic phenomenon that enables the drug microparticles to be precisely fabricated stops working above a critical flow rate?—?they go from making bubbles to making unstable jets." Typical flow rates are a milliliter-per-hour, far too slow to be of use in an industrial setting. Since increasing the flow rate is not an option, the only way to scale up production is to increase the number of devices. Previous attempts at large-scale parallelization struggled with another trade-off. In order to distribute flow evenly to all of the devices on the chip, each individual device must have a large pressure drop across it relative to the pressure drop along the delivery channels that feed it. This results in each device running slower than they would if they were fed individually. The Penn researchers solved this problem by separating the devices into two, one component that provides the required pressure drop and another downstream that makes the particles. This allows many devices to be incorporated in parallel without having an effect on the throughput of each one. "By incorporating high-aspect-ratio flow resistors upstream of each device," Yadavali said, "we can decouple individual droplet design from the system-level design. which allows us to incorporate any type of microfluidic particle generator we want, and as many as we can fit onto a chip." Using lithography to simultaneously etch 10,260 devices into a four-inch silicon wafer, sandwiching it between two glass plates to make hollow channels, and hooking up its single sets of inlets and outlets, the Penn team's system produces an effective flow rate than is more than ten thousand times faster than what can be typically achieved in a microfluidic device. Credit: University of Pennsylvania Using lithography to simultaneously etch 10,260 devices into a four-inch silicon wafer, sandwiching it between two glass plates to make hollow channels, and hooking up its single sets of inlets and outlets, the Penn team's system produces an effective flow rate than is more than ten thousand times faster than what can be typically achieved in a microfluidic device. The Penn team first tested their system by making simple oil-in-water droplets, at a rate of more than 1 trillion droplets per hour. To demonstrate it with materials more relevant to drug manufacturing, they also made biocompatible microparticles out of polycaprolactone, at a rate of about 328 billion particles per hour. "Drugs can be mixed into polycaprolactone microparticles, so that controlled amounts of drug can be gradually released as the particle dissolves," Sagar said. "The rate that the drug leaves the particle is dependent on the particle size, which is why having a consistent size is so important." The researchers only mixed the polycaprolactone with water; testing on a real drug would have been prohibitively expensive given their system's rate of production. "We at GSK are delighted to be part of a research collaboration with Daeyeon and David's research groups. Congratulations on an exquisite and impactful publication," said Lai. The researcher's microfluidic system is currently capable of this kind of simple drug packaging, but other, more complicated manufacturing techniques are possible. "We are now working to implement additional microfluidic operations onto our chip, including miniaturized versions of solvent extraction, crystallization, and other traditional chemical engineering processes," Issadore said. "By bringing more of the operations necessary to formulate the drug onto our chip, precise 'designer' microparticle drug formulations can be produced at an industrial scale." <|im_end|>

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1002, 3880, 6400, 6530, 22884, 1105, 42830, 315, 1855, 3756, 1359, 86083, 402, 8115, 1071, 11, 330, 906, 649, 1654, 85489, 3927, 7118, 11053, 2955, 505, 279, 1887, 11852, 2955, 13, 902, 6276, 603, 311, 33435, 904, 955, 315, 8162, 67125, 292, 19320, 14143, 584, 1390, 11, 323, 439, 1690, 439, 584, 649, 5052, 8800, 264, 16797, 1210, 12362, 46282, 5814, 311, 25291, 1880, 331, 220, 605, 11, 11387, 7766, 1139, 264, 3116, 25224, 51692, 10667, 809, 11, 28974, 287, 433, 1990, 1403, 9168, 25485, 311, 1304, 42902, 12006, 11, 323, 9903, 287, 709, 1202, 3254, 7437, 315, 304, 10145, 323, 28183, 11, 279, 13813, 2128, 596, 1887, 19159, 459, 7524, 6530, 4478, 1109, 374, 810, 1109, 5899, 16579, 3115, 10819, 1109, 1148, 649, 387, 11383, 17427, 304, 264, 8162, 67125, 292, 3756, 13, 16666, 25, 3907, 315, 20355, 12362, 46282, 5814, 311, 25291, 1880, 331, 220, 605, 11, 11387, 7766, 1139, 264, 3116, 25224, 51692, 10667, 809, 11, 28974, 287, 433, 1990, 1403, 9168, 25485, 311, 1304, 42902, 12006, 11, 323, 9903, 287, 709, 1202, 3254, 7437, 315, 304, 10145, 323, 28183, 11, 279, 13813, 2128, 596, 1887, 19159, 459, 7524, 6530, 4478, 1109, 374, 810, 1109, 5899, 16579, 3115, 10819, 1109, 1148, 649, 387, 11383, 17427, 304, 264, 8162, 67125, 292, 3756, 13, 578, 13813, 2128, 1176, 12793, 872, 1887, 555, 3339, 4382, 5707, 3502, 55051, 7118, 90592, 11, 520, 264, 4478, 315, 810, 1109, 220, 16, 32610, 7118, 90592, 824, 6596, 13, 2057, 20461, 433, 449, 7384, 810, 9959, 311, 5623, 15266, 11, 814, 1101, 1903, 6160, 12255, 38179, 19748, 897, 16641, 704, 315, 1499, 3418, 391, 1098, 533, 606, 11, 520, 264, 4478, 315, 922, 220, 16884, 7239, 19252, 824, 6596, 13, 330, 9023, 13602, 649, 387, 9709, 1139, 1499, 3418, 391, 1098, 533, 606, 19748, 897, 16641, 11, 779, 430, 14400, 15055, 315, 5623, 649, 387, 27115, 6004, 439, 279, 19320, 14091, 18685, 1359, 328, 38812, 1071, 13, 330, 791, 4478, 430, 279, 5623, 11141, 279, 19320, 374, 18222, 389, 279, 19320, 1404, 11, 902, 374, 3249, 3515, 264, 13263, 1404, 374, 779, 3062, 1210, 578, 12074, 1193, 9709, 279, 1499, 3418, 391, 1098, 533, 606, 449, 3090, 26, 7649, 389, 264, 1972, 5623, 1053, 617, 1027, 48486, 3210, 11646, 2728, 872, 1887, 596, 4478, 315, 5788, 13, 330, 1687, 520, 480, 16074, 527, 35072, 311, 387, 961, 315, 264, 3495, 20632, 449, 14569, 19494, 263, 323, 6941, 596, 3495, 5315, 13, 71641, 389, 459, 59708, 323, 98990, 17009, 1359, 1071, 445, 2192, 13, 578, 32185, 596, 8162, 67125, 292, 1887, 374, 5131, 13171, 315, 420, 3169, 315, 4382, 5623, 24066, 11, 719, 1023, 11, 810, 17395, 15266, 12823, 527, 3284, 13, 330, 1687, 527, 1457, 3318, 311, 4305, 5217, 8162, 67125, 292, 7677, 8800, 1057, 16797, 11, 2737, 13726, 2693, 1534, 11028, 315, 69996, 33289, 11, 64568, 2065, 11, 323, 1023, 8776, 11742, 15009, 11618, 1359, 16314, 329, 461, 1071, 13, 330, 1383, 12967, 810, 315, 279, 7677, 5995, 311, 89959, 279, 5623, 8800, 1057, 16797, 11, 24473, 364, 25894, 261, 6, 19748, 897, 7203, 5623, 98077, 649, 387, 9124, 520, 459, 13076, 5569, 1210, 220, 128257, 198 ]

2,791

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The origin of the supermassive black holes that inhabit the centres of massive galaxies remains unclear 1 , 2 . Direct-collapse black holes—remnants of supermassive stars, with masses around 10,000 times that of the Sun—are ideal seed candidates 3 , 4 , 5 , 6 . However, their very existence and their formation environment in the early Universe are still under debate, and their supposed rarity makes modelling their formation difficult 7 , 8 . Models have shown that rapid collapse of pre-galactic gas (with a mass infall rate above some critical value) in metal-free haloes is a requirement for the formation of a protostellar core that will then form a supermassive star 9 , 10 . Here we report a radiation hydrodynamics simulation of early galaxy formation 11 , 12 that produces metal-free haloes massive enough and with sufficiently high mass infall rates to form supermassive stars. We find that pre-galactic haloes and their associated gas clouds that are exposed to a Lyman–Werner intensity roughly three times the intensity of the background radiation and that undergo at least one period of rapid mass growth early in their evolution are ideal environments for the formation of supermassive stars. The rapid growth induces substantial dynamical heating 13 , 14 , amplifying the Lyman–Werner suppression that originates from a group of young galaxies 20 kiloparsecs away. Our results strongly indicate that the dynamics of structure formation, rather than a critical Lyman–Werner flux, is the main driver of the formation of massive black holes in the early Universe. We find that the seeds of massive black holes may be much more common than previously considered in overdense regions of the early Universe, with a co-moving number density up to 10 −3 per cubic megaparsec. Main Standard cold dark-matter cosmologies predict that large-scale structure forms hierarchically. Smaller objects that form at early times subsequently merge and grow into larger objects. The existence of supermassive black holes 15 , 16 with masses of around 10 9 M ʘ (where M ʘ is the solar mass) only 800 Myr after the Big Bang indicates that there must have been an early intense convergence of mass in ‘rare’ locations, occurring only roughly ten times per co-moving cubic gigaparsec. We performed cosmological radiation hydrodynamics simulations (Renaissance simulations; see Methods ) using the code Enzo 17 to elucidate the formation of the first generation of stars and galaxies in the Universe 11 , 12 . The simulations include models for the formation of massive metal-free (population III) stars and subsequently of metal-enriched stars similar to those found in the Galaxy. We follow the effects of the ionizing radiation of these stars 18 and of supernova explosions on their environments as galaxies first assemble, both of which are important in regulating early galaxy formation. Motivated by the possible early formation of supermassive stars (SMSs), we analyse the region from the Renaissance simulation suite that is centred on the densest cosmological co-moving volume (133.6 Mpc 3 ), which contains 822 galaxies at its ending redshift of z = 15 (270 Myr after the Big Bang). We identify candidate SMS host haloes by searching the simulation for metal-free atomic-cooling haloes without prior star formation at z = 15. We place no constraints on the level of Lyman–Werner flux impacting the haloes. There are 670 atomic-cooling haloes, ten of which are metal-free and have not hosted prior star formation (Extended Data Table 1 ). The remaining atomic-cooling haloes have formed stars prompted by either H 2 or metal-line cooling and are not conducive to the formation of SMSs (and subsequently direct-collapse black holes, DCBHs). Out of these ten haloes, we concentrate on two—the most massive halo (MMH) and the halo exposed to the most Lyman–Werner radiation flux (LWH). We resample the mass distributions of these two haloes at z = 20 and at a mass resolution higher by a factor of 169, and re-simulate them to study their gravitational collapse in more detail. Both haloes assemble in a region 10–25 kpc away from a group of young galaxies that have photo-ionized, photo-heated and chemically enriched the surrounding environments (Fig. 1 ). At z = 18, the young galaxies near the MMH (Fig. 1a–d ) have created an amorphous H ii region with a maximum extent of 20 kpc. As the star-formation rates grow in these young (massive) galaxies, the Lyman–Werner intensities increase from J LW ≈ 1 J 21 at z = 18 within 5 physical kpc of the galaxies to J LW ≈ 30 J 21 at z = 15, where J 21 is the intensity of the background radiation in units of 10 −21 erg cm −2 s −1 Hz −1 sr −1 . The only other source of Lyman–Werner radiation comes from four nearby haloes that host population III stars, 3–5 kpc from the LWH. Both target haloes are impacted by a Lyman–Werner intensity of J LW ≈ 3 J 21 at z = 15 (Fig. 1d, h ). This flux is 6 to 600 times lower than previous estimates for the critical Lyman–Werner flux necessary for SMS formation 19 , 20 , 21 . Fig. 1: Thermal and chemical evolution of the immediate pre-galactic environment. a – h , Projections of the temperature (orange), metallicity (blue; Z ʘ is the metallicity of the Sun) and gas density (black) of a region 40 kpc across and with a depth of 8 kpc centred on the MMH ( a–d ) and the LWH ( e–h ). The MMH and LWH are indicated by arrows. The heated and metal-enriched volumes around early galaxies and population III stars grow from z = 18 to z = 15 (62 Myr). The dotted, dash-dotted, dashed and solid contours indicate where the average Lyman–Werner flux is 1 J 21 , 3 J 21 , 10 J 21 and 30 J 21 . Both candidate haloes, which host the formation of massive black holes, have 3 J 21 , are just outside of the cosmological H", "role": "user" }, { "content": "The light released from around the first massive black holes in the universe is so intense that it is able to reach telescopes across the entire expanse of the universe. Incredibly, the light from the most distant black holes (or quasars) has been traveling to us for more than 13 billion light years. However, we do not know how these monster black holes formed. New research led by researchers from Georgia Institute of Technology, Dublin City University, Michigan State University, the University of California at San Diego, the San Diego Supercomputer Center and IBM, provides a new and extremely promising avenue for solving this cosmic riddle. The team showed that when galaxies assemble extremely rapidly—and sometimes violently—that can lead to the formation of very massive black holes. In these rare galaxies, normal star formation is disrupted and black hole formation takes over. The new study finds that massive black holes form in dense starless regions that are growing rapidly, turning upside down the long-accepted belief that massive black hole formation was limited to regions bombarded by the powerful radiation of nearby galaxies. Conclusions of the study, reported on January 23rd in the journal Nature and supported by funding from the National Science Foundation, the European Union and NASA, also finds that massive black holes are much more common in the universe than previously thought. The key criteria for determining where massive black holes formed during the universe's infancy relates to the rapid growth of pre-galactic gas clouds that are the forerunners of all present-day galaxies, meaning that most supermassive black holes have a common origin forming in this newly discovered scenario, said John Wise, an associate professor in the Center for Relativistic Astrophysics at Georgia Tech and the paper's corresponding author. Dark matter collapses into halos that are the gravitational glue for all galaxies. Early rapid growth of these halos prevented the formation of stars that would have competed with black holes for gaseous matter flowing into the area. \"In this study, we have uncovered a totally new mechanism that sparks the formation of massive black holes in particular dark matter halos,\" Wise said. \"Instead of just considering radiation, we need to look at how quickly the halos grow. We don't need that much physics to understand it—just how the dark matter is distributed and how gravity will affect that. Forming a massive black hole requires being in a rare region with an intense convergence of matter.\" When the research team found these black hole formation sites in the simulation, they were at first stumped, said John Regan, research fellow in the Centre for Astrophysics and Relativity in Dublin City University. The previously accepted paradigm was that massive black holes could only form when exposed to high levels of nearby radiation. This two-part visualization by the Advanced Visualization Lab at the National Center for Supercomputing Applications starts shortly after the Big Bang, and shows the evolution of the first galaxies in the universe over the first 400 million years, in increments of about 4 million years. The second part of the visualization stops time at the 400 million year mark, and flies the viewer through the data, breaking down the different variables that are being visualized - filaments of dense gas, pockets of elevated temperature, ionized gas, and ultraviolet light. Credit: Advanced Visualization Lab at the National Center for Supercomputing Applications \"Previous theories suggested this should only happen when the sites were exposed to high levels of star-formation killing radiation,\" he said. \"As we delved deeper, we saw that these sites were undergoing a period of extremely rapid growth. That was the key. The violent and turbulent nature of the rapid assembly, the violent crashing together of the galaxy's foundations during the galaxy's birth prevented normal star formation and led to perfect conditions for black hole formation instead. This research shifts the previous paradigm and opens up a whole new area of research.\" The earlier theory relied on intense ultraviolet radiation from a nearby galaxy to inhibit the formation of stars in the black hole-forming halo, said Michael Norman, director of the San Diego Supercomputer Center at UC San Diego and one of the work's authors. \"While UV radiation is still a factor, our work has shown that it is not the dominant factor, at least in our simulations,\" he explained. The research was based on the Renaissance Simulation suite, a 70-terabyte data set created on the Blue Waters supercomputer between 2011 and 2014 to help scientists understand how the universe evolved during its early years. To learn more about specific regions where massive black holes were likely to develop, the researchers examined the simulation data and found ten specific dark matter halos that should have formed stars given their masses but only contained a dense gas cloud. Using the Stampede2 supercomputer, they then re-simulated two of those halos—each about 2,400 light-years across—at much higher resolution to understand details of what was happening in them 270 million years after the Big Bang. \"It was only in these overly-dense regions of the universe that we saw these black holes forming,\" Wise said. \"The dark matter creates most of the gravity, and then the gas falls into that gravitational potential, where it can form stars or a massive black hole.\" The Renaissance Simulations are the most comprehensive simulations of the earliest stages of the gravitational assembly of the pristine gas composed of hydrogen and helium and cold dark matter leading to the formation of the first stars and galaxies. They use a technique known as adaptive mesh refinement to zoom in on dense clumps forming stars or black holes. In addition, they cover a large enough region of the early universe to form thousands of objects—a requirement if one is interested in rare objects, as is the case here. \"The high resolution, rich physics and large sample of collapsing halos were all needed to achieve this result,\" said Norman. The improved resolution of the simulation done for two candidate regions allowed the scientists to see turbulence and the inflow of gas and clumps of matter forming as the black hole precursors began to condense and spin. Their growth rate was dramatic. Zoom of the inner 30 light-years of the dark matter halo. The rotating gaseous disk breaks apart into three clumps that collapse under their own gravity to form supermassive stars. Credit: John Wise, Georgia Institute of Technology \"Astronomers observe supermassive black holes that have grown to a billion solar masses in 800 million years,\" Wise said. \"Doing that required an intense convergence of mass in that region. You would expect that in regions where galaxies were forming at very early times.\" Another aspect of the research is that the halos that give birth to black holes may be more common than previously believed. \"An exciting component of this work is the discovery that these types of halos, though rare, may be common enough,\" said Brian O'Shea, a professor at Michigan State University. \"We predict that this scenario would happen enough to be the origin of the most massive black holes that are observed, both early in the universe and in galaxies at the present day.\" Future work with these simulations will look at the lifecycle of these massive black hole formation galaxies, studying the formation, growth and evolution of the first massive black holes across time. \"Our next goal is to probe the further evolution of these exotic objects. Where are these black holes today? Can we detect evidence of them in the local universe or with gravitational waves?\" Regan asked. For these new answers, the research team—and others—may return to the simulations. \"The Renaissance Simulations are sufficiently rich that other discoveries can be made using data already computed,\" said Norman. \"For this reason we have created a public archive at SDSC containing called the Renaissance Simulations Laboratory where others can pursue questions of their own.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The origin of the supermassive black holes that inhabit the centres of massive galaxies remains unclear 1 , 2 . Direct-collapse black holes—remnants of supermassive stars, with masses around 10,000 times that of the Sun—are ideal seed candidates 3 , 4 , 5 , 6 . However, their very existence and their formation environment in the early Universe are still under debate, and their supposed rarity makes modelling their formation difficult 7 , 8 . Models have shown that rapid collapse of pre-galactic gas (with a mass infall rate above some critical value) in metal-free haloes is a requirement for the formation of a protostellar core that will then form a supermassive star 9 , 10 . Here we report a radiation hydrodynamics simulation of early galaxy formation 11 , 12 that produces metal-free haloes massive enough and with sufficiently high mass infall rates to form supermassive stars. We find that pre-galactic haloes and their associated gas clouds that are exposed to a Lyman–Werner intensity roughly three times the intensity of the background radiation and that undergo at least one period of rapid mass growth early in their evolution are ideal environments for the formation of supermassive stars. The rapid growth induces substantial dynamical heating 13 , 14 , amplifying the Lyman–Werner suppression that originates from a group of young galaxies 20 kiloparsecs away. Our results strongly indicate that the dynamics of structure formation, rather than a critical Lyman–Werner flux, is the main driver of the formation of massive black holes in the early Universe. We find that the seeds of massive black holes may be much more common than previously considered in overdense regions of the early Universe, with a co-moving number density up to 10 −3 per cubic megaparsec. Main Standard cold dark-matter cosmologies predict that large-scale structure forms hierarchically. Smaller objects that form at early times subsequently merge and grow into larger objects. The existence of supermassive black holes 15 , 16 with masses of around 10 9 M ʘ (where M ʘ is the solar mass) only 800 Myr after the Big Bang indicates that there must have been an early intense convergence of mass in ‘rare’ locations, occurring only roughly ten times per co-moving cubic gigaparsec. We performed cosmological radiation hydrodynamics simulations (Renaissance simulations; see Methods ) using the code Enzo 17 to elucidate the formation of the first generation of stars and galaxies in the Universe 11 , 12 . The simulations include models for the formation of massive metal-free (population III) stars and subsequently of metal-enriched stars similar to those found in the Galaxy. We follow the effects of the ionizing radiation of these stars 18 and of supernova explosions on their environments as galaxies first assemble, both of which are important in regulating early galaxy formation. Motivated by the possible early formation of supermassive stars (SMSs), we analyse the region from the Renaissance simulation suite that is centred on the densest cosmological co-moving volume (133.6 Mpc 3 ), which contains 822 galaxies at its ending redshift of z = 15 (270 Myr after the Big Bang). We identify candidate SMS host haloes by searching the simulation for metal-free atomic-cooling haloes without prior star formation at z = 15. We place no constraints on the level of Lyman–Werner flux impacting the haloes. There are 670 atomic-cooling haloes, ten of which are metal-free and have not hosted prior star formation (Extended Data Table 1 ). The remaining atomic-cooling haloes have formed stars prompted by either H 2 or metal-line cooling and are not conducive to the formation of SMSs (and subsequently direct-collapse black holes, DCBHs). Out of these ten haloes, we concentrate on two—the most massive halo (MMH) and the halo exposed to the most Lyman–Werner radiation flux (LWH). We resample the mass distributions of these two haloes at z = 20 and at a mass resolution higher by a factor of 169, and re-simulate them to study their gravitational collapse in more detail. Both haloes assemble in a region 10–25 kpc away from a group of young galaxies that have photo-ionized, photo-heated and chemically enriched the surrounding environments (Fig. 1 ). At z = 18, the young galaxies near the MMH (Fig. 1a–d ) have created an amorphous H ii region with a maximum extent of 20 kpc. As the star-formation rates grow in these young (massive) galaxies, the Lyman–Werner intensities increase from J LW ≈ 1 J 21 at z = 18 within 5 physical kpc of the galaxies to J LW ≈ 30 J 21 at z = 15, where J 21 is the intensity of the background radiation in units of 10 −21 erg cm −2 s −1 Hz −1 sr −1 . The only other source of Lyman–Werner radiation comes from four nearby haloes that host population III stars, 3–5 kpc from the LWH. Both target haloes are impacted by a Lyman–Werner intensity of J LW ≈ 3 J 21 at z = 15 (Fig. 1d, h ). This flux is 6 to 600 times lower than previous estimates for the critical Lyman–Werner flux necessary for SMS formation 19 , 20 , 21 . Fig. 1: Thermal and chemical evolution of the immediate pre-galactic environment. a – h , Projections of the temperature (orange), metallicity (blue; Z ʘ is the metallicity of the Sun) and gas density (black) of a region 40 kpc across and with a depth of 8 kpc centred on the MMH ( a–d ) and the LWH ( e–h ). The MMH and LWH are indicated by arrows. The heated and metal-enriched volumes around early galaxies and population III stars grow from z = 18 to z = 15 (62 Myr). The dotted, dash-dotted, dashed and solid contours indicate where the average Lyman–Werner flux is 1 J 21 , 3 J 21 , 10 J 21 and 30 J 21 . Both candidate haloes, which host the formation of massive black holes, have 3 J 21 , are just outside of the cosmological H<|im_end|> <|im_start|>assistant The light released from around the first massive black holes in the universe is so intense that it is able to reach telescopes across the entire expanse of the universe. Incredibly, the light from the most distant black holes (or quasars) has been traveling to us for more than 13 billion light years. However, we do not know how these monster black holes formed. New research led by researchers from Georgia Institute of Technology, Dublin City University, Michigan State University, the University of California at San Diego, the San Diego Supercomputer Center and IBM, provides a new and extremely promising avenue for solving this cosmic riddle. The team showed that when galaxies assemble extremely rapidly—and sometimes violently—that can lead to the formation of very massive black holes. In these rare galaxies, normal star formation is disrupted and black hole formation takes over. The new study finds that massive black holes form in dense starless regions that are growing rapidly, turning upside down the long-accepted belief that massive black hole formation was limited to regions bombarded by the powerful radiation of nearby galaxies. Conclusions of the study, reported on January 23rd in the journal Nature and supported by funding from the National Science Foundation, the European Union and NASA, also finds that massive black holes are much more common in the universe than previously thought. The key criteria for determining where massive black holes formed during the universe's infancy relates to the rapid growth of pre-galactic gas clouds that are the forerunners of all present-day galaxies, meaning that most supermassive black holes have a common origin forming in this newly discovered scenario, said John Wise, an associate professor in the Center for Relativistic Astrophysics at Georgia Tech and the paper's corresponding author. Dark matter collapses into halos that are the gravitational glue for all galaxies. Early rapid growth of these halos prevented the formation of stars that would have competed with black holes for gaseous matter flowing into the area. "In this study, we have uncovered a totally new mechanism that sparks the formation of massive black holes in particular dark matter halos," Wise said. "Instead of just considering radiation, we need to look at how quickly the halos grow. We don't need that much physics to understand it—just how the dark matter is distributed and how gravity will affect that. Forming a massive black hole requires being in a rare region with an intense convergence of matter." When the research team found these black hole formation sites in the simulation, they were at first stumped, said John Regan, research fellow in the Centre for Astrophysics and Relativity in Dublin City University. The previously accepted paradigm was that massive black holes could only form when exposed to high levels of nearby radiation. This two-part visualization by the Advanced Visualization Lab at the National Center for Supercomputing Applications starts shortly after the Big Bang, and shows the evolution of the first galaxies in the universe over the first 400 million years, in increments of about 4 million years. The second part of the visualization stops time at the 400 million year mark, and flies the viewer through the data, breaking down the different variables that are being visualized - filaments of dense gas, pockets of elevated temperature, ionized gas, and ultraviolet light. Credit: Advanced Visualization Lab at the National Center for Supercomputing Applications "Previous theories suggested this should only happen when the sites were exposed to high levels of star-formation killing radiation," he said. "As we delved deeper, we saw that these sites were undergoing a period of extremely rapid growth. That was the key. The violent and turbulent nature of the rapid assembly, the violent crashing together of the galaxy's foundations during the galaxy's birth prevented normal star formation and led to perfect conditions for black hole formation instead. This research shifts the previous paradigm and opens up a whole new area of research." The earlier theory relied on intense ultraviolet radiation from a nearby galaxy to inhibit the formation of stars in the black hole-forming halo, said Michael Norman, director of the San Diego Supercomputer Center at UC San Diego and one of the work's authors. "While UV radiation is still a factor, our work has shown that it is not the dominant factor, at least in our simulations," he explained. The research was based on the Renaissance Simulation suite, a 70-terabyte data set created on the Blue Waters supercomputer between 2011 and 2014 to help scientists understand how the universe evolved during its early years. To learn more about specific regions where massive black holes were likely to develop, the researchers examined the simulation data and found ten specific dark matter halos that should have formed stars given their masses but only contained a dense gas cloud. Using the Stampede2 supercomputer, they then re-simulated two of those halos—each about 2,400 light-years across—at much higher resolution to understand details of what was happening in them 270 million years after the Big Bang. "It was only in these overly-dense regions of the universe that we saw these black holes forming," Wise said. "The dark matter creates most of the gravity, and then the gas falls into that gravitational potential, where it can form stars or a massive black hole." The Renaissance Simulations are the most comprehensive simulations of the earliest stages of the gravitational assembly of the pristine gas composed of hydrogen and helium and cold dark matter leading to the formation of the first stars and galaxies. They use a technique known as adaptive mesh refinement to zoom in on dense clumps forming stars or black holes. In addition, they cover a large enough region of the early universe to form thousands of objects—a requirement if one is interested in rare objects, as is the case here. "The high resolution, rich physics and large sample of collapsing halos were all needed to achieve this result," said Norman. The improved resolution of the simulation done for two candidate regions allowed the scientists to see turbulence and the inflow of gas and clumps of matter forming as the black hole precursors began to condense and spin. Their growth rate was dramatic. Zoom of the inner 30 light-years of the dark matter halo. The rotating gaseous disk breaks apart into three clumps that collapse under their own gravity to form supermassive stars. Credit: John Wise, Georgia Institute of Technology "Astronomers observe supermassive black holes that have grown to a billion solar masses in 800 million years," Wise said. "Doing that required an intense convergence of mass in that region. You would expect that in regions where galaxies were forming at very early times." Another aspect of the research is that the halos that give birth to black holes may be more common than previously believed. "An exciting component of this work is the discovery that these types of halos, though rare, may be common enough," said Brian O'Shea, a professor at Michigan State University. "We predict that this scenario would happen enough to be the origin of the most massive black holes that are observed, both early in the universe and in galaxies at the present day." Future work with these simulations will look at the lifecycle of these massive black hole formation galaxies, studying the formation, growth and evolution of the first massive black holes across time. "Our next goal is to probe the further evolution of these exotic objects. Where are these black holes today? Can we detect evidence of them in the local universe or with gravitational waves?" Regan asked. For these new answers, the research team—and others—may return to the simulations. "The Renaissance Simulations are sufficiently rich that other discoveries can be made using data already computed," said Norman. "For this reason we have created a public archive at SDSC containing called the Renaissance Simulations Laboratory where others can pursue questions of their own." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite–disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( ) to facilitate future research and meta-analyses. Main Deep molecular profiling of human blood has the potential to identify new pathways to diseases, improve risk prediction and enable stratified prevention and management 1 . Prospective studies have shown the promise of deep phenotypic profiling for precision medicine 2 , 3 but these were very-small-scale and focused on single diseases 4 , 5 . Many pathways are shared across different diseases and one in four patients now presents with two or more chronic conditions at the same time, referred to as multimorbidity 6 , 7 . The incidence of NCD multimorbidity is increasing not only in high-income 8 , 9 but also in middle- and low-income countries 7 , 10 , which poses major challenges for health-care systems globally. The co-occurrence of conditions, such as type 2 diabetes (T2D) and cardiovascular diseases, is common and previous work has shown a high degree of interconnectivity with other diseases 11 . The lack of horizontal integration between specialities delivering care for patients with coexisting diseases means that multimorbidity is more likely to be seen as a random assortment of individual conditions. There is now a call by public health authorities and policymakers for a shift to recognizing multimorbidity as an accumulation of largely predictable clusters of diseases in the same person 12 . However, knowledge about shared etiologies of less obviously related diseases is sparse. Molecular profiling has the potential to identify pathways simultaneously and systematically across many different incident diseases assessed objectively and at scale. Research into the determinants of NCD multimorbidity is a high priority 12 but, to our knowledge, investigations of in-depth molecular profiles in large prospective cohorts with comprehensive, long-term clinical follow-up have not been previously undertaken. Detailed information on modifiable factors that underlie and drive shared risk, which is required to establish actionable insights for the prevention and management of multimorbidity 13 , is also lacking. The human blood metabolome provides a comprehensive readout of human physiology obtained through untargeted assessment of hundreds of small circulating molecules, which reflect the influences and interactions of genetics, lifestyle, environment, medical treatment and microbial activity 14 . We investigated the associations between baseline levels of 1,014 metabolites assessed through untargeted profiling of plasma samples and the onset of 27 NCDs, all-cause mortality and NCD multimorbidity (Extended Data Fig. 1 ). Clinical outcomes were assessed using electronic health record hospitalization and cancer registry data in over 11,000 participants (219,415 person years of follow-up) of the European Prospective Investigation into Cancer (EPIC)-Norfolk study 15 . We systematically analyzed and established a comprehensive catalog of risk factor–metabolite–disease associations to address unanswered questions related to the shared etiology and drivers of multiple chronic conditions and multimorbidity. We sought to characterize: (1) pathways at baseline shared across multiple incident conditions to identify those that predispose individuals to multimorbidity; (2) which of the identified metabolite–disease associations are driven by modifiable clinical and other risk factors to identify targets of interventions; and (3) metabolites most strongly associated with the onset of NCD multimorbidity. We share our results through an open-access web server ( ) to maximize the use of this resource, thereby considerably augmenting existing efforts 16 . Results We used data from the EPIC-Norfolk cohort, which includes 25,639 middle-aged participants from the general population of Norfolk, UK 15 . A quasi-random subsample of 11,966 participants (mean age of 60 years, s.d. = 9 years, 53.7% females) was selected for metabolomic profiling using the Metabolon HD4 platform; detailed characteristics of participants and metabolites can be found in Supplementary Tables 1 – 3 . Small molecule profiles of incident diseases Plasma levels of 458 metabolites were significantly associated with at least one incident disease or all-cause mortality representing 1,226 associations in total (trait-wise Bonferroni cutoff for significance accounting for the number of metabolites: P < 4.95 × 10 −5 ; Extended Data Fig. 2 ). All-cause mortality was associated with most of those metabolites ( n = 268) followed by incident T2D ( n = 214), chronic obstructive pulmonary disease (COPD) ( n = 142), coronary heart disease (CHD) ( n = 127), heart failure ( n = 110), renal disease ( n = 110), peripheral arterial disease (PAD) ( n = 95), lung cancer ( n = 43), liver disease ( n = 39), atrial fibrillation ( n = 27), abdominal aortic aneurysm (AAA) ( n = 21) and asthma ( n = 16). We observed only few associations with incident colon cancer ( n = 5), cataract ( n = 5), cerebral stroke ( n = 2), stomach cancer ( n = 1) and Parkinson’s disease ( n = 1). The five most significant associations for each of the incident diseases and all-cause mortality are shown in Extended Data Fig. 3 . The number of metabolites associated with each disease outcome was partly explained by the number of cases for each disease and hence the power to detect an association (Extended Data Fig. 4 ). Specifically, incident T2D, COPD, PAD and lung cancer were associated with more metabolites than expected based on the overall relationship between", "role": "user" }, { "content": "A new study published today in Nature Medicine has identified key risk factors that increase the likelihood of individuals developing not only one but multiple non-communicable diseases, which include cardiovascular disease, cancer, chronic respiratory disease and diabetes. The analysis of over 11,000 people found that rather than being due to chance, there are often underlying biological links in individuals with multimorbidity, which is defined as the co-occurrence of two or more long-term health conditions and is a growing public health challenge. Multimorbidity, which affects about two thirds of people aged 65 years or over in the UK, impairs an individual's quality of life over and above the cumulative burden from each individual disease. Understanding which diseases co-occur not at random but through common mechanisms can aid the identification of preventive strategies and lead to improvements in health care. A research team led by Dr. Claudia Langenberg at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and Berlin Institute of Health, Charité University Medicine Berlin, Germany, analysed the levels of 1,014 metabolites in more than 11,000 participants in the European Prospective Investigation into Cancer (EPIC)-Norfolk study. These metabolites are small circulating molecules, such as sugars, vitamins, or lipids, which objectively reflect influences and interactions of genetics, lifestyle, environment, medical treatment, and gut microbes, on human physiology. By integrating all of the available data to gain a holistic view, the team was able to identify and document the association of these metabolites with 27 different non-communicable diseases that are frequently observed in multimorbidity, finding that almost half of the metabolites examined were associated with at least one of the 27 diseases. Two-thirds of the disease associated metabolites were shared by multiple diseases and hence with the onset of multimorbidity, for example elevated plasma levels of the carbohydrate N-acetylneuraminate were associated with a higher risk of 14 diseases. The researchers then examined the relationship between more than 50 characteristics of EPIC-Norfolk study participants identified when they were enrolled onto the study, ranging from waist-to-hip-ratio to smoking behaviour, to identify to which extend the profound changes in small molecules can explain the effect of common risk factors onto disease risk. This analysis highlighted poor kidney and liver health, blood glucose and lipids, gut microbial diversity, and lifestyle factors as potential targets tor prevention or treatment to lower the burden of multimorbidity. Dr. Claudia Langenberg, who led the study at the MRC Epidemiology Unit said: \"Such a deep understanding of molecular process has the potential to not only improve treatment of disease, but also aid earlier identification of individuals at risk. For example, we found that several metabolites measured were better predictors of future kidney-related disease risk than the current standard clinical tests.\" \"This work has only been possible because we were able to measure the concentrations of hundreds of small molecules in patient's blood using stored samples taken up to twenty years before the onset of any disease, and the electronic health record linkage of more than 11,000 EPIC-Norfolk study participants.\" Dr. Maik Pietzner, co-lead author of the study at the MRC Epidemiology Unit, added: \"Our observation that two-thirds of the small molecules were linked to at least two, even seemingly unrelated, diseases strongly contrasts the disease-centric approach still common in biomedical research. People do not usually develop just one long-term disease, so by taking a broader approach rather than just focusing on one disease at a time we can gain a more useful understanding of the underlying biological processes. Treatments that target pathways that are shared by two or more of a patient's conditions may be better able to provide benefit in a more consistent way that avoids increasing the risk of other conditions.\" Dr. Ivan Pavlov, programme lead at the Medical Research Council, said: \"This study moves us one step further towards understanding the biochemical pathways involved in multimorbidity, which is not just critical for early disease detection and prediction, but identifying these metabolic footprints could help to develop preventive therapeutics in the future. Importantly, the paper discovers possible links between seemingly unrelated diseases opening potential new avenues for research.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite–disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( ) to facilitate future research and meta-analyses. Main Deep molecular profiling of human blood has the potential to identify new pathways to diseases, improve risk prediction and enable stratified prevention and management 1 . Prospective studies have shown the promise of deep phenotypic profiling for precision medicine 2 , 3 but these were very-small-scale and focused on single diseases 4 , 5 . Many pathways are shared across different diseases and one in four patients now presents with two or more chronic conditions at the same time, referred to as multimorbidity 6 , 7 . The incidence of NCD multimorbidity is increasing not only in high-income 8 , 9 but also in middle- and low-income countries 7 , 10 , which poses major challenges for health-care systems globally. The co-occurrence of conditions, such as type 2 diabetes (T2D) and cardiovascular diseases, is common and previous work has shown a high degree of interconnectivity with other diseases 11 . The lack of horizontal integration between specialities delivering care for patients with coexisting diseases means that multimorbidity is more likely to be seen as a random assortment of individual conditions. There is now a call by public health authorities and policymakers for a shift to recognizing multimorbidity as an accumulation of largely predictable clusters of diseases in the same person 12 . However, knowledge about shared etiologies of less obviously related diseases is sparse. Molecular profiling has the potential to identify pathways simultaneously and systematically across many different incident diseases assessed objectively and at scale. Research into the determinants of NCD multimorbidity is a high priority 12 but, to our knowledge, investigations of in-depth molecular profiles in large prospective cohorts with comprehensive, long-term clinical follow-up have not been previously undertaken. Detailed information on modifiable factors that underlie and drive shared risk, which is required to establish actionable insights for the prevention and management of multimorbidity 13 , is also lacking. The human blood metabolome provides a comprehensive readout of human physiology obtained through untargeted assessment of hundreds of small circulating molecules, which reflect the influences and interactions of genetics, lifestyle, environment, medical treatment and microbial activity 14 . We investigated the associations between baseline levels of 1,014 metabolites assessed through untargeted profiling of plasma samples and the onset of 27 NCDs, all-cause mortality and NCD multimorbidity (Extended Data Fig. 1 ). Clinical outcomes were assessed using electronic health record hospitalization and cancer registry data in over 11,000 participants (219,415 person years of follow-up) of the European Prospective Investigation into Cancer (EPIC)-Norfolk study 15 . We systematically analyzed and established a comprehensive catalog of risk factor–metabolite–disease associations to address unanswered questions related to the shared etiology and drivers of multiple chronic conditions and multimorbidity. We sought to characterize: (1) pathways at baseline shared across multiple incident conditions to identify those that predispose individuals to multimorbidity; (2) which of the identified metabolite–disease associations are driven by modifiable clinical and other risk factors to identify targets of interventions; and (3) metabolites most strongly associated with the onset of NCD multimorbidity. We share our results through an open-access web server ( ) to maximize the use of this resource, thereby considerably augmenting existing efforts 16 . Results We used data from the EPIC-Norfolk cohort, which includes 25,639 middle-aged participants from the general population of Norfolk, UK 15 . A quasi-random subsample of 11,966 participants (mean age of 60 years, s.d. = 9 years, 53.7% females) was selected for metabolomic profiling using the Metabolon HD4 platform; detailed characteristics of participants and metabolites can be found in Supplementary Tables 1 – 3 . Small molecule profiles of incident diseases Plasma levels of 458 metabolites were significantly associated with at least one incident disease or all-cause mortality representing 1,226 associations in total (trait-wise Bonferroni cutoff for significance accounting for the number of metabolites: P < 4.95 × 10 −5 ; Extended Data Fig. 2 ). All-cause mortality was associated with most of those metabolites ( n = 268) followed by incident T2D ( n = 214), chronic obstructive pulmonary disease (COPD) ( n = 142), coronary heart disease (CHD) ( n = 127), heart failure ( n = 110), renal disease ( n = 110), peripheral arterial disease (PAD) ( n = 95), lung cancer ( n = 43), liver disease ( n = 39), atrial fibrillation ( n = 27), abdominal aortic aneurysm (AAA) ( n = 21) and asthma ( n = 16). We observed only few associations with incident colon cancer ( n = 5), cataract ( n = 5), cerebral stroke ( n = 2), stomach cancer ( n = 1) and Parkinson’s disease ( n = 1). The five most significant associations for each of the incident diseases and all-cause mortality are shown in Extended Data Fig. 3 . The number of metabolites associated with each disease outcome was partly explained by the number of cases for each disease and hence the power to detect an association (Extended Data Fig. 4 ). Specifically, incident T2D, COPD, PAD and lung cancer were associated with more metabolites than expected based on the overall relationship between<|im_end|> <|im_start|>assistant A new study published today in Nature Medicine has identified key risk factors that increase the likelihood of individuals developing not only one but multiple non-communicable diseases, which include cardiovascular disease, cancer, chronic respiratory disease and diabetes. The analysis of over 11,000 people found that rather than being due to chance, there are often underlying biological links in individuals with multimorbidity, which is defined as the co-occurrence of two or more long-term health conditions and is a growing public health challenge. Multimorbidity, which affects about two thirds of people aged 65 years or over in the UK, impairs an individual's quality of life over and above the cumulative burden from each individual disease. Understanding which diseases co-occur not at random but through common mechanisms can aid the identification of preventive strategies and lead to improvements in health care. A research team led by Dr. Claudia Langenberg at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and Berlin Institute of Health, Charité University Medicine Berlin, Germany, analysed the levels of 1,014 metabolites in more than 11,000 participants in the European Prospective Investigation into Cancer (EPIC)-Norfolk study. These metabolites are small circulating molecules, such as sugars, vitamins, or lipids, which objectively reflect influences and interactions of genetics, lifestyle, environment, medical treatment, and gut microbes, on human physiology. By integrating all of the available data to gain a holistic view, the team was able to identify and document the association of these metabolites with 27 different non-communicable diseases that are frequently observed in multimorbidity, finding that almost half of the metabolites examined were associated with at least one of the 27 diseases. Two-thirds of the disease associated metabolites were shared by multiple diseases and hence with the onset of multimorbidity, for example elevated plasma levels of the carbohydrate N-acetylneuraminate were associated with a higher risk of 14 diseases. The researchers then examined the relationship between more than 50 characteristics of EPIC-Norfolk study participants identified when they were enrolled onto the study, ranging from waist-to-hip-ratio to smoking behaviour, to identify to which extend the profound changes in small molecules can explain the effect of common risk factors onto disease risk. This analysis highlighted poor kidney and liver health, blood glucose and lipids, gut microbial diversity, and lifestyle factors as potential targets tor prevention or treatment to lower the burden of multimorbidity. Dr. Claudia Langenberg, who led the study at the MRC Epidemiology Unit said: "Such a deep understanding of molecular process has the potential to not only improve treatment of disease, but also aid earlier identification of individuals at risk. For example, we found that several metabolites measured were better predictors of future kidney-related disease risk than the current standard clinical tests." "This work has only been possible because we were able to measure the concentrations of hundreds of small molecules in patient's blood using stored samples taken up to twenty years before the onset of any disease, and the electronic health record linkage of more than 11,000 EPIC-Norfolk study participants." Dr. Maik Pietzner, co-lead author of the study at the MRC Epidemiology Unit, added: "Our observation that two-thirds of the small molecules were linked to at least two, even seemingly unrelated, diseases strongly contrasts the disease-centric approach still common in biomedical research. People do not usually develop just one long-term disease, so by taking a broader approach rather than just focusing on one disease at a time we can gain a more useful understanding of the underlying biological processes. Treatments that target pathways that are shared by two or more of a patient's conditions may be better able to provide benefit in a more consistent way that avoids increasing the risk of other conditions." Dr. Ivan Pavlov, programme lead at the Medical Research Council, said: "This study moves us one step further towards understanding the biochemical pathways involved in multimorbidity, which is not just critical for early disease detection and prediction, but identifying these metabolic footprints could help to develop preventive therapeutics in the future. Importantly, the paper discovers possible links between seemingly unrelated diseases opening potential new avenues for research." <|im_end|>

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1401, 5326, 9547, 430, 5376, 279, 29736, 315, 7931, 11469, 539, 1193, 832, 719, 5361, 2536, 12, 26660, 481, 19338, 11, 902, 2997, 41713, 8624, 11, 9572, 11, 21249, 42631, 8624, 323, 20335, 13, 578, 6492, 315, 927, 220, 806, 11, 931, 1274, 1766, 430, 4856, 1109, 1694, 4245, 311, 6140, 11, 1070, 527, 3629, 16940, 24156, 7902, 304, 7931, 449, 80149, 30986, 19025, 11, 902, 374, 4613, 439, 279, 1080, 12, 14310, 21201, 315, 1403, 477, 810, 1317, 9860, 2890, 4787, 323, 374, 264, 7982, 586, 2890, 8815, 13, 22950, 318, 30986, 19025, 11, 902, 22223, 922, 1403, 94237, 315, 1274, 20330, 220, 2397, 1667, 477, 927, 304, 279, 6560, 11, 3242, 4825, 459, 3927, 596, 4367, 315, 2324, 927, 323, 3485, 279, 40944, 23104, 505, 1855, 3927, 8624, 13, 46551, 902, 19338, 1080, 12, 511, 2407, 539, 520, 4288, 719, 1555, 4279, 24717, 649, 12576, 279, 22654, 315, 71123, 15174, 323, 3063, 311, 18637, 304, 2890, 2512, 13, 362, 3495, 2128, 6197, 555, 2999, 13, 81156, 23272, 56936, 520, 279, 13235, 8483, 9251, 320, 44, 7532, 8, 88953, 2508, 8113, 520, 279, 3907, 315, 24562, 323, 20437, 10181, 315, 6401, 11, 4969, 13109, 3907, 19152, 20437, 11, 10057, 11, 67458, 279, 5990, 315, 220, 16, 11, 15901, 28168, 3695, 304, 810, 1109, 220, 806, 11, 931, 13324, 304, 279, 7665, 32134, 9262, 47997, 1139, 26211, 320, 9377, 1341, 7435, 33763, 42031, 4007, 13, 4314, 28168, 3695, 527, 2678, 54828, 35715, 11, 1778, 439, 70913, 11, 46192, 11, 477, 19588, 3447, 11, 902, 85121, 8881, 34453, 323, 22639, 315, 56104, 11, 19433, 11, 4676, 11, 6593, 6514, 11, 323, 18340, 80727, 11, 389, 3823, 78152, 13, 3296, 54952, 682, 315, 279, 2561, 828, 311, 8895, 264, 61876, 1684, 11, 279, 2128, 574, 3025, 311, 10765, 323, 2246, 279, 15360, 315, 1521, 28168, 3695, 449, 220, 1544, 2204, 2536, 12, 26660, 481, 19338, 430, 527, 14134, 13468, 304, 80149, 30986, 19025, 11, 9455, 430, 4661, 4376, 315, 279, 28168, 3695, 25078, 1051, 5938, 449, 520, 3325, 832, 315, 279, 220, 1544, 19338, 13, 9220, 45726, 315, 279, 8624, 5938, 28168, 3695, 1051, 6222, 555, 5361, 19338, 323, 16472, 449, 279, 42080, 315, 80149, 30986, 19025, 11, 369, 3187, 32389, 32426, 5990, 315, 279, 67732, 452, 38698, 87348, 818, 324, 309, 3357, 1051, 5938, 449, 264, 5190, 5326, 315, 220, 975, 19338, 13, 578, 12074, 1243, 25078, 279, 5133, 1990, 810, 1109, 220, 1135, 17910, 315, 19613, 1341, 11500, 269, 42031, 4007, 13324, 11054, 994, 814, 1051, 37191, 8800, 279, 4007, 11, 24950, 505, 29142, 4791, 12, 2200, 3880, 6400, 311, 20149, 17432, 11, 311, 10765, 311, 902, 13334, 279, 28254, 4442, 304, 2678, 35715, 649, 10552, 279, 2515, 315, 4279, 5326, 9547, 8800, 8624, 5326, 13, 1115, 6492, 27463, 8009, 39042, 323, 26587, 2890, 11, 6680, 34323, 323, 19588, 3447, 11, 18340, 75418, 20057, 11, 323, 19433, 9547, 439, 4754, 11811, 5801, 27344, 477, 6514, 311, 4827, 279, 23104, 315, 80149, 30986, 19025, 13, 2999, 13, 81156, 23272, 56936, 11, 889, 6197, 279, 4007, 520, 279, 386, 7532, 88953, 2508, 8113, 1071, 25, 330, 21365, 264, 5655, 8830, 315, 31206, 1920, 706, 279, 4754, 311, 539, 1193, 7417, 6514, 315, 8624, 11, 719, 1101, 12576, 6931, 22654, 315, 7931, 520, 5326, 13, 1789, 3187, 11, 584, 1766, 430, 3892, 28168, 3695, 17303, 1051, 2731, 95222, 315, 3938, 39042, 14228, 8624, 5326, 1109, 279, 1510, 5410, 14830, 7177, 1210, 330, 2028, 990, 706, 1193, 1027, 3284, 1606, 584, 1051, 3025, 311, 6767, 279, 32466, 315, 11758, 315, 2678, 35715, 304, 8893, 596, 6680, 1701, 9967, 10688, 4529, 709, 311, 17510, 1667, 1603, 279, 42080, 315, 904, 8624, 11, 323, 279, 14683, 2890, 3335, 72541, 315, 810, 1109, 220, 806, 11, 931, 19613, 1341, 11500, 269, 42031, 4007, 13324, 1210, 2999, 13, 11583, 1609, 86288, 89, 1215, 11, 1080, 12, 27152, 3229, 315, 279, 4007, 520, 279, 386, 7532, 88953, 2508, 8113, 11, 3779, 25, 330, 8140, 22695, 430, 1403, 45726, 315, 279, 2678, 35715, 1051, 10815, 311, 520, 3325, 1403, 11, 1524, 23490, 46305, 11, 19338, 16917, 83379, 279, 8624, 65524, 5603, 2103, 4279, 304, 94612, 3495, 13, 9029, 656, 539, 6118, 2274, 1120, 832, 1317, 9860, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings. We detected 46 mCNVs in probands and 19 mCNVs in siblings, affecting 2.8–73.8% of cells. Probands carried a significant burden of large (>4-Mb) mCNVs, which were detected in 25 probands but only one sibling (odds ratio = 11.4, 95% confidence interval = 1.5–84.2, P = 7.4 × 10 −4 ). Event size positively correlated with severity of ASD symptoms ( P = 0.016). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD (eg, 16p11.2 ). We further experimentally validated two mCNVs in postmortem brain tissue from 59 additional probands. These results indicate that mCNVs contribute a previously unexplained component of ASD risk. Main The genetic architecture of ASD is complex. Common variants, rare variants and germline de novo variants contribute substantially to risk 1 , 2 , 3 . Germline de novo CNVs (dnCNVs) play a central role, with such events observed in 5–10% of ASD probands 4 , 5 , 6 . Archetypal dnCNVs are recurrently observed in ASD probands, including duplications of 15q11–13, duplications and deletions of 16p11.2 and focal deletions of NRXN1 (ref. 6 ). However, despite substantial progress understanding the genetic risk of ASD, a large portion of ASD susceptibility cannot be explained by known risk variants 7 , 8 . Early-developmental (mosaic) mutations have been proposed as a possible source of some unexplained ASD susceptibility 9 . Unlike de novo variants, which occur in parental germ cells and are, thus, present in all cells of the body, mosaic mutations arise after fertilization—sometimes during embryonic development 10 —and are present in only a fraction of cells. Nonetheless, both de novo and mosaic variants arise free from the reproductive pressures of natural selection, and, thus, the hypothesis that mosaic variants contribute to sporadic disease is an attractive one. Several studies have linked mosaic single-nucleotide variants to ASD 11 , 12 , 13 and causally implicated them in several other neurological disorders 14 , 15 , 16 . mCNVs have recently been linked to developmental disorders 17 ; however, the contribution of mCNVs to ASD risk is currently unknown. In this study, we systematically analyzed mCNVs (gains, losses and copy number neutral losses of heterozygosity (CNN-LOH)) in 11,457 ASD-affected families using genotype array data from the Simons Simplex Collection (SSC) 18 and the Simons Powering Autism Research for Knowledge (SPARK) datasets 19 , drawing upon recent advances in statistical phasing 20 and the pedigree structure of the data to sensitively detect mCNVs 21 . In both cohorts, we found a significant burden of mCNVs in probands relative to their unaffected siblings. This burden was driven by the presence of large (>4-Mb) mCNVs in probands, and increased event size significantly associated with increased severity of ASD symptoms. We additionally computationally detected and experimentally validated two mCNVs present in whole-genome sequencing (WGS) of brain tissue from an additional 59 probands. These results provide strong evidence that mCNVs contribute to ASD risk. Results Detection of mCNVs in ASD cohorts We sought to characterize the contribution of mCNVs arising during early development to ASD risk. We analyzed blood-derived genotype array intensity data from 2,591 autism-affected families in the SSC cohort 18 and saliva-derived genotype intensity data from 8,866 autism-affected families in the SPARK cohort 19 . All SSC probands and siblings were 3–18 years old at enrollment; most SPARK probands and siblings were in or near the same age range, with a small fraction of older probands (1.2% between the ages of 30 and 40 and 0.3% over the age of 40; Supplementary Fig. 1a ). After data quality control ( Methods ), 12,077 probands and 5,500 siblings remained (Table 1 ). On average, 900,935 genotyped variants remained in SSC samples and 579,300 in SPARK samples, due to differences in genotyping density between arrays. Table 1 Counts of samples carrying mCNVs Full size table We performed haplotype phasing using both a population reference panel and the pedigree structure of the data to obtain near-perfect long-range phase information in offspring. We leveraged the phase information to sensitively detect mCNVs in autosomes of probands and siblings using Mosaic Chromosomal Alterations caller (MoChA) 22 and checked parental genotypes to ensure that events were not germline ( Methods ; see URLs). We excluded sex chromosomes to avoid confounding from the imbalanced sex ratio between probands and siblings (9,776:2,301 males:females in probands versus 2,718:2,782 in siblings). Following previous studies 21 , 23 , we filtered mCNV calls that exhibited evidence of DNA contamination, and we restricted our analysis to events for which copy number state could be confidently determined ( Methods and Supplementary Fig. 2 ). We further excluded mCNVs frequently observed in age-related clonal hematopoiesis (specifically, focal deletions at IGH and IGL and low-cell-fraction CNN-LOH events 21 , 23 , 24 , 25 ), which we expected to be present in a very small fraction of samples (<1%, given the young ages of participants) and unrelated to ASD status. We verified that genotyping intensity deviations within the remaining mCNVs were consistent with estimated mosaic cell fraction and copy number state (Supplementary Fig. 3 ). We detected 64 mCNVs in 59 individuals (35 gains, 24 losses and five CNN-LOH in 0.34% of SSC and SPARK samples; Table 1 and Supplementary Table 1 ) ranging in cell fraction—ie, proportion of cells harboring a mosaic event—from 2.8% to 73.8% (median = 27.1%) and in size from 49.3 kb to 249.2 Mb (median = 2.5 Mb) (Fig. 1a ). All but one carrier was younger than 28 years (oldest: 47 years; median: 12 years). Of the 64 detected mCNVs, 45 events were present in 44 unique probands (0.36%), and 19 events were present in", "role": "user" }, { "content": "Two studies in today's Nature Neuroscience, led by researchers at Boston Children's Hospital, Brigham and Women's Hospital (BWH), and Harvard Medical School (HMS), implicate mosaic mutations arising during embryonic development as a cause of autism spectrum disorder (ASD). The findings open new areas for exploring the genetics of ASD and could eventually inform diagnostic testing. Mosaic mutations affect only a portion of a person's cells. Rather than being inherited, they arise as a \"mistake\" introduced when a stem cell divides. A mutation in a stem cell will only be passed to the cells that descend from it, producing the mosaic pattern. When mosaic mutations occur during embryonic development, they can appear in the brain and affect the function of neurons. The earlier in development a mutation happens, the more cells will carry it. Characterizing mosaic mutations in the brain The two studies were part of the Brain Somatic Mosaicism Network, funded by the National Institute of Mental Health. The first study used deep, ultra-high-resolution whole-genome sequencing to quantify and characterize mosaic mutations in the frontal cortex of people with and without ASD. It was led by Rachel Rodin, MD, Ph.D. and Christopher Walsh, MD, Ph.D., of Boston Children's, and Yanmei Dou, Ph.D. and Peter Park, Ph.D., of HMS. When the researchers examined samples of brain tissue from 59 deceased people with ASD and 15 controls—the largest cohort of brain samples ever studied—they found that most of the brains had mosaic \"point\" mutations (alterations in a single \"letter\" of genetic code). They calculated that embryos acquire several such mutations with each cell division, and estimate that about half of us carry potentially harmful mosaic mutations in at least 2 percent of our brain cells. In the brains of people with ASD, however, mosaic mutations were more likely to affect parts of the genome that have a pivotal role in brain function. Specifically, they tended to land in \"enhancers,\" portions of DNA that do not code for genes but regulate whether a gene is turned on or off. \"In the brains of people with autism, mutations accumulate at the same rate as normal, but they are more likely to fall into an enhancer region,\" says Rodin, first author on the paper. \"We think this is because gene enhancers and promoters tend to be in DNA that's unwound and more exposed, which probably makes them more susceptible to mutations during cell division.\" \"Mutations in enhancers are a hidden kind of mutation that you don't see in typical diagnostic exome sequencing, and it may help explain ASD in some people,\" notes Walsh, chief of genetics and genomics at Boston Children's and co-senior author on the paper with Park, who led the study's computational analyses. \"We also need to better understand the effects of these mutations on neurons.\" Mosaic deletions and duplications The second study is the first large-scale investigation of copy number variants (CNVs) in people with ASD that occur in a mosaic pattern. As opposed to point mutations in a single gene, CNVs are deletions or duplications of whole segments of a chromosome, which may contain multiple genes. A team led by Maxwell Sherman, MS of BWH, Po-Ru Loh, Ph.D. of BWH, Park, and Walsh studied blood samples from about 12,000 people with autism and 5,500 unaffected siblings provided by the Simons Simplex Collection and the Simons Powering Autism Research for Knowledge (SPARK) datasets. They used blood as a proxy for brain tissue and applied novel computational techniques to sensitively detect mosaic mutations that likely arose during embryonic development. \"People have been interested in CNVs in autism for a long time, and would occasionally notice that some of them were mosaic, but no one had really looked at them in a large-scale study,\" says Loh, co-senior author on the paper with Walsh and Park. From these large samples, the team identified a total of 46 mosaic CNVs in the autism group and 19 in siblings. The CNVs affected 2.8 to 73.8 percent of blood cells sampled from each subject. Size matters Notably, the people with ASD were especially likely to have very large CNVs, with some involving 25 percent or more of a chromosome. The CNVs spanned a median of 7.8 million bases in the ASD group, versus 0.59 million bases in controls. \"This is one of the more interesting and surprising aspects of our study,\" says Sherman, the paper's first author and a Ph.D. student at MIT. \"The kids with ASD had very large CNVs that often hit dozens of genes, and likely included genes important for development. If the CNVs were in all their cells, rather than in a mosaic pattern, they would likely be lethal.\" The study also suggested that the larger the CNVs, the greater the severity of autism as assessed with a standard clinical measure. Another surprise was that smaller CNVs already known to be associated with ASD when found in all cells, such as deletions or duplications of 16p11.2 or 22q11.2, were not associated with autism when they occurred in a mosaic pattern. \"This suggests that in order to get autism, you have to mess up a large number of cells in the brain in a pretty substantial way,\" says Walsh. \"We're fairly sure that these large CNVs change the behavior of the neurons that carry them.\" \"We don't really know what cell fraction is important, or what particular chromosomes are most susceptible,\" notes Loh. \"These events are still very rare, even in people with autism.As larger cohorts are assembled, we hope to get some finer-grained insights.\" The findings of these studies could eventually be incorporated into diagnostic testing in children with autism. Testing could incorporate the non-coding portions of the genome, such as gene enhancers and promoters, and include higher-resolution chromosomal analysis to identify large mosaic CNVs. For now, the findings add to the ever-evolving autism puzzle, deepening the mystery of why so many different genetic mechanisms can lead to the same presentation of autism. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings. We detected 46 mCNVs in probands and 19 mCNVs in siblings, affecting 2.8–73.8% of cells. Probands carried a significant burden of large (>4-Mb) mCNVs, which were detected in 25 probands but only one sibling (odds ratio = 11.4, 95% confidence interval = 1.5–84.2, P = 7.4 × 10 −4 ). Event size positively correlated with severity of ASD symptoms ( P = 0.016). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD (eg, 16p11.2 ). We further experimentally validated two mCNVs in postmortem brain tissue from 59 additional probands. These results indicate that mCNVs contribute a previously unexplained component of ASD risk. Main The genetic architecture of ASD is complex. Common variants, rare variants and germline de novo variants contribute substantially to risk 1 , 2 , 3 . Germline de novo CNVs (dnCNVs) play a central role, with such events observed in 5–10% of ASD probands 4 , 5 , 6 . Archetypal dnCNVs are recurrently observed in ASD probands, including duplications of 15q11–13, duplications and deletions of 16p11.2 and focal deletions of NRXN1 (ref. 6 ). However, despite substantial progress understanding the genetic risk of ASD, a large portion of ASD susceptibility cannot be explained by known risk variants 7 , 8 . Early-developmental (mosaic) mutations have been proposed as a possible source of some unexplained ASD susceptibility 9 . Unlike de novo variants, which occur in parental germ cells and are, thus, present in all cells of the body, mosaic mutations arise after fertilization—sometimes during embryonic development 10 —and are present in only a fraction of cells. Nonetheless, both de novo and mosaic variants arise free from the reproductive pressures of natural selection, and, thus, the hypothesis that mosaic variants contribute to sporadic disease is an attractive one. Several studies have linked mosaic single-nucleotide variants to ASD 11 , 12 , 13 and causally implicated them in several other neurological disorders 14 , 15 , 16 . mCNVs have recently been linked to developmental disorders 17 ; however, the contribution of mCNVs to ASD risk is currently unknown. In this study, we systematically analyzed mCNVs (gains, losses and copy number neutral losses of heterozygosity (CNN-LOH)) in 11,457 ASD-affected families using genotype array data from the Simons Simplex Collection (SSC) 18 and the Simons Powering Autism Research for Knowledge (SPARK) datasets 19 , drawing upon recent advances in statistical phasing 20 and the pedigree structure of the data to sensitively detect mCNVs 21 . In both cohorts, we found a significant burden of mCNVs in probands relative to their unaffected siblings. This burden was driven by the presence of large (>4-Mb) mCNVs in probands, and increased event size significantly associated with increased severity of ASD symptoms. We additionally computationally detected and experimentally validated two mCNVs present in whole-genome sequencing (WGS) of brain tissue from an additional 59 probands. These results provide strong evidence that mCNVs contribute to ASD risk. Results Detection of mCNVs in ASD cohorts We sought to characterize the contribution of mCNVs arising during early development to ASD risk. We analyzed blood-derived genotype array intensity data from 2,591 autism-affected families in the SSC cohort 18 and saliva-derived genotype intensity data from 8,866 autism-affected families in the SPARK cohort 19 . All SSC probands and siblings were 3–18 years old at enrollment; most SPARK probands and siblings were in or near the same age range, with a small fraction of older probands (1.2% between the ages of 30 and 40 and 0.3% over the age of 40; Supplementary Fig. 1a ). After data quality control ( Methods ), 12,077 probands and 5,500 siblings remained (Table 1 ). On average, 900,935 genotyped variants remained in SSC samples and 579,300 in SPARK samples, due to differences in genotyping density between arrays. Table 1 Counts of samples carrying mCNVs Full size table We performed haplotype phasing using both a population reference panel and the pedigree structure of the data to obtain near-perfect long-range phase information in offspring. We leveraged the phase information to sensitively detect mCNVs in autosomes of probands and siblings using Mosaic Chromosomal Alterations caller (MoChA) 22 and checked parental genotypes to ensure that events were not germline ( Methods ; see URLs). We excluded sex chromosomes to avoid confounding from the imbalanced sex ratio between probands and siblings (9,776:2,301 males:females in probands versus 2,718:2,782 in siblings). Following previous studies 21 , 23 , we filtered mCNV calls that exhibited evidence of DNA contamination, and we restricted our analysis to events for which copy number state could be confidently determined ( Methods and Supplementary Fig. 2 ). We further excluded mCNVs frequently observed in age-related clonal hematopoiesis (specifically, focal deletions at IGH and IGL and low-cell-fraction CNN-LOH events 21 , 23 , 24 , 25 ), which we expected to be present in a very small fraction of samples (<1%, given the young ages of participants) and unrelated to ASD status. We verified that genotyping intensity deviations within the remaining mCNVs were consistent with estimated mosaic cell fraction and copy number state (Supplementary Fig. 3 ). We detected 64 mCNVs in 59 individuals (35 gains, 24 losses and five CNN-LOH in 0.34% of SSC and SPARK samples; Table 1 and Supplementary Table 1 ) ranging in cell fraction—ie, proportion of cells harboring a mosaic event—from 2.8% to 73.8% (median = 27.1%) and in size from 49.3 kb to 249.2 Mb (median = 2.5 Mb) (Fig. 1a ). All but one carrier was younger than 28 years (oldest: 47 years; median: 12 years). Of the 64 detected mCNVs, 45 events were present in 44 unique probands (0.36%), and 19 events were present in<|im_end|> <|im_start|>assistant Two studies in today's Nature Neuroscience, led by researchers at Boston Children's Hospital, Brigham and Women's Hospital (BWH), and Harvard Medical School (HMS), implicate mosaic mutations arising during embryonic development as a cause of autism spectrum disorder (ASD). The findings open new areas for exploring the genetics of ASD and could eventually inform diagnostic testing. Mosaic mutations affect only a portion of a person's cells. Rather than being inherited, they arise as a "mistake" introduced when a stem cell divides. A mutation in a stem cell will only be passed to the cells that descend from it, producing the mosaic pattern. When mosaic mutations occur during embryonic development, they can appear in the brain and affect the function of neurons. The earlier in development a mutation happens, the more cells will carry it. Characterizing mosaic mutations in the brain The two studies were part of the Brain Somatic Mosaicism Network, funded by the National Institute of Mental Health. The first study used deep, ultra-high-resolution whole-genome sequencing to quantify and characterize mosaic mutations in the frontal cortex of people with and without ASD. It was led by Rachel Rodin, MD, Ph.D. and Christopher Walsh, MD, Ph.D., of Boston Children's, and Yanmei Dou, Ph.D. and Peter Park, Ph.D., of HMS. When the researchers examined samples of brain tissue from 59 deceased people with ASD and 15 controls—the largest cohort of brain samples ever studied—they found that most of the brains had mosaic "point" mutations (alterations in a single "letter" of genetic code). They calculated that embryos acquire several such mutations with each cell division, and estimate that about half of us carry potentially harmful mosaic mutations in at least 2 percent of our brain cells. In the brains of people with ASD, however, mosaic mutations were more likely to affect parts of the genome that have a pivotal role in brain function. Specifically, they tended to land in "enhancers," portions of DNA that do not code for genes but regulate whether a gene is turned on or off. "In the brains of people with autism, mutations accumulate at the same rate as normal, but they are more likely to fall into an enhancer region," says Rodin, first author on the paper. "We think this is because gene enhancers and promoters tend to be in DNA that's unwound and more exposed, which probably makes them more susceptible to mutations during cell division." "Mutations in enhancers are a hidden kind of mutation that you don't see in typical diagnostic exome sequencing, and it may help explain ASD in some people," notes Walsh, chief of genetics and genomics at Boston Children's and co-senior author on the paper with Park, who led the study's computational analyses. "We also need to better understand the effects of these mutations on neurons." Mosaic deletions and duplications The second study is the first large-scale investigation of copy number variants (CNVs) in people with ASD that occur in a mosaic pattern. As opposed to point mutations in a single gene, CNVs are deletions or duplications of whole segments of a chromosome, which may contain multiple genes. A team led by Maxwell Sherman, MS of BWH, Po-Ru Loh, Ph.D. of BWH, Park, and Walsh studied blood samples from about 12,000 people with autism and 5,500 unaffected siblings provided by the Simons Simplex Collection and the Simons Powering Autism Research for Knowledge (SPARK) datasets. They used blood as a proxy for brain tissue and applied novel computational techniques to sensitively detect mosaic mutations that likely arose during embryonic development. "People have been interested in CNVs in autism for a long time, and would occasionally notice that some of them were mosaic, but no one had really looked at them in a large-scale study," says Loh, co-senior author on the paper with Walsh and Park. From these large samples, the team identified a total of 46 mosaic CNVs in the autism group and 19 in siblings. The CNVs affected 2.8 to 73.8 percent of blood cells sampled from each subject. Size matters Notably, the people with ASD were especially likely to have very large CNVs, with some involving 25 percent or more of a chromosome. The CNVs spanned a median of 7.8 million bases in the ASD group, versus 0.59 million bases in controls. "This is one of the more interesting and surprising aspects of our study," says Sherman, the paper's first author and a Ph.D. student at MIT. "The kids with ASD had very large CNVs that often hit dozens of genes, and likely included genes important for development. If the CNVs were in all their cells, rather than in a mosaic pattern, they would likely be lethal." The study also suggested that the larger the CNVs, the greater the severity of autism as assessed with a standard clinical measure. Another surprise was that smaller CNVs already known to be associated with ASD when found in all cells, such as deletions or duplications of 16p11.2 or 22q11.2, were not associated with autism when they occurred in a mosaic pattern. "This suggests that in order to get autism, you have to mess up a large number of cells in the brain in a pretty substantial way," says Walsh. "We're fairly sure that these large CNVs change the behavior of the neurons that carry them." "We don't really know what cell fraction is important, or what particular chromosomes are most susceptible," notes Loh. "These events are still very rare, even in people with autism.As larger cohorts are assembled, we hope to get some finer-grained insights." The findings of these studies could eventually be incorporated into diagnostic testing in children with autism. Testing could incorporate the non-coding portions of the genome, such as gene enhancers and promoters, and include higher-resolution chromosomal analysis to identify large mosaic CNVs. For now, the findings add to the ever-evolving autism puzzle, deepening the mystery of why so many different genetic mechanisms can lead to the same presentation of autism. <|im_end|>

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3619, 279, 6372, 315, 1521, 34684, 389, 34313, 1210, 386, 45883, 19825, 919, 323, 27444, 811, 578, 2132, 4007, 374, 279, 1176, 3544, 13230, 8990, 315, 3048, 1396, 27103, 320, 29768, 52837, 8, 304, 1274, 449, 78294, 430, 12446, 304, 264, 71624, 5497, 13, 1666, 16475, 311, 1486, 34684, 304, 264, 3254, 15207, 11, 25914, 52837, 527, 19825, 919, 477, 27444, 811, 315, 4459, 21282, 315, 264, 51815, 11, 902, 1253, 6782, 5361, 21389, 13, 362, 2128, 6197, 555, 59497, 52983, 11, 10504, 315, 426, 20484, 11, 14128, 11151, 84, 445, 2319, 11, 2405, 920, 13, 315, 426, 20484, 11, 5657, 11, 323, 52294, 20041, 6680, 10688, 505, 922, 220, 717, 11, 931, 1274, 449, 38281, 323, 220, 20, 11, 2636, 78622, 37783, 3984, 555, 279, 4567, 2439, 9170, 87, 11348, 323, 279, 4567, 2439, 7572, 287, 78763, 8483, 369, 33025, 320, 4695, 9272, 8, 30525, 13, 2435, 1511, 6680, 439, 264, 13594, 369, 8271, 20438, 323, 9435, 11775, 55580, 12823, 311, 74633, 3210, 11388, 71624, 34684, 430, 4461, 51063, 2391, 44481, 14338, 4500, 13, 330, 16298, 617, 1027, 8173, 304, 25914, 52837, 304, 38281, 369, 264, 1317, 892, 11, 323, 1053, 23781, 5406, 430, 1063, 315, 1124, 1051, 71624, 11, 719, 912, 832, 1047, 2216, 7111, 520, 1124, 304, 264, 3544, 13230, 4007, 1359, 2795, 445, 2319, 11, 1080, 1355, 268, 2521, 3229, 389, 279, 5684, 449, 52294, 323, 5657, 13, 5659, 1521, 3544, 10688, 11, 279, 2128, 11054, 264, 2860, 315, 220, 2790, 71624, 25914, 52837, 304, 279, 38281, 1912, 323, 220, 777, 304, 37783, 13, 578, 25914, 52837, 11754, 220, 17, 13, 23, 311, 220, 5958, 13, 23, 3346, 315, 6680, 7917, 49976, 505, 1855, 3917, 13, 8645, 13146, 2876, 2915, 11, 279, 1274, 449, 78294, 1051, 5423, 4461, 311, 617, 1633, 3544, 25914, 52837, 11, 449, 1063, 16239, 220, 914, 3346, 477, 810, 315, 264, 51815, 13, 578, 25914, 52837, 9575, 19212, 264, 23369, 315, 220, 22, 13, 23, 3610, 23963, 304, 279, 78294, 1912, 11, 19579, 220, 15, 13, 2946, 3610, 23963, 304, 11835, 13, 330, 2028, 374, 832, 315, 279, 810, 7185, 323, 15206, 13878, 315, 1057, 4007, 1359, 2795, 52983, 11, 279, 5684, 596, 1176, 3229, 323, 264, 2405, 920, 13, 5575, 520, 15210, 13, 330, 791, 6980, 449, 78294, 1047, 1633, 3544, 25914, 52837, 430, 3629, 4295, 22700, 315, 21389, 11, 323, 4461, 5343, 21389, 3062, 369, 4500, 13, 1442, 279, 25914, 52837, 1051, 304, 682, 872, 7917, 11, 4856, 1109, 304, 264, 71624, 5497, 11, 814, 1053, 4461, 387, 45089, 1210, 578, 4007, 1101, 12090, 430, 279, 8294, 279, 25914, 52837, 11, 279, 7191, 279, 31020, 315, 38281, 439, 32448, 449, 264, 5410, 14830, 6767, 13, 13596, 13051, 574, 430, 9333, 25914, 52837, 2736, 3967, 311, 387, 5938, 449, 78294, 994, 1766, 304, 682, 7917, 11, 1778, 439, 19825, 919, 477, 27444, 811, 315, 220, 845, 79, 806, 13, 17, 477, 220, 1313, 80, 806, 13, 17, 11, 1051, 539, 5938, 449, 38281, 994, 814, 10222, 304, 264, 71624, 5497, 13, 330, 2028, 13533, 430, 304, 2015, 311, 636, 38281, 11, 499, 617, 311, 9622, 709, 264, 3544, 1396, 315, 7917, 304, 279, 8271, 304, 264, 5128, 12190, 1648, 1359, 2795, 52294, 13, 330, 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2,802

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott–Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner. Introduction Hematopoietic malignancies are a leading cause of cancer incidence and death, with an estimated 690,000 deaths and 1,186,590 new cases worldwide in 2018 1 . Hematopoietic malignancies are a heterogeneous collection of lymphoproliferative or myeloproliferative diseases, which can develop in the bone marrow, blood, lymph nodes, and lymphatic or nonlymphatic organs 2 . These types of malignancies are mainly characterized by uncontrolled cellular proliferation, enhanced motility, and invasiveness into adjacent or distal tissues, allowing cells to spread and invade other tissues in the body. In this study, we focused on the common lymphoproliferative hematopoietic malignancies, leukemia and Non-Hodgkin’s lymphoma (NHL) 3 , 4 . Hematopoietic malignancies accounted for ~10% of all cancer-associated deaths in 2018, with NHL and leukemia as the leading hematological cancers 1 . Current treatments for hematopoietic malignancies are still based mainly on chemotherapy and radiotherapy, and are usually followed by hematopoietic stem cell transplantation in cases of leukemia 5 . These treatments are nonspecific and accompanied by severe side effects including sensitivity to infections, hair loss, chronic fatigue, heart disorders, infertility, and secondary cancers 6 . Immune-based therapies, such as monoclonal antibodies, bispecific antibodies, immune checkpoint inhibitors, immunomodulators, and adoptive cell transfer (ACT), have shown significant clinical benefits, although many patients still fail to respond to these treatments due to primary, adaptive, and acquired resistance 7 . In the case of checkpoint inhibitors, treatment with Nivolumab (anti-PD-1) showed promising clinical results for Hodgkin’s lymphoma patients 8 but low complete response rates for NHL patients 9 . Furthermore, modest results were obtained using a combination treatment with anti-CTLA-4 and anti-PD-1 antibodies 9 , 10 , 11 . In addition, treatments with anti-CD19 chimeric antigen receptor-modified T (CAR-T) cells in patients with relapsed acute lymphoblastic leukemia (ALL) or refractory B-cell lymphomas showed limited success 12 , 13 . Although these new immune-based treatments might help to minimize the severe side effects of chemotherapy and radiotherapy, there are many reports of patients who still develop severe side effects from damage to healthy bystander cells, renal damage, cytokine release syndrome, and graft-versus-host disease (GVHD) 14 , 15 , 16 . Therefore, the development of new drugs to treat hematopoietic malignancies with minimal side effects and higher efficacy is still a critical unmet need. Hematopoietic malignancies are varied in terms of the origin of the neoplastic cells, and are genetically diverse due to random mutations and chromosomal translocation events resulting from viral infections or genome instability 17 . The formation of neoplasms is a multistep process in which the cells acquire biological capabilities known as hallmarks of cancer, that ultimately transform them into malignant cells 18 . The cytoskeleton, and in particularly the actin-network, are vital in order to carry out these newly acquired enhanced cellular capabilities 19 , 20 , 21 . These hallmarks of cancer enable malignant cells to become autonomously activated 22 , 23 , 24 , to independently and uncontrollably proliferate, and to increasingly migrate 19 , 25 , invade, and metastasize to adjacent and distal tissues 26 . These activities are defined as actin-dependent processes 21 . Wiskott–Aldrich Syndrome protein (WASp) belongs to a family of actin nucleation-promoting factors (NPFs) that regulate actin-cytoskeleton network rearrangement by activating the actin-related protein 2/3 (Arp2/3) complex. WASp is exclusively expressed in hematopoietic cells 27 , and thus has a unique role in their cellular activities 28 , 29 , 30 . This vital role of WASp can be seen in patients with Wiskott–Aldrich Syndrome (WAS) or X-linked thrombocytopenia (XLT). WAS patients exhibit a broad range of immune deficiencies due to the absence or decrease in WASp expression, respectively 31 . Although WASp itself has a pivotal role in healthy hematopoietic cell function 32 , 33 , 34 , 35 , its function in malignant hematopoietic cells is still unclear. Other WASp homologs from the WASp NPF family of proteins, such as Neural Wiskott–Aldrich Syndrome protein (N-WASp), WASp family verprolin homologous protein (WAVE) 1–3, Wiskott–Aldrich syndrome protein and SCAR homologue (WASH), WASp homolog associated with actin, membranes and microtubules (WHAMM), and junction mediating regulatory protein (JMY), are ubiquitously expressed in most healthy cell types, and have a well described role in various types of cancers as key players in mediating molecular pathogenesis 26 , 36 , 37 , 38 , 39 . In our previous studies, we established the molecular mechanism regulating WASp degradation 40 . Following cellular activation, WASp undergoes ubiquitylation on lysine residues 76 and 81, located at the WASp homology-1 (WH1) domain, directing WASp to proteasomal degradation. Furthermore, we demonstrated that WASp-interacting protein (WIP) masks WASp ubiquitylation sites at the WH1 domain, thereby protecting it from degradation 41 . Upon cellular activation, WASp is recruited to the membrane, and is activated by the small G-protein, Cdc42, which binds to its GTPase-binding domain (GBD); concurrently, WASp is phosphorylated on tyrosine 291. This activation releases WASp from its auto-inhibitiory state and results in a partial dissociation from the C’-terminus of WIP at the N’-terminal WH1 domain of WASp, while retaining its interaction between the C’ terminus of WASp and the N’-terminus of WIP. As a result, WASp is subsequently degraded by the Cbl E3 ubiquitin ligases 40 , 41 , 42 , 43", "role": "user" }, { "content": "Researchers at Bar-Ilan University in Israel have revealed a novel treatment approach in the fight against hematologic cancers. The new method, developed by Prof. Mira Barda-Saad and her research team from the Mina and Everard Goodman Faculty of Life Sciences, involves attacking the cytoskeletal protein, called WASp, which has a unique structural condition in active hematologic cancer cells. In order to carry out their malignant functions, cancer cells depend on actin, a protein that plays a key role in the cytoskeleton. Malignant cells need actin to be active, proliferate, migrate and invade. The WASp protein controls actin's activity and structure. The Bar-Ilan team focused on destroying WASp in malignant cells and demonstrated that the degradation of WASp assists in inhibiting and destroying these malignant cells. Their research was recently published in the journal Nature Communications. To date, the involvement of WASp in cancer has not been completely understood, but it is known to be found in cancer cells in a unique \"open\" structure that allows it to be identified and manipulated. Inducing the degradation of \"open\" WASp can destroy mainly malignant cells without threatening healthy cells, and can even be used to treat most types of hematologic cancers. In order to damage the cytoskeleton of the malignant cell, the research team performed screening to identify SMCs (small molecule compounds) that degrade the WASp compound in its \"open\" structural condition. To identify the SMCs they used bio convergence technologies, which combine biology with various engineering technologies—in this case, artificial intelligence and machine learning (AI/ML). By using a device developed by Prof. Yanai Ofran of Bar-Ilan, small molecules were identified in Prof. Barda-Saad's lab that do, in fact, damage cancer cells without posing too much risk to healthy cells. The researchers proved the efficacy of using SMCs to inhibit proliferation and destroy the malignant cells in laboratory experiments using cells taken from actual patients, in cooperation with Sheba Hospital, as well as a mouse model carrying human blood cancer. The WASp protein interacts with another protein, WIP, which binds to a specific point known as the \"recognition site\" and protects it against degradation. The SMCs bind to the recognition site and prevent the two proteins from binding together, thereby promoting degradation of the WASp, which is no longer protected by WIP. \"The idea arose in my lab when we discovered the process of WASp protection during a study that was published in 2014 in the journal Science Signaling,\" relates Prof Barda-Saad. \"This primary research led to the development of a new treatment strategy.\" This study, which has been underway since 2015 with funding from the Israel Innovation Authority, may provide a response for types of hematologic cancers for which treatment has not yet been found. The focused targeting of WASp, which aims to damage the cytoskeleton of the blood cancer cells, could replace treatments such as chemotherapy and other biological therapies which, because of their non-specificity, damage not only cancer cells but other cells in the body, or cause cancer cells to become resistant to treatment. Previous knowledge of WASp degradation sites, also identified in Prof. Barda-Saad's lab, enabled researchers to define the various properties of the binding sites and allowed them to predict the types of SMCs that would bind to the interphase between the WASp and WIP proteins, and separate them. The research team used machine learning to predict the WASp interactions with its environment and identify molecules that would not block the WASp degradation sites. The moment these molecules were found, the researchers verified their activity through molecular and biochemical experimental work with cell cultures, and later on with a mouse model carrying human malignant tumors. Prof. Barda-Saad notes that SMCs are already being used for various medical purposes, and they can be administered to patients through the blood system or by ingestion. One indicator of the safety of this new treatment strategy is the structure of WASp in normal blood cells: it is a \"closed\" structure, compared with the open structure found in malignant blood cells, which prevents the SMCs from binding to the recognition site. Therefore, theoretically speaking, using the SMCs does not pose any significant risk. Nonetheless, the concept must understandably undergo pre-clinical and clinical safety trials, as is standard procedure with any drug. This research focuses primarily on non-Hodgkin's lymphoma, but since other types of hematologic cancers also express the target protein, which is not expressed in cells that are not blood cells, there is a good chance that this can work for them, as well. For Prof. Barda-Saad, development of this new therapeutic strategy is more than just a scientific achievement. \"For many years during my doctoral and post-doctoral studies at the Weizmann Institute, and later on with the NIH in Maryland in the US, I concentrated on basic research. Several cases of cancer discovered in my family caused me to adopt an applicative approach—how could I take the primary knowledge and use it to develop a therapeutic strategy,\" she says. \"The process is lengthy and drawn out because it demands a deep understanding of how cells work and how cancer cells are different from normal cells—what are their weak points that can be exploited? In this research we used the vast knowledge we acquired in order to design an applicative strategy.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott–Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner. Introduction Hematopoietic malignancies are a leading cause of cancer incidence and death, with an estimated 690,000 deaths and 1,186,590 new cases worldwide in 2018 1 . Hematopoietic malignancies are a heterogeneous collection of lymphoproliferative or myeloproliferative diseases, which can develop in the bone marrow, blood, lymph nodes, and lymphatic or nonlymphatic organs 2 . These types of malignancies are mainly characterized by uncontrolled cellular proliferation, enhanced motility, and invasiveness into adjacent or distal tissues, allowing cells to spread and invade other tissues in the body. In this study, we focused on the common lymphoproliferative hematopoietic malignancies, leukemia and Non-Hodgkin’s lymphoma (NHL) 3 , 4 . Hematopoietic malignancies accounted for ~10% of all cancer-associated deaths in 2018, with NHL and leukemia as the leading hematological cancers 1 . Current treatments for hematopoietic malignancies are still based mainly on chemotherapy and radiotherapy, and are usually followed by hematopoietic stem cell transplantation in cases of leukemia 5 . These treatments are nonspecific and accompanied by severe side effects including sensitivity to infections, hair loss, chronic fatigue, heart disorders, infertility, and secondary cancers 6 . Immune-based therapies, such as monoclonal antibodies, bispecific antibodies, immune checkpoint inhibitors, immunomodulators, and adoptive cell transfer (ACT), have shown significant clinical benefits, although many patients still fail to respond to these treatments due to primary, adaptive, and acquired resistance 7 . In the case of checkpoint inhibitors, treatment with Nivolumab (anti-PD-1) showed promising clinical results for Hodgkin’s lymphoma patients 8 but low complete response rates for NHL patients 9 . Furthermore, modest results were obtained using a combination treatment with anti-CTLA-4 and anti-PD-1 antibodies 9 , 10 , 11 . In addition, treatments with anti-CD19 chimeric antigen receptor-modified T (CAR-T) cells in patients with relapsed acute lymphoblastic leukemia (ALL) or refractory B-cell lymphomas showed limited success 12 , 13 . Although these new immune-based treatments might help to minimize the severe side effects of chemotherapy and radiotherapy, there are many reports of patients who still develop severe side effects from damage to healthy bystander cells, renal damage, cytokine release syndrome, and graft-versus-host disease (GVHD) 14 , 15 , 16 . Therefore, the development of new drugs to treat hematopoietic malignancies with minimal side effects and higher efficacy is still a critical unmet need. Hematopoietic malignancies are varied in terms of the origin of the neoplastic cells, and are genetically diverse due to random mutations and chromosomal translocation events resulting from viral infections or genome instability 17 . The formation of neoplasms is a multistep process in which the cells acquire biological capabilities known as hallmarks of cancer, that ultimately transform them into malignant cells 18 . The cytoskeleton, and in particularly the actin-network, are vital in order to carry out these newly acquired enhanced cellular capabilities 19 , 20 , 21 . These hallmarks of cancer enable malignant cells to become autonomously activated 22 , 23 , 24 , to independently and uncontrollably proliferate, and to increasingly migrate 19 , 25 , invade, and metastasize to adjacent and distal tissues 26 . These activities are defined as actin-dependent processes 21 . Wiskott–Aldrich Syndrome protein (WASp) belongs to a family of actin nucleation-promoting factors (NPFs) that regulate actin-cytoskeleton network rearrangement by activating the actin-related protein 2/3 (Arp2/3) complex. WASp is exclusively expressed in hematopoietic cells 27 , and thus has a unique role in their cellular activities 28 , 29 , 30 . This vital role of WASp can be seen in patients with Wiskott–Aldrich Syndrome (WAS) or X-linked thrombocytopenia (XLT). WAS patients exhibit a broad range of immune deficiencies due to the absence or decrease in WASp expression, respectively 31 . Although WASp itself has a pivotal role in healthy hematopoietic cell function 32 , 33 , 34 , 35 , its function in malignant hematopoietic cells is still unclear. Other WASp homologs from the WASp NPF family of proteins, such as Neural Wiskott–Aldrich Syndrome protein (N-WASp), WASp family verprolin homologous protein (WAVE) 1–3, Wiskott–Aldrich syndrome protein and SCAR homologue (WASH), WASp homolog associated with actin, membranes and microtubules (WHAMM), and junction mediating regulatory protein (JMY), are ubiquitously expressed in most healthy cell types, and have a well described role in various types of cancers as key players in mediating molecular pathogenesis 26 , 36 , 37 , 38 , 39 . In our previous studies, we established the molecular mechanism regulating WASp degradation 40 . Following cellular activation, WASp undergoes ubiquitylation on lysine residues 76 and 81, located at the WASp homology-1 (WH1) domain, directing WASp to proteasomal degradation. Furthermore, we demonstrated that WASp-interacting protein (WIP) masks WASp ubiquitylation sites at the WH1 domain, thereby protecting it from degradation 41 . Upon cellular activation, WASp is recruited to the membrane, and is activated by the small G-protein, Cdc42, which binds to its GTPase-binding domain (GBD); concurrently, WASp is phosphorylated on tyrosine 291. This activation releases WASp from its auto-inhibitiory state and results in a partial dissociation from the C’-terminus of WIP at the N’-terminal WH1 domain of WASp, while retaining its interaction between the C’ terminus of WASp and the N’-terminus of WIP. As a result, WASp is subsequently degraded by the Cbl E3 ubiquitin ligases 40 , 41 , 42 , 43<|im_end|> <|im_start|>assistant Researchers at Bar-Ilan University in Israel have revealed a novel treatment approach in the fight against hematologic cancers. The new method, developed by Prof. Mira Barda-Saad and her research team from the Mina and Everard Goodman Faculty of Life Sciences, involves attacking the cytoskeletal protein, called WASp, which has a unique structural condition in active hematologic cancer cells. In order to carry out their malignant functions, cancer cells depend on actin, a protein that plays a key role in the cytoskeleton. Malignant cells need actin to be active, proliferate, migrate and invade. The WASp protein controls actin's activity and structure. The Bar-Ilan team focused on destroying WASp in malignant cells and demonstrated that the degradation of WASp assists in inhibiting and destroying these malignant cells. Their research was recently published in the journal Nature Communications. To date, the involvement of WASp in cancer has not been completely understood, but it is known to be found in cancer cells in a unique "open" structure that allows it to be identified and manipulated. Inducing the degradation of "open" WASp can destroy mainly malignant cells without threatening healthy cells, and can even be used to treat most types of hematologic cancers. In order to damage the cytoskeleton of the malignant cell, the research team performed screening to identify SMCs (small molecule compounds) that degrade the WASp compound in its "open" structural condition. To identify the SMCs they used bio convergence technologies, which combine biology with various engineering technologies—in this case, artificial intelligence and machine learning (AI/ML). By using a device developed by Prof. Yanai Ofran of Bar-Ilan, small molecules were identified in Prof. Barda-Saad's lab that do, in fact, damage cancer cells without posing too much risk to healthy cells. The researchers proved the efficacy of using SMCs to inhibit proliferation and destroy the malignant cells in laboratory experiments using cells taken from actual patients, in cooperation with Sheba Hospital, as well as a mouse model carrying human blood cancer. The WASp protein interacts with another protein, WIP, which binds to a specific point known as the "recognition site" and protects it against degradation. The SMCs bind to the recognition site and prevent the two proteins from binding together, thereby promoting degradation of the WASp, which is no longer protected by WIP. "The idea arose in my lab when we discovered the process of WASp protection during a study that was published in 2014 in the journal Science Signaling," relates Prof Barda-Saad. "This primary research led to the development of a new treatment strategy." This study, which has been underway since 2015 with funding from the Israel Innovation Authority, may provide a response for types of hematologic cancers for which treatment has not yet been found. The focused targeting of WASp, which aims to damage the cytoskeleton of the blood cancer cells, could replace treatments such as chemotherapy and other biological therapies which, because of their non-specificity, damage not only cancer cells but other cells in the body, or cause cancer cells to become resistant to treatment. Previous knowledge of WASp degradation sites, also identified in Prof. Barda-Saad's lab, enabled researchers to define the various properties of the binding sites and allowed them to predict the types of SMCs that would bind to the interphase between the WASp and WIP proteins, and separate them. The research team used machine learning to predict the WASp interactions with its environment and identify molecules that would not block the WASp degradation sites. The moment these molecules were found, the researchers verified their activity through molecular and biochemical experimental work with cell cultures, and later on with a mouse model carrying human malignant tumors. Prof. Barda-Saad notes that SMCs are already being used for various medical purposes, and they can be administered to patients through the blood system or by ingestion. One indicator of the safety of this new treatment strategy is the structure of WASp in normal blood cells: it is a "closed" structure, compared with the open structure found in malignant blood cells, which prevents the SMCs from binding to the recognition site. Therefore, theoretically speaking, using the SMCs does not pose any significant risk. Nonetheless, the concept must understandably undergo pre-clinical and clinical safety trials, as is standard procedure with any drug. This research focuses primarily on non-Hodgkin's lymphoma, but since other types of hematologic cancers also express the target protein, which is not expressed in cells that are not blood cells, there is a good chance that this can work for them, as well. For Prof. Barda-Saad, development of this new therapeutic strategy is more than just a scientific achievement. "For many years during my doctoral and post-doctoral studies at the Weizmann Institute, and later on with the NIH in Maryland in the US, I concentrated on basic research. Several cases of cancer discovered in my family caused me to adopt an applicative approach—how could I take the primary knowledge and use it to develop a therapeutic strategy," she says. "The process is lengthy and drawn out because it demands a deep understanding of how cells work and how cancer cells are different from normal cells—what are their weak points that can be exploited? In this research we used the vast knowledge we acquired in order to design an applicative strategy." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Advancing synthetic biology to the multicellular level requires the development of multiple cell-to-cell communication channels that propagate information with minimal signal interference. The development of quorum-sensing devices, the cornerstone technology for building microbial communities with coordinated system behaviour, has largely focused on cognate acyl-homoserine lactone (AHL)/transcription factor pairs, while the use of non-cognate pairs as a design feature has received limited attention. Here, we demonstrate a large library of AHL-receiver devices, with all cognate and non-cognate chemical signal interactions quantified, and we develop a software tool that automatically selects orthogonal communication channels. We use this approach to identify up to four orthogonal channels in silico, and experimentally demonstrate the simultaneous use of three channels in co-culture. The development of multiple non-interfering cell-to-cell communication channels is an enabling step that facilitates the design of synthetic consortia for applications including distributed bio-computation, increased bioprocess efficiency, cell specialisation and spatial organisation. Introduction Synthetic biology research and applications to date have mostly been focused on the engineering of homogeneous or monoclonal designer cell populations to perform functions ranging from bio-computation 1 , to bioproduction of biomaterials 2 and chemicals 3 , and biosensing 4 , 5 among others. De novo implementation of genetic circuits of increasing complexity and size in living cells is an important challenge in synthetic biology. Obstacles include unwanted interactions between genetic parts 6 , restrictions on the number of available genetic parts 1 , limits to the size of DNA that can be transformed into the host cell and metabolic burden to the host chassis 7 . The use of consortia of organisms could potentially alleviate these bottlenecks provided that the functionality of the genetic circuit can be distributed among different cell populations 8 . Additionally, the use of synthetic consortia could expand the capabilities and applications of synthetic biology by enabling compartmentalisation 9 , cell specialisation 10 , parallel bio-computation 11 , increased bioprocess efficiency 12 and spatial organisation 13 . A vital component for the engineering of synthetic consortia is devices that enable communication between the different populations to coordinate their behaviour. Quorum-sensing systems, especially those based on small molecules such as acyl-homoserine lactones (AHLs), have become the favoured technology for engineering cell-to-cell communication 14 because of their simple genetic architecture. AHLs are produced enzymatically by the expression of a single enzyme, such as the acyl-homoserine-lactone synthase protein that is the product of the luxI gene 15 . AHL molecules can freely diffuse in the intracellular and extracellular environment. Intracellularly, AHLs bind transcription factor proteins, which results in an activated complex that can bind a specific quorum-sensing promoter to initiate transcription of downstream genes 16 . The most frequently used quorum-sensing parts, the LuxR protein and its cognate P lux promoter have been assembled into a AHL-receiver device that has been extensively characterised in terms of its input–output response, dynamic performance upon induction, specificity to other AHL molecules, and evolutionary reliability 17 . Various studies have sought to increase the number of available AHL communication modules with functional devices built from the biological components of the las 18 , tra 18 , rpa 18 , rhl 19 , cin 19 and esa 20 quorum-sensing systems. Nevertheless, quorum-sensing devices can exhibit various degrees of crosstalk either in the form of AHL molecules binding to non-cognate transcription factors (chemical crosstalk) or transcription factors binding to non-cognate promoters (genetic crosstalk) 13 . The degree of orthogonality between designed AHL communication modules can be quantified by high-throughput screening as demonstrated for a set of designed AHL-receiver devices of the lux, las, rpa and tra quorum systems 18 . For this set of devices only the tra and rpa devices were determined to be completely orthogonal for both chemical and genetic crosstalk 18 . However, a number of strategies have been demonstrated for minimising crosstalk, e.g. modulating the expression levels of the transcription factor that influence the response of the device or quorum-sensing promoter engineering 13 . In this research, we aim to increase the number of available tools for the engineering of microbial communities. Initially, we design and construct AHL-receiver devices from genetic components of the rhl, lux, tra, las, cin and rpa quorum-sensing systems and characterise their input–output behaviour at the individual cell level. Next, we characterise the functionality of these AHL-receiver devices in the presence of non-cognate AHL inducers. In doing so, we create, to the best of our knowledge, the largest characterised library of quorum-sensing devices with mapped chemical crosstalk interactions. The size of this database and the emerging combinatorial complexity hinder manual search for possible communication channels, and thus calls for an automated process. The fact that this database contains data about all possible combinations of AHL-receiver devices and AHL inducers enables us to create a software tool to automatically select orthogonal AHL communication channels. This automated process facilitates the design of synthetic microbial consortia. We demonstrate the power of this approach by experimentally validating one of the algorithmically proposed designs for the specific control of gene expression through three non-interfering AHL communication channels in a polyclonal E. coli co-culture. The large number of cell-to-cell communication devices built and characterised here in combination with the developed software tool for automatic identification of non-interfering communication channels facilitate the design of synthetic microbial communities with multiplex interaction engineered to allow the development of applications in biotechnology, ecology and medical intervention. Results Design and characterisation of AHL-receiver devices To expand the pool of well-characterised cell-to-cell communication tools for engineering microbial consortia, synthetic AHL-receiver devices were constructed, which employed components from six quorum-sensing systems (Fig. 1 ). The engineered systems incorporated genetic elements from the lux system 21 ( Vibrio fisheri ), the rhl 22 , 23 and las 24 , 25 systems ( Pseudomonas aeruginosa ), the cin 26 system ( Rhizobium leguminosarum ), the tra 27 system ( Agrobacterium tumefaciens ) and the rpa 28 system ( Rhodopseudomonas palustris ). The cognate AHL inducer signal molecule for each system is indicated in Fig. 1a . The AHL-receiver devices share", "role": "user" }, { "content": "Scientists have designed a type of translator that allows different types of bacteria to 'talk' to each other. The findings, from scientists at Imperial College London, allow bacteria that don't usually live together – such as those that normally live on the skin, and those that live in the sea, to communicate. The research, published in Nature Communications, could pave the way for engineering new bacteria systems to aid a number of processes, such as producing green energy. Dr. Guy-Bart Stan, co-lead author from the Department of Bioengineering, said: \"In nature, bacteria happily communicate and cooperate with other bacteria they know and recognise – for instance brewing is sometimes only possible via different bacteria and yeasts working together.\" Dr. Karen Polizzi, co-lead author from the Department of Life Sciences, added: \"However bacteria only 'talk' with other bacteria they are used to working with. If you take bacteria that don't interact in nature – such as those from the soil and those from the sea, they don't communicate, as they are simply not speaking the same language.\" She continued: \"But by developing a new translation system, we have shown we can efficiently enable different bacteria communities to speak to each other. This creates the possibility of artificially engineering very complex systems, with multiple bacteria coordinating their actions to carry out complex tasks. We could use this to produce everything from biofuels to composite biomaterials.\" Opening communication channels The findings aid the field of synthetic biology, which involves engineering new biological systems to advance medicine, bioenergy, food production or manufacturing. Advances in synthetic biology to date have included cheaper production of anti-malarial agents, new biofuels, and even microbe-produced spider-silk. At the heart of the new findings is the system bacteria normally use to communicate, called 'quorum sensing'. This involves bacteria 'speaking' to each other through the release and detection of small molecules. The system allows bacteria to share information about their environment, and the size of their population. Dr. Nicholas Kylilis, postdoc and study author in the Department of Bioengineering added: \"Synthetic bacterial communities can be used to carry out complex bio-computations in a parallel fashion and coordinate complex tasks.\"This helps them work with their neighbours to coordinate tasks, grow in size, and share food. However, bacteria only work with microorganisms they know. In the latest research, the team re-engineered quorum sensing systems from various bacterial species found in soil, sea, pond water, and on skin, to create six new communication channels between bacteria. Encouraging teamwork The scientists, from the Imperial College Centre for Synthetic Biology, also developed a computer tool to help scientists select the best communication channels to use in their bacterial system. Dr. Zoltan Tuza, postdoc and author in the the Department of Bioengineering explained: \"The computer algorithm helps you chose the right communication channel from the start, rather than spending a lot of time finding out which bacteria understand each other. The researchers will now focus on encouraging different types of bacteria to efficiently work together to complete tasks. \"We've managed to get them to talk to each other – the next step is encouraging them to work efficiently with each other,\" said Dr. Stan. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Advancing synthetic biology to the multicellular level requires the development of multiple cell-to-cell communication channels that propagate information with minimal signal interference. The development of quorum-sensing devices, the cornerstone technology for building microbial communities with coordinated system behaviour, has largely focused on cognate acyl-homoserine lactone (AHL)/transcription factor pairs, while the use of non-cognate pairs as a design feature has received limited attention. Here, we demonstrate a large library of AHL-receiver devices, with all cognate and non-cognate chemical signal interactions quantified, and we develop a software tool that automatically selects orthogonal communication channels. We use this approach to identify up to four orthogonal channels in silico, and experimentally demonstrate the simultaneous use of three channels in co-culture. The development of multiple non-interfering cell-to-cell communication channels is an enabling step that facilitates the design of synthetic consortia for applications including distributed bio-computation, increased bioprocess efficiency, cell specialisation and spatial organisation. Introduction Synthetic biology research and applications to date have mostly been focused on the engineering of homogeneous or monoclonal designer cell populations to perform functions ranging from bio-computation 1 , to bioproduction of biomaterials 2 and chemicals 3 , and biosensing 4 , 5 among others. De novo implementation of genetic circuits of increasing complexity and size in living cells is an important challenge in synthetic biology. Obstacles include unwanted interactions between genetic parts 6 , restrictions on the number of available genetic parts 1 , limits to the size of DNA that can be transformed into the host cell and metabolic burden to the host chassis 7 . The use of consortia of organisms could potentially alleviate these bottlenecks provided that the functionality of the genetic circuit can be distributed among different cell populations 8 . Additionally, the use of synthetic consortia could expand the capabilities and applications of synthetic biology by enabling compartmentalisation 9 , cell specialisation 10 , parallel bio-computation 11 , increased bioprocess efficiency 12 and spatial organisation 13 . A vital component for the engineering of synthetic consortia is devices that enable communication between the different populations to coordinate their behaviour. Quorum-sensing systems, especially those based on small molecules such as acyl-homoserine lactones (AHLs), have become the favoured technology for engineering cell-to-cell communication 14 because of their simple genetic architecture. AHLs are produced enzymatically by the expression of a single enzyme, such as the acyl-homoserine-lactone synthase protein that is the product of the luxI gene 15 . AHL molecules can freely diffuse in the intracellular and extracellular environment. Intracellularly, AHLs bind transcription factor proteins, which results in an activated complex that can bind a specific quorum-sensing promoter to initiate transcription of downstream genes 16 . The most frequently used quorum-sensing parts, the LuxR protein and its cognate P lux promoter have been assembled into a AHL-receiver device that has been extensively characterised in terms of its input–output response, dynamic performance upon induction, specificity to other AHL molecules, and evolutionary reliability 17 . Various studies have sought to increase the number of available AHL communication modules with functional devices built from the biological components of the las 18 , tra 18 , rpa 18 , rhl 19 , cin 19 and esa 20 quorum-sensing systems. Nevertheless, quorum-sensing devices can exhibit various degrees of crosstalk either in the form of AHL molecules binding to non-cognate transcription factors (chemical crosstalk) or transcription factors binding to non-cognate promoters (genetic crosstalk) 13 . The degree of orthogonality between designed AHL communication modules can be quantified by high-throughput screening as demonstrated for a set of designed AHL-receiver devices of the lux, las, rpa and tra quorum systems 18 . For this set of devices only the tra and rpa devices were determined to be completely orthogonal for both chemical and genetic crosstalk 18 . However, a number of strategies have been demonstrated for minimising crosstalk, e.g. modulating the expression levels of the transcription factor that influence the response of the device or quorum-sensing promoter engineering 13 . In this research, we aim to increase the number of available tools for the engineering of microbial communities. Initially, we design and construct AHL-receiver devices from genetic components of the rhl, lux, tra, las, cin and rpa quorum-sensing systems and characterise their input–output behaviour at the individual cell level. Next, we characterise the functionality of these AHL-receiver devices in the presence of non-cognate AHL inducers. In doing so, we create, to the best of our knowledge, the largest characterised library of quorum-sensing devices with mapped chemical crosstalk interactions. The size of this database and the emerging combinatorial complexity hinder manual search for possible communication channels, and thus calls for an automated process. The fact that this database contains data about all possible combinations of AHL-receiver devices and AHL inducers enables us to create a software tool to automatically select orthogonal AHL communication channels. This automated process facilitates the design of synthetic microbial consortia. We demonstrate the power of this approach by experimentally validating one of the algorithmically proposed designs for the specific control of gene expression through three non-interfering AHL communication channels in a polyclonal E. coli co-culture. The large number of cell-to-cell communication devices built and characterised here in combination with the developed software tool for automatic identification of non-interfering communication channels facilitate the design of synthetic microbial communities with multiplex interaction engineered to allow the development of applications in biotechnology, ecology and medical intervention. Results Design and characterisation of AHL-receiver devices To expand the pool of well-characterised cell-to-cell communication tools for engineering microbial consortia, synthetic AHL-receiver devices were constructed, which employed components from six quorum-sensing systems (Fig. 1 ). The engineered systems incorporated genetic elements from the lux system 21 ( Vibrio fisheri ), the rhl 22 , 23 and las 24 , 25 systems ( Pseudomonas aeruginosa ), the cin 26 system ( Rhizobium leguminosarum ), the tra 27 system ( Agrobacterium tumefaciens ) and the rpa 28 system ( Rhodopseudomonas palustris ). The cognate AHL inducer signal molecule for each system is indicated in Fig. 1a . The AHL-receiver devices share<|im_end|> <|im_start|>assistant Scientists have designed a type of translator that allows different types of bacteria to 'talk' to each other. The findings, from scientists at Imperial College London, allow bacteria that don't usually live together – such as those that normally live on the skin, and those that live in the sea, to communicate. The research, published in Nature Communications, could pave the way for engineering new bacteria systems to aid a number of processes, such as producing green energy. Dr. Guy-Bart Stan, co-lead author from the Department of Bioengineering, said: "In nature, bacteria happily communicate and cooperate with other bacteria they know and recognise – for instance brewing is sometimes only possible via different bacteria and yeasts working together." Dr. Karen Polizzi, co-lead author from the Department of Life Sciences, added: "However bacteria only 'talk' with other bacteria they are used to working with. If you take bacteria that don't interact in nature – such as those from the soil and those from the sea, they don't communicate, as they are simply not speaking the same language." She continued: "But by developing a new translation system, we have shown we can efficiently enable different bacteria communities to speak to each other. This creates the possibility of artificially engineering very complex systems, with multiple bacteria coordinating their actions to carry out complex tasks. We could use this to produce everything from biofuels to composite biomaterials." Opening communication channels The findings aid the field of synthetic biology, which involves engineering new biological systems to advance medicine, bioenergy, food production or manufacturing. Advances in synthetic biology to date have included cheaper production of anti-malarial agents, new biofuels, and even microbe-produced spider-silk. At the heart of the new findings is the system bacteria normally use to communicate, called 'quorum sensing'. This involves bacteria 'speaking' to each other through the release and detection of small molecules. The system allows bacteria to share information about their environment, and the size of their population. Dr. Nicholas Kylilis, postdoc and study author in the Department of Bioengineering added: "Synthetic bacterial communities can be used to carry out complex bio-computations in a parallel fashion and coordinate complex tasks."This helps them work with their neighbours to coordinate tasks, grow in size, and share food. However, bacteria only work with microorganisms they know. In the latest research, the team re-engineered quorum sensing systems from various bacterial species found in soil, sea, pond water, and on skin, to create six new communication channels between bacteria. Encouraging teamwork The scientists, from the Imperial College Centre for Synthetic Biology, also developed a computer tool to help scientists select the best communication channels to use in their bacterial system. Dr. Zoltan Tuza, postdoc and author in the the Department of Bioengineering explained: "The computer algorithm helps you chose the right communication channel from the start, rather than spending a lot of time finding out which bacteria understand each other. The researchers will now focus on encouraging different types of bacteria to efficiently work together to complete tasks. "We've managed to get them to talk to each other – the next step is encouraging them to work efficiently with each other," said Dr. Stan. <|im_end|>

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2,050

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase ( n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.643C>T (p.Arg215*) variant ( P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant ( P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene. Main The risk of breast cancer varies among women, and genetic susceptibility has an important role in the etiology of the disease; highly penetrant alleles are estimated to account for up to 10% of all breast cancers 1 . Two major breast cancer susceptibility genes, BRCA1 and BRCA2 , were identified in the 1990s and are responsible for ∼ 15 to 20% of inherited breast cancers 1 , 2 , 3 . Since then, other susceptibility genes, such as ATM , CHEK2 , NBN , PALB2 , PTEN and TP53 , have been identified 4 , 5 , 6 , 7 , 8 , 9 . Together, all known breast cancer susceptibility genes are estimated to account for one-half of hereditary breast cancer cases 1 . The genes responsible for the remaining ∼ 50% are yet to be determined. In this study, we used whole-exome sequencing to investigate patients with familial breast cancer selected from Polish and Quebec-based French-Canadian populations—two populations that harbor multiple founder mutations in known breast cancer susceptibility genes owing to common ancestors 10 , 11 , 12 , 13 , 14 . The strategy in the initial discovery phase was to study a limited number of families with breast cancer to identify genes for which multiple probands had a common mutant allele. Then, through two validation phases, we surveyed selected alleles of the candidate gene in much larger sets of patients with breast cancer. In aggregate, we studied 15,189 breast cancer cases and 11,838 controls. In the discovery phase, we conducted whole-exome sequencing on 144 Polish and 51 French-Canadian women with breast cancer. These cases were selected on the basis of their strong family histories of breast cancer and/or their young ages of onset. All were negative for the numerous founder mutations in BRCA1 , BRCA2 , CHEK2 , NBN and PALB2 that are present in the Polish and French-Canadian populations 10 , 11 , 12 , 13 , 14 . Some of the Polish cases, however, were found to carry non-founder mutations in several of these genes by whole-exome sequencing 15 . To prioritize genes for further study, we identified genes in which a truncating mutation (nonsense mutation, essential splice-site mutation, frameshift insertion or deletion, or start codon mutation) was observed in at least two cases from each of the two populations. We excluded from consideration variants with a minor allele frequency (MAF) greater than 1% (either in an in-house database or in publicly available mutation databases), assuming these to be benign or low-penetrance variants. We identified several genes harboring rare, truncating variants in each population, but only one gene, RECQL , harbored multiple rare, truncating variants in both populations and had a function known to be related to cancer. Among the 195 Polish and French-Canadian cases included in the discovery phase, we identified 5 patients (2.6%) who carried different truncating mutations in RECQL ( Table 1 ), which we confirmed by Sanger sequencing. In comparison, 8 carriers of truncating mutations in RECQL were seen among 4,300 European-American individuals (0.2%) in the National Heart, Lung, and Blood Institute (NHLBI) exome database ( P = 0.0002). Although the NHLBI exome samples are not from Polish or French-Canadian individuals, the marked difference in the prevalence of truncating mutations in the NHLBI exome database in comparison to our breast cancer cases was sufficiently large to warrant further investigation of RECQL . Two mutation carriers also had a positive family history of ovarian cancer. In two French-Canadian pedigrees (harboring c.132_135delGAAA and c.426delT mutations), we tested one affected relative by Sanger sequencing to confirm carrier status ( Fig. 1 ). DNA was also available from the breast cancers of the probands in these two pedigrees; Sanger sequencing of RECQL in the tumor tissues did not show loss of heterozygosity (LOH) or a second-hit mutation in RECQL . Finally, we observed 4 RECQL missense variants among these 195 patients, all with MAF ≤1% among the European-American population of the NHLBI exome study ( Supplementary Table 1 ); all were confirmed by Sanger sequencing. Table 1 RECQL truncating mutations identified in Polish and French-Canadian patients with breast cancer Full size table Figure 1: Pedigrees for two RECQL mutation carriers. Pedigrees corresponding to two French-Canadian families and sequencing chromatopherograms of RECQL non-recurrent mutations identified during the discovery phase. ( a ) Pedigree and germline and tumor chromatopherograms confirming the presence of c.132_135delGAAA (p.Lys45fs) and the lack of LOH. ( b ) Pedigree and germline and tumor chromatopherograms confirming the presence of c.426delT (p.Ser142fs) and the lack of LOH. L, left; R, right. Numbers besides cancer names indicate age at diagnosis in years. Numbers within some individual symbols indicate the number of siblings with the same specifications. Full size image In the first validation phase of the study, we sequenced the entire 14 coding exons of RECQL ( NM_002907.3 ) among a non-overlapping set of 950 patients with familial breast cancer (475 Polish and 475 French Canadian) who were negative for BRCA1 and BRCA2 population-specific founder mutations. Although we did not observe any of the 5 original RECQL mutations identified in the discovery", "role": "user" }, { "content": "A new breast cancer gene has been identified in a study led by Women's College Hospital (WCH) researcher Dr. Mohammad Akbari, who is also an assistant professor with the Dalla Lana School of Public Health at the University of Toronto. The study, which was published online today in Nature Genetics, describes how mutations in a gene called RECQL are strongly linked to the onset of breast cancer in two populations of Polish and French-Canadian women. \"Our work is an exciting step in identifying all of the relevant genes that are associated with inherited breast cancer,\" said Dr. Akbari, who collaborated with fellow WCH senior researcher Dr. Steven Narod, as well as with Drs. Cezary Cybulski and Jan Lubi?ski from Pomeranian Medical University in Poland and Dr. William Foulkes from McGill University. The Toronto and Polish groups are longstanding research collaborators. Approximately 10 per cent of all breast cancer cases are hereditary, though it's believed that only half of all breast cancer susceptibility genes are known. In this study, about 20,000 different genes were studied, among 195 breast cancer patients with strong family histories of breast cancer who did not have a mutation in BRCA1 or BRCA2. The patients came from two populations—a Polish group and a French-Canadian group—who are genetically very homogenous. Dr. Akbari then led the team that confirmed the association of the identified gene, RECQL, with breast cancer by studying 25,000 more patients and unaffected people from these two populations. \"This study showed that studying specific founder populations like Polish and French-Canadian women is an excellent approach for identifying disease-associated genes,\" explained Dr. Narod, director of the familial breast cancer research unit at Women's College Research Institute and a professor with the Dalla Lana School of Public Health at the University of Toronto and coauthor on the study. Specific, recurrent RECQL mutations within both the Polish and French-Canadian populations were identified in this study. Within the Polish group, one type of RECQL mutation showed a five-fold increased risk for developing breast cancer compared to individuals without a mutation. Meanwhile, within the French-Canadian population, another type of RECQL mutation occurred 50 times more frequently among familial breast cancer patients, compared to population controls. Though RECQL mutations appeared to be quite rare, the authors observed a very high penetrance rate - that is, in the populations studied they estimate that up to one-half of women who have a mutation are destined to get breast cancer. They expect that women from other countries will be studied shortly. Dr. Akbari also supports the value of screening all women with breast cancer for genetic mutations, such as those occurring in RECQL. Based on a woman's genetic profile, appropriate targeted therapies could be selected.\"In the future, we might be able to select or develop treatments that can work around or correct relevant genetic mutations that are linked to breast cancer,\" explained Dr. Akbari. \"This opens the door for new and better ways of approaching treatment.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase ( n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.643C>T (p.Arg215*) variant ( P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant ( P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene. Main The risk of breast cancer varies among women, and genetic susceptibility has an important role in the etiology of the disease; highly penetrant alleles are estimated to account for up to 10% of all breast cancers 1 . Two major breast cancer susceptibility genes, BRCA1 and BRCA2 , were identified in the 1990s and are responsible for ∼ 15 to 20% of inherited breast cancers 1 , 2 , 3 . Since then, other susceptibility genes, such as ATM , CHEK2 , NBN , PALB2 , PTEN and TP53 , have been identified 4 , 5 , 6 , 7 , 8 , 9 . Together, all known breast cancer susceptibility genes are estimated to account for one-half of hereditary breast cancer cases 1 . The genes responsible for the remaining ∼ 50% are yet to be determined. In this study, we used whole-exome sequencing to investigate patients with familial breast cancer selected from Polish and Quebec-based French-Canadian populations—two populations that harbor multiple founder mutations in known breast cancer susceptibility genes owing to common ancestors 10 , 11 , 12 , 13 , 14 . The strategy in the initial discovery phase was to study a limited number of families with breast cancer to identify genes for which multiple probands had a common mutant allele. Then, through two validation phases, we surveyed selected alleles of the candidate gene in much larger sets of patients with breast cancer. In aggregate, we studied 15,189 breast cancer cases and 11,838 controls. In the discovery phase, we conducted whole-exome sequencing on 144 Polish and 51 French-Canadian women with breast cancer. These cases were selected on the basis of their strong family histories of breast cancer and/or their young ages of onset. All were negative for the numerous founder mutations in BRCA1 , BRCA2 , CHEK2 , NBN and PALB2 that are present in the Polish and French-Canadian populations 10 , 11 , 12 , 13 , 14 . Some of the Polish cases, however, were found to carry non-founder mutations in several of these genes by whole-exome sequencing 15 . To prioritize genes for further study, we identified genes in which a truncating mutation (nonsense mutation, essential splice-site mutation, frameshift insertion or deletion, or start codon mutation) was observed in at least two cases from each of the two populations. We excluded from consideration variants with a minor allele frequency (MAF) greater than 1% (either in an in-house database or in publicly available mutation databases), assuming these to be benign or low-penetrance variants. We identified several genes harboring rare, truncating variants in each population, but only one gene, RECQL , harbored multiple rare, truncating variants in both populations and had a function known to be related to cancer. Among the 195 Polish and French-Canadian cases included in the discovery phase, we identified 5 patients (2.6%) who carried different truncating mutations in RECQL ( Table 1 ), which we confirmed by Sanger sequencing. In comparison, 8 carriers of truncating mutations in RECQL were seen among 4,300 European-American individuals (0.2%) in the National Heart, Lung, and Blood Institute (NHLBI) exome database ( P = 0.0002). Although the NHLBI exome samples are not from Polish or French-Canadian individuals, the marked difference in the prevalence of truncating mutations in the NHLBI exome database in comparison to our breast cancer cases was sufficiently large to warrant further investigation of RECQL . Two mutation carriers also had a positive family history of ovarian cancer. In two French-Canadian pedigrees (harboring c.132_135delGAAA and c.426delT mutations), we tested one affected relative by Sanger sequencing to confirm carrier status ( Fig. 1 ). DNA was also available from the breast cancers of the probands in these two pedigrees; Sanger sequencing of RECQL in the tumor tissues did not show loss of heterozygosity (LOH) or a second-hit mutation in RECQL . Finally, we observed 4 RECQL missense variants among these 195 patients, all with MAF ≤1% among the European-American population of the NHLBI exome study ( Supplementary Table 1 ); all were confirmed by Sanger sequencing. Table 1 RECQL truncating mutations identified in Polish and French-Canadian patients with breast cancer Full size table Figure 1: Pedigrees for two RECQL mutation carriers. Pedigrees corresponding to two French-Canadian families and sequencing chromatopherograms of RECQL non-recurrent mutations identified during the discovery phase. ( a ) Pedigree and germline and tumor chromatopherograms confirming the presence of c.132_135delGAAA (p.Lys45fs) and the lack of LOH. ( b ) Pedigree and germline and tumor chromatopherograms confirming the presence of c.426delT (p.Ser142fs) and the lack of LOH. L, left; R, right. Numbers besides cancer names indicate age at diagnosis in years. Numbers within some individual symbols indicate the number of siblings with the same specifications. Full size image In the first validation phase of the study, we sequenced the entire 14 coding exons of RECQL ( NM_002907.3 ) among a non-overlapping set of 950 patients with familial breast cancer (475 Polish and 475 French Canadian) who were negative for BRCA1 and BRCA2 population-specific founder mutations. Although we did not observe any of the 5 original RECQL mutations identified in the discovery<|im_end|> <|im_start|>assistant A new breast cancer gene has been identified in a study led by Women's College Hospital (WCH) researcher Dr. Mohammad Akbari, who is also an assistant professor with the Dalla Lana School of Public Health at the University of Toronto. The study, which was published online today in Nature Genetics, describes how mutations in a gene called RECQL are strongly linked to the onset of breast cancer in two populations of Polish and French-Canadian women. "Our work is an exciting step in identifying all of the relevant genes that are associated with inherited breast cancer," said Dr. Akbari, who collaborated with fellow WCH senior researcher Dr. Steven Narod, as well as with Drs. Cezary Cybulski and Jan Lubi?ski from Pomeranian Medical University in Poland and Dr. William Foulkes from McGill University. The Toronto and Polish groups are longstanding research collaborators. Approximately 10 per cent of all breast cancer cases are hereditary, though it's believed that only half of all breast cancer susceptibility genes are known. In this study, about 20,000 different genes were studied, among 195 breast cancer patients with strong family histories of breast cancer who did not have a mutation in BRCA1 or BRCA2. The patients came from two populations—a Polish group and a French-Canadian group—who are genetically very homogenous. Dr. Akbari then led the team that confirmed the association of the identified gene, RECQL, with breast cancer by studying 25,000 more patients and unaffected people from these two populations. "This study showed that studying specific founder populations like Polish and French-Canadian women is an excellent approach for identifying disease-associated genes," explained Dr. Narod, director of the familial breast cancer research unit at Women's College Research Institute and a professor with the Dalla Lana School of Public Health at the University of Toronto and coauthor on the study. Specific, recurrent RECQL mutations within both the Polish and French-Canadian populations were identified in this study. Within the Polish group, one type of RECQL mutation showed a five-fold increased risk for developing breast cancer compared to individuals without a mutation. Meanwhile, within the French-Canadian population, another type of RECQL mutation occurred 50 times more frequently among familial breast cancer patients, compared to population controls. Though RECQL mutations appeared to be quite rare, the authors observed a very high penetrance rate - that is, in the populations studied they estimate that up to one-half of women who have a mutation are destined to get breast cancer. They expect that women from other countries will be studied shortly. Dr. Akbari also supports the value of screening all women with breast cancer for genetic mutations, such as those occurring in RECQL. Based on a woman's genetic profile, appropriate targeted therapies could be selected."In the future, we might be able to select or develop treatments that can work around or correct relevant genetic mutations that are linked to breast cancer," explained Dr. Akbari. "This opens the door for new and better ways of approaching treatment." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Noble metal nanoparticles stabilized by organic ligands are important for applications in assembly, site-specific bioconjugate labelling and sensing, drug delivery and medical therapy, molecular recognition and molecular electronics, and catalysis. Here we report crystal structures and theoretical analysis of three Ag 44 (SR) 30 and three Au 12 Ag 32 (SR) 30 intermetallic nanoclusters stabilized with fluorinated arylthiols (SR=SPhF, SPhF 2 or SPhCF 3 ). The nanocluster forms a Keplerate solid of concentric icosahedral and dodecahedral atom shells, protected by six Ag 2 (SR) 5 units. Positive counterions in the crystal indicate a high negative charge of 4 − per nanoparticle, and density functional theory calculations explain the stability as an 18-electron superatom shell closure in the metal core. Highly featured optical absorption spectra in the ultraviolet–visible region are analysed using time-dependent density functional perturbation theory. This work forms a basis for further understanding, engineering and controlling of stability as well as electronic and optical properties of these novel nanomaterials. Introduction Noble metal nanoparticles stabilized by organic ligand layer are the subject of an increasing number of studies owing to their applications in assembly, bio-labelling and sensing, drug delivery and medical therapy, molecular recognition and molecular electronics, and catalysis. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 Size, composition and surface structure are important factors determining the physical, chemical and biological properties of monolayer-protected noble metal nanoparticles. 4 , 11 , 12 To achieve chemical fine-tuning, understanding of their structures at the molecular level is crucial. 13 , 14 , 15 Thiol-stabilized Au nanoclusters represent an important class of noble metal nanoparticles whose molecular structures have been characterized by X-ray single-crystal diffractions 15 , 16 , 17 , 18 , 19 and successfully adopted to precisely tailor their electronic and surface properties. 20 , 21 However, in contrast to thiol-stabilized Au nanoclusters, no crystal structure determination has been reported on all-thiol-protected silver nanoparticles, although Ag or Au/Ag nanoclusters with uniform size and even with precise number of atoms have been widely achieved. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 Here we report on the first successful crystal structure determination and theoretical analysis of six all-thiol-protected silver and silver-gold intermetallic nanoparticles, namely three Ag 44 (SR) 30 and three Au 12 Ag 32 (SR) 30 nanoclusters stabilized with fluorinated arylthiols (SR=SPhF, SPhF 2 or SPhCF 3 ). The metal core forms a Keplerate solid of concentric icosahedral and dodecahedral atom shells, protected by six Ag 2 (SR) 5 units in octahedral geometry. The crystal unit cell includes positive counterions indicating a high negative charge of 4 − per nanocluster, and density functional theory (DFT) calculations confirm the expected electronic structure with an 18-electron superatom shell closure in the metal core. The nanoparticles display highly featured optical absorption spectra in the ultraviolet–visible region, and the theoretical analysis of the transitions reveals an important role played by the electron-rich ligand layer. Our results form a basis for further understanding, engineering and controlling of stability as well as electronic and optical properties of these interesting building blocks of novel nanomaterials. Results Synthesis A typical synthesis of [M 12 Ag 32 (SR) 30 ] 4− clusters involved the chemical reduction of metal precursors (that is, AgBF 4 and ClAuPPh 3 ) by an aqueous NaBH 4 in the presence of fluorinated arylthiol and PPh 4 Br in a mixed solvent of dichloromethane and methanol at 0 °C in an ice bath (see Methods for details). The crystallization of [M 12 Ag 32 (SR) 30 ] 4− clusters was performed by layering hexane into the CH 2 Cl 2 solutions of clusters at 4 °C. Slow recrystallization led to the formation of high-quality millimeter-sized single crystals ( Supplementary Fig. S1a ) for single-crystal analysis. Six different single crystals containing all-thiol-protected silver and silver-gold intermetallic clusters were successfully obtained depending on the fluorinated arylthiol used and also whether the Au precursor was introduced ( Table 1 and Supplementary Tables S1–S6 ). The obtained crystals are readily dissolved in organic solvents, such as CH 2 Cl 2 and DMF, to give transparent brown solutions ( Supplementary Fig. S1b ). It is noteworthy that one-batch synthesis of [M 12 Ag 32 (SR) 30 ] 4− clusters on a scale of tens of grams has been achieved by scaling up the reaction ( Supplementary Fig. S2 ). Table 1 A summary of crystallographic data for selected synthesized clusters with various surface thiolates*. Full size table Atomic structure As revealed by single-crystal analysis, all of the six crystals containing [M 12 Ag 32 (SR) 30 ] 4− (M=Ag, Au) clusters co-crystallized with PPh 4 + . Each cluster consists of a Keplerate two-shell M 12 @Ag 20 core protected by six Ag 2 (SR) 5 units on its surface ( Fig. 1a ). 34 , 35 The core of [M 12 Ag 32 (SR) 30 ] 4− clusters can be depicted as two concentric icosahedral and dodecahedral metal shells. The first shell is a hollow icosahedral cage of M 12 . The 20 M 3 faces of the icosahedral M 12 cage are fully face-capped by Ag atoms to form a two-shell M 12 @Ag 20 cage in a nearly perfect I h point symmetry ( Fig. 1b ). The M–M distances in the first M 12 shell are averaged at 2.780 and 2.829 Å, respectively, for the case of [Au 12 Ag 32 (SPhF 2 ) 30 ] 4− and [Ag 44 (SPhF 2 ) 30 ] 4− . As shown in Table 2 , the average M–M bond lengths in the first M 12 shell in all [M 12 Ag 32 (SR) 30 ] 4− clusters are slightly shorter than the M–M distance (2.884 Å for Au and 2.889 Å for Ag) in bulk face-centered cubic Au/Ag. The M–Ag distances between the M 12 core and the Ag 20 shell are", "role": "user" }, { "content": "Researchers at the Xiamen University in China and the University of Jyväskylä in Finland have characterized a series of stable 1.5 nm metal nanoclusters containing 44 metal atoms, stabilized by 30 organic thiol molecules on the surface. Two types of clusters were synthesized, containing either 44 silver atoms or an intermetallic cluster of 12 gold and 32 silver atoms. The work in the University of Jyväskylä is funded by the Academy of Finland. The special electronic structure of the clusters leads to peaked absorption of radiation in a wide region of ultraviolet and visible parts of the electromagnetic spectrum. These novel nanomaterials were synthesized first in 2009 by a group at MIT in the USA, but their atomic structure has not been known until now. This is the first case of a very stable silver-based cluster nanomaterial that can be synthesized in a macroscopic scale, currently of the order of 10 grams from one synthesis. This material is expected to be widely studied for optical, sensing and electron-transfer applications in the future. The results were reported online in Nature Communications on 4 September 2013. The experimental work was done in Xiamen by the group of Professor Nanfeng Zheng and the computational work by the group of Professor Hannu Häkkinen in the University of Jyväskylä. The other researchers involved were Huayang Yang, Yu Wang and Huaqi Huang in Xiamen University and Lars Gell, Sami Malola and Lauri Lehtovaara in the University of Jyväskylä. The computations were made at the CSC – IT Centre for Science in Espoo, Finland, and at the HRLS-GAUSS Centre in Stuttgart, Germany. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Noble metal nanoparticles stabilized by organic ligands are important for applications in assembly, site-specific bioconjugate labelling and sensing, drug delivery and medical therapy, molecular recognition and molecular electronics, and catalysis. Here we report crystal structures and theoretical analysis of three Ag 44 (SR) 30 and three Au 12 Ag 32 (SR) 30 intermetallic nanoclusters stabilized with fluorinated arylthiols (SR=SPhF, SPhF 2 or SPhCF 3 ). The nanocluster forms a Keplerate solid of concentric icosahedral and dodecahedral atom shells, protected by six Ag 2 (SR) 5 units. Positive counterions in the crystal indicate a high negative charge of 4 − per nanoparticle, and density functional theory calculations explain the stability as an 18-electron superatom shell closure in the metal core. Highly featured optical absorption spectra in the ultraviolet–visible region are analysed using time-dependent density functional perturbation theory. This work forms a basis for further understanding, engineering and controlling of stability as well as electronic and optical properties of these novel nanomaterials. Introduction Noble metal nanoparticles stabilized by organic ligand layer are the subject of an increasing number of studies owing to their applications in assembly, bio-labelling and sensing, drug delivery and medical therapy, molecular recognition and molecular electronics, and catalysis. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 Size, composition and surface structure are important factors determining the physical, chemical and biological properties of monolayer-protected noble metal nanoparticles. 4 , 11 , 12 To achieve chemical fine-tuning, understanding of their structures at the molecular level is crucial. 13 , 14 , 15 Thiol-stabilized Au nanoclusters represent an important class of noble metal nanoparticles whose molecular structures have been characterized by X-ray single-crystal diffractions 15 , 16 , 17 , 18 , 19 and successfully adopted to precisely tailor their electronic and surface properties. 20 , 21 However, in contrast to thiol-stabilized Au nanoclusters, no crystal structure determination has been reported on all-thiol-protected silver nanoparticles, although Ag or Au/Ag nanoclusters with uniform size and even with precise number of atoms have been widely achieved. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 Here we report on the first successful crystal structure determination and theoretical analysis of six all-thiol-protected silver and silver-gold intermetallic nanoparticles, namely three Ag 44 (SR) 30 and three Au 12 Ag 32 (SR) 30 nanoclusters stabilized with fluorinated arylthiols (SR=SPhF, SPhF 2 or SPhCF 3 ). The metal core forms a Keplerate solid of concentric icosahedral and dodecahedral atom shells, protected by six Ag 2 (SR) 5 units in octahedral geometry. The crystal unit cell includes positive counterions indicating a high negative charge of 4 − per nanocluster, and density functional theory (DFT) calculations confirm the expected electronic structure with an 18-electron superatom shell closure in the metal core. The nanoparticles display highly featured optical absorption spectra in the ultraviolet–visible region, and the theoretical analysis of the transitions reveals an important role played by the electron-rich ligand layer. Our results form a basis for further understanding, engineering and controlling of stability as well as electronic and optical properties of these interesting building blocks of novel nanomaterials. Results Synthesis A typical synthesis of [M 12 Ag 32 (SR) 30 ] 4− clusters involved the chemical reduction of metal precursors (that is, AgBF 4 and ClAuPPh 3 ) by an aqueous NaBH 4 in the presence of fluorinated arylthiol and PPh 4 Br in a mixed solvent of dichloromethane and methanol at 0 °C in an ice bath (see Methods for details). The crystallization of [M 12 Ag 32 (SR) 30 ] 4− clusters was performed by layering hexane into the CH 2 Cl 2 solutions of clusters at 4 °C. Slow recrystallization led to the formation of high-quality millimeter-sized single crystals ( Supplementary Fig. S1a ) for single-crystal analysis. Six different single crystals containing all-thiol-protected silver and silver-gold intermetallic clusters were successfully obtained depending on the fluorinated arylthiol used and also whether the Au precursor was introduced ( Table 1 and Supplementary Tables S1–S6 ). The obtained crystals are readily dissolved in organic solvents, such as CH 2 Cl 2 and DMF, to give transparent brown solutions ( Supplementary Fig. S1b ). It is noteworthy that one-batch synthesis of [M 12 Ag 32 (SR) 30 ] 4− clusters on a scale of tens of grams has been achieved by scaling up the reaction ( Supplementary Fig. S2 ). Table 1 A summary of crystallographic data for selected synthesized clusters with various surface thiolates*. Full size table Atomic structure As revealed by single-crystal analysis, all of the six crystals containing [M 12 Ag 32 (SR) 30 ] 4− (M=Ag, Au) clusters co-crystallized with PPh 4 + . Each cluster consists of a Keplerate two-shell M 12 @Ag 20 core protected by six Ag 2 (SR) 5 units on its surface ( Fig. 1a ). 34 , 35 The core of [M 12 Ag 32 (SR) 30 ] 4− clusters can be depicted as two concentric icosahedral and dodecahedral metal shells. The first shell is a hollow icosahedral cage of M 12 . The 20 M 3 faces of the icosahedral M 12 cage are fully face-capped by Ag atoms to form a two-shell M 12 @Ag 20 cage in a nearly perfect I h point symmetry ( Fig. 1b ). The M–M distances in the first M 12 shell are averaged at 2.780 and 2.829 Å, respectively, for the case of [Au 12 Ag 32 (SPhF 2 ) 30 ] 4− and [Ag 44 (SPhF 2 ) 30 ] 4− . As shown in Table 2 , the average M–M bond lengths in the first M 12 shell in all [M 12 Ag 32 (SR) 30 ] 4− clusters are slightly shorter than the M–M distance (2.884 Å for Au and 2.889 Å for Ag) in bulk face-centered cubic Au/Ag. The M–Ag distances between the M 12 core and the Ag 20 shell are<|im_end|> <|im_start|>assistant Researchers at the Xiamen University in China and the University of Jyväskylä in Finland have characterized a series of stable 1.5 nm metal nanoclusters containing 44 metal atoms, stabilized by 30 organic thiol molecules on the surface. Two types of clusters were synthesized, containing either 44 silver atoms or an intermetallic cluster of 12 gold and 32 silver atoms. The work in the University of Jyväskylä is funded by the Academy of Finland. The special electronic structure of the clusters leads to peaked absorption of radiation in a wide region of ultraviolet and visible parts of the electromagnetic spectrum. These novel nanomaterials were synthesized first in 2009 by a group at MIT in the USA, but their atomic structure has not been known until now. This is the first case of a very stable silver-based cluster nanomaterial that can be synthesized in a macroscopic scale, currently of the order of 10 grams from one synthesis. This material is expected to be widely studied for optical, sensing and electron-transfer applications in the future. The results were reported online in Nature Communications on 4 September 2013. The experimental work was done in Xiamen by the group of Professor Nanfeng Zheng and the computational work by the group of Professor Hannu Häkkinen in the University of Jyväskylä. The other researchers involved were Huayang Yang, Yu Wang and Huaqi Huang in Xiamen University and Lars Gell, Sami Malola and Lauri Lehtovaara in the University of Jyväskylä. The computations were made at the CSC – IT Centre for Science in Espoo, Finland, and at the HRLS-GAUSS Centre in Stuttgart, Germany. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Matter-wave interferometry has become an essential tool in studies on the foundations of quantum physics 1 and for precision measurements 2 , 3 , 4 , 5 , 6 . Mechanical gratings have played an important role as coherent beamsplitters for atoms 7 , molecules and clusters 8 , 9 , because the basic diffraction mechanism is the same for all particles. However, polarizable objects may experience van der Waals shifts when they pass the grating walls 10 , 11 , and the undesired dephasing may prevent interferometry with massive objects 12 . Here, we explore how to minimize this perturbation by reducing the thickness of the diffraction mask to its ultimate physical limit, that is, the thickness of a single atom. We have fabricated diffraction masks in single-layer and bilayer graphene as well as in a 1 nm thin carbonaceous biphenyl membrane. We identify conditions to transform an array of single-layer graphene nanoribbons into a grating of carbon nanoscrolls. We show that all these ultrathin nanomasks can be used for high-contrast quantum diffraction of massive molecules. They can be seen as a nanomechanical answer to the question debated by Bohr and Einstein 13 of whether a softly suspended double slit would destroy quantum interference. In agreement with Bohr's reasoning we show that quantum coherence prevails, even in the limit of atomically thin gratings. Main The key to all matter-wave interferometry is coherent beamsplitters, which divide each incident wave into separated wavelets with well-defined phase relations 2 , 14 . Modern atom interferometry often uses the momentum recoil of resonant laser light to split the atomic wave 15 , 16 , but mechanical masks 7 , 9 , as well as optical phase 17 or absorption 18 gratings, can also be used to divide a matter-wave front. The universality of mechanical gratings is compromised by the van der Waals potential, so it is important to ask to what extent it is possible to minimize this interaction by reducing the grating thickness. This technological feat—to create freestanding nanogratings in even a single layer of atoms 19 —is accompanied by the fundamental question of whether the path of a massive particle through the multi-slit array will become significantly entangled with the mechanical motion of the recoiling ultrathin structure. If this were the case we would expect to observe loss of the interference contrast. Using a focused ion beam we were able to mill a periodic diffraction grating into a single layer of graphene that was suspended over a silicon nitride (SiN x ) membrane ( Fig. 1a ; see Methods and Supplementary Section 1 for details). The nanoribbons (64 ± 3 nm wide) were written with a period of 88 ± 3 nm ( Fig. 1c ). These spontaneously transform into carbon nanoscrolls 20 , here with a diameter down to 8 nm ( Fig. 1b , Supplementary Section 1.3 ). However, scanning transmission electron microscopy (STEM) revealed that shorter grating bars form stable, flat single-layer graphene structures ( Fig. 1e ). Figure 1: Exploring the ultimate limit of nanomechanical diffraction gratings. a , Gratings written into single-layer graphene suspended across a holey SiN x membrane. b , c , Carbon nanoscrolls spontaneously form when the aspect ratio of the graphene nanoribbons becomes too high. Folds and contaminations can prevent the membrane from curling. d , STEM visualizes the hexagonal atomic structure of single-layer graphene. e , Reducing the length of the 40-nm-wide nanoribbons to 250 nm prevents curling. f , Adding another layer of carbon atoms (bilayer graphene) allows us to substantially extend the aspect ratio and keep the grating flat. g , Large-area gratings can also be written into a carbonaceous biphenyl membrane. h , Grating in silicon nitride (thickness of 45 nm). Full size image We were also able to write gratings into bilayer graphene suspended across a lacey carbon mesh ( Fig. 1f ). The second layer of carbon atoms suppresses the formation of nanoscrolls entirely on the observed scale. Bilayer graphene may also form bonds at open cuts and thus expose closed edges and a thicker wall than expected based on the number of layers alone 21 . We compared these structures to an insulating structure of almost identical thickness, the carbonaceous biphenyl membrane 22 (also on lacey carbon, Fig. 1g ), and reference all images to the diffraction of molecules at a 45-nm-thick silicon nitride grating ( Fig. 1h ) 23 . Figure 1 demonstrates that stable structures can be written even into atomically thin membranes. The diffraction pattern behind a purely absorptive periodic mask—that is, without any phase modulation—can be described as the convolution of two contributions: diffraction at each single slit of width s and diffraction at an array of infinitely thin slits of period d . The fringe positions are well described by wave theory. The fringe amplitudes are modulated by the single-slit diffraction pattern. On comparing Fig. 2a–e , vast differences in the diffraction at geometrically similar gratings can be seen. With 45-nm-thick silicon nitride ( Fig. 2a ) we observe interference up to the ninth diffraction order, which can only be understood if we complement the quantum wave model by the assumption that the position-dependent phases accumulated in the presence of van der Waals forces alter the effective transmission function. Approximating this interaction by reducing the effective slit width 10 ( Supplementary Section 3 ) allows us to estimate the strength of the van der Waals interactions. For silicon nitride the analysis yields an effective slit width s eff of 15 nm—a reduction of the open width by s / s eff = 3.3. This influence is strongly reduced for the single-layer graphene grating, probably the thinnest conceivable diffraction element ( Fig. 2e , s / s eff = 1.7). As expected, this leads to a strong suppression of all diffraction orders beyond the first. This holds true—and even more so—for gratings made from nanoscrolls ( s / s eff = 1.3), which maximize the opening fraction (the ratio of", "role": "user" }, { "content": "Quantum physics tell us that even massive particles can behave like waves, as if they could be in several places at once. This phenomenon is typically proven in the diffraction of a matter wave at a grating. In a European collaboration, researchers carried this idea to the extreme and observed the delocalization of molecules at the thinnest possible grating, a mask milled into a single layer of atoms. The presented experiments explore the technical limits of matter wave technologies and respond to a famous Gedanken experiment by Einstein and Bohr of almost 80 years ago. The results are published in the journal Nature Nanotechnology. The quantum mechanical wave nature of matter is the basis for a number of modern technologies like high resolution electron microscopy, neutron-based studies on solid state materials or highly sensitive inertial sensors working with atoms. The research in the group around Prof. Markus Arndt at the University of Vienna is focused on how one can extend such technologies to large molecules and cluster. In order to demonstrate the quantum mechanical nature of a massive object it has to be delocalized first. This is achieved by virtue of Heisenberg's uncertainty relation: If molecules are emitted from a point-like source, they start to 'forget' their position after a while and delocalize. If you place a grating into their way, they cannot know, not even in principle, through which slit they are flying. It is as if they traversed several slits at the same time. This results in a characteristic distribution of particles behind the grating, known as the diffraction or interference pattern. It can only be understood if we take the particles' quantum mechanical wave nature into account. At the technological limit In a European collaboration (NANOQUESTFIT) together with partners around Professor Ori Cheshnovsky at Tel Aviv University (where all nanomasks were written), as well as with support by groups in Jena (growth of biphenyl membranes, Prof. Turchanin), and Vienna (High-Resolution Electron Microscopy, Prof. Meyer) they now demonstrated for the first time that such gratings can be fabricated even from the thinnest conceivable membranes. They milled transmission masks into ultra-thin membranes of silicon nitride, biphenyl molecules or carbon with a focussed ion beam and analysed them with ultra-high resolution electron microscopy. The team succeeded in fabricating stable and sufficiently large gratings even in atomically thin single layer graphene. In previous quantum experiments of the same EU collaboration, the thickness of diffraction masks was already as thin as a hundredth of the diameter of a hair. However, even such structures were still too thick for the diffraction of molecules composed of dozens of atoms. The same force that allows geckos to climb walls restricts the applicability of material gratings in quantum diffraction experiments: Molecules are attracted to the grating bars like the geckos' toes to the wall. However, once they stick to the surface they are lost to the experiment. A grand challenge was to reduce the material thickness and thus the attractive interactions of these masks down to the ultimate limit while retaining a mechanically stable structure. \"These are the thinnest possible diffraction masks for matter wave optics. And they do their job very well\", says Christian Brand, the lead author of this publication. \"Given the gratings' thickness of a millionth of a millimetre, the interaction time between the mask and the molecule is roughly a trillion times shorter than a second. We see that this is compatible with high contrast quantum interference\". A thought experiment of Bohr and Einstein The bars of the nanogratings look resemble the strings of a miniature harp. One may therefore wonder whether the molecules induce vibrations in these strings when they are deflected to the left or the right during quantum diffraction. If this were the case the grating bars could reveal the molecular path through the grating and quantum interference should be destroyed. The experiment thus realizes a thought experiment that was discussed by Nils Bohr and Albert Einstein already decades ago: They asked whether it is possible to know the path a quantum takes through a double slit while observing its wave nature. The solution to this riddle is again provided by Heisenberg's uncertainty principle: Although the molecules give the grating a little kick in the diffraction process this recoil remains always smaller than the quantum mechanical momentum uncertainty of the grating itself. It therefore remains undetectable. Here it is shown that this applies even to membranes that are only one atom thick. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Matter-wave interferometry has become an essential tool in studies on the foundations of quantum physics 1 and for precision measurements 2 , 3 , 4 , 5 , 6 . Mechanical gratings have played an important role as coherent beamsplitters for atoms 7 , molecules and clusters 8 , 9 , because the basic diffraction mechanism is the same for all particles. However, polarizable objects may experience van der Waals shifts when they pass the grating walls 10 , 11 , and the undesired dephasing may prevent interferometry with massive objects 12 . Here, we explore how to minimize this perturbation by reducing the thickness of the diffraction mask to its ultimate physical limit, that is, the thickness of a single atom. We have fabricated diffraction masks in single-layer and bilayer graphene as well as in a 1 nm thin carbonaceous biphenyl membrane. We identify conditions to transform an array of single-layer graphene nanoribbons into a grating of carbon nanoscrolls. We show that all these ultrathin nanomasks can be used for high-contrast quantum diffraction of massive molecules. They can be seen as a nanomechanical answer to the question debated by Bohr and Einstein 13 of whether a softly suspended double slit would destroy quantum interference. In agreement with Bohr's reasoning we show that quantum coherence prevails, even in the limit of atomically thin gratings. Main The key to all matter-wave interferometry is coherent beamsplitters, which divide each incident wave into separated wavelets with well-defined phase relations 2 , 14 . Modern atom interferometry often uses the momentum recoil of resonant laser light to split the atomic wave 15 , 16 , but mechanical masks 7 , 9 , as well as optical phase 17 or absorption 18 gratings, can also be used to divide a matter-wave front. The universality of mechanical gratings is compromised by the van der Waals potential, so it is important to ask to what extent it is possible to minimize this interaction by reducing the grating thickness. This technological feat—to create freestanding nanogratings in even a single layer of atoms 19 —is accompanied by the fundamental question of whether the path of a massive particle through the multi-slit array will become significantly entangled with the mechanical motion of the recoiling ultrathin structure. If this were the case we would expect to observe loss of the interference contrast. Using a focused ion beam we were able to mill a periodic diffraction grating into a single layer of graphene that was suspended over a silicon nitride (SiN x ) membrane ( Fig. 1a ; see Methods and Supplementary Section 1 for details). The nanoribbons (64 ± 3 nm wide) were written with a period of 88 ± 3 nm ( Fig. 1c ). These spontaneously transform into carbon nanoscrolls 20 , here with a diameter down to 8 nm ( Fig. 1b , Supplementary Section 1.3 ). However, scanning transmission electron microscopy (STEM) revealed that shorter grating bars form stable, flat single-layer graphene structures ( Fig. 1e ). Figure 1: Exploring the ultimate limit of nanomechanical diffraction gratings. a , Gratings written into single-layer graphene suspended across a holey SiN x membrane. b , c , Carbon nanoscrolls spontaneously form when the aspect ratio of the graphene nanoribbons becomes too high. Folds and contaminations can prevent the membrane from curling. d , STEM visualizes the hexagonal atomic structure of single-layer graphene. e , Reducing the length of the 40-nm-wide nanoribbons to 250 nm prevents curling. f , Adding another layer of carbon atoms (bilayer graphene) allows us to substantially extend the aspect ratio and keep the grating flat. g , Large-area gratings can also be written into a carbonaceous biphenyl membrane. h , Grating in silicon nitride (thickness of 45 nm). Full size image We were also able to write gratings into bilayer graphene suspended across a lacey carbon mesh ( Fig. 1f ). The second layer of carbon atoms suppresses the formation of nanoscrolls entirely on the observed scale. Bilayer graphene may also form bonds at open cuts and thus expose closed edges and a thicker wall than expected based on the number of layers alone 21 . We compared these structures to an insulating structure of almost identical thickness, the carbonaceous biphenyl membrane 22 (also on lacey carbon, Fig. 1g ), and reference all images to the diffraction of molecules at a 45-nm-thick silicon nitride grating ( Fig. 1h ) 23 . Figure 1 demonstrates that stable structures can be written even into atomically thin membranes. The diffraction pattern behind a purely absorptive periodic mask—that is, without any phase modulation—can be described as the convolution of two contributions: diffraction at each single slit of width s and diffraction at an array of infinitely thin slits of period d . The fringe positions are well described by wave theory. The fringe amplitudes are modulated by the single-slit diffraction pattern. On comparing Fig. 2a–e , vast differences in the diffraction at geometrically similar gratings can be seen. With 45-nm-thick silicon nitride ( Fig. 2a ) we observe interference up to the ninth diffraction order, which can only be understood if we complement the quantum wave model by the assumption that the position-dependent phases accumulated in the presence of van der Waals forces alter the effective transmission function. Approximating this interaction by reducing the effective slit width 10 ( Supplementary Section 3 ) allows us to estimate the strength of the van der Waals interactions. For silicon nitride the analysis yields an effective slit width s eff of 15 nm—a reduction of the open width by s / s eff = 3.3. This influence is strongly reduced for the single-layer graphene grating, probably the thinnest conceivable diffraction element ( Fig. 2e , s / s eff = 1.7). As expected, this leads to a strong suppression of all diffraction orders beyond the first. This holds true—and even more so—for gratings made from nanoscrolls ( s / s eff = 1.3), which maximize the opening fraction (the ratio of<|im_end|> <|im_start|>assistant Quantum physics tell us that even massive particles can behave like waves, as if they could be in several places at once. This phenomenon is typically proven in the diffraction of a matter wave at a grating. In a European collaboration, researchers carried this idea to the extreme and observed the delocalization of molecules at the thinnest possible grating, a mask milled into a single layer of atoms. The presented experiments explore the technical limits of matter wave technologies and respond to a famous Gedanken experiment by Einstein and Bohr of almost 80 years ago. The results are published in the journal Nature Nanotechnology. The quantum mechanical wave nature of matter is the basis for a number of modern technologies like high resolution electron microscopy, neutron-based studies on solid state materials or highly sensitive inertial sensors working with atoms. The research in the group around Prof. Markus Arndt at the University of Vienna is focused on how one can extend such technologies to large molecules and cluster. In order to demonstrate the quantum mechanical nature of a massive object it has to be delocalized first. This is achieved by virtue of Heisenberg's uncertainty relation: If molecules are emitted from a point-like source, they start to 'forget' their position after a while and delocalize. If you place a grating into their way, they cannot know, not even in principle, through which slit they are flying. It is as if they traversed several slits at the same time. This results in a characteristic distribution of particles behind the grating, known as the diffraction or interference pattern. It can only be understood if we take the particles' quantum mechanical wave nature into account. At the technological limit In a European collaboration (NANOQUESTFIT) together with partners around Professor Ori Cheshnovsky at Tel Aviv University (where all nanomasks were written), as well as with support by groups in Jena (growth of biphenyl membranes, Prof. Turchanin), and Vienna (High-Resolution Electron Microscopy, Prof. Meyer) they now demonstrated for the first time that such gratings can be fabricated even from the thinnest conceivable membranes. They milled transmission masks into ultra-thin membranes of silicon nitride, biphenyl molecules or carbon with a focussed ion beam and analysed them with ultra-high resolution electron microscopy. The team succeeded in fabricating stable and sufficiently large gratings even in atomically thin single layer graphene. In previous quantum experiments of the same EU collaboration, the thickness of diffraction masks was already as thin as a hundredth of the diameter of a hair. However, even such structures were still too thick for the diffraction of molecules composed of dozens of atoms. The same force that allows geckos to climb walls restricts the applicability of material gratings in quantum diffraction experiments: Molecules are attracted to the grating bars like the geckos' toes to the wall. However, once they stick to the surface they are lost to the experiment. A grand challenge was to reduce the material thickness and thus the attractive interactions of these masks down to the ultimate limit while retaining a mechanically stable structure. "These are the thinnest possible diffraction masks for matter wave optics. And they do their job very well", says Christian Brand, the lead author of this publication. "Given the gratings' thickness of a millionth of a millimetre, the interaction time between the mask and the molecule is roughly a trillion times shorter than a second. We see that this is compatible with high contrast quantum interference". A thought experiment of Bohr and Einstein The bars of the nanogratings look resemble the strings of a miniature harp. One may therefore wonder whether the molecules induce vibrations in these strings when they are deflected to the left or the right during quantum diffraction. If this were the case the grating bars could reveal the molecular path through the grating and quantum interference should be destroyed. The experiment thus realizes a thought experiment that was discussed by Nils Bohr and Albert Einstein already decades ago: They asked whether it is possible to know the path a quantum takes through a double slit while observing its wave nature. The solution to this riddle is again provided by Heisenberg's uncertainty principle: Although the molecules give the grating a little kick in the diffraction process this recoil remains always smaller than the quantum mechanical momentum uncertainty of the grating itself. It therefore remains undetectable. Here it is shown that this applies even to membranes that are only one atom thick. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Developmental plasticity of root system architecture is crucial for plant performance in nutrient-poor soils. Roots of plants grown under mild nitrogen (N) deficiency show a foraging response characterized by increased root length but mechanisms underlying this developmental plasticity are still elusive. By employing natural variation in Arabidopsis accessions, we show that the brassinosteroid (BR) signaling kinase BSK3 modulates root elongation under mild N deficiency. In particular, a proline to leucine substitution in the predicted kinase domain of BSK3 enhances BR sensitivity and signaling to increase the extent of root elongation. We further show that low N specifically upregulates transcript levels of the BR co-receptor BAK1 to activate BR signaling and stimulate root elongation. Altogether, our results uncover a role of BR signaling in root elongation under low N. The BSK3 alleles identified here provide targets for improving root growth of crops growing under limited N conditions. Introduction In quantitative terms, nitrogen (N) is the mineral element required in largest amounts by plants. However, soils in natural or agro-ecosystems often do not provide sufficient levels of N to sustain optimal plant growth and development. As soil N constantly undergoes transformation processes, pool sizes of different inorganic and organic N forms change frequently, so that plant-available N pools can vary largely over time and within very short horizontal and vertical distances 1 . Thus, to optimize access to N under limiting conditions, root systems must continuously sense and respond to local or temporal fluctuations in N availability 2 , 3 , 4 . Previous experiments with Arabidopsis thaliana have shown that specific root architectural modifications can be induced by nutrient-derived signals that act locally 5 , 6 , 7 , 8 or systemically 9 , 10 . In growth substrates with heterogeneous N availability, plant roots preferentially colonize N-enriched patches by targeted lateral root development. Whereas nitrate (NO 3 − ) mainly stimulates lateral root elongation 5 , 6 , 11 , ammonium (NH 4 + ) induces lateral root branching 7 , supporting the view that these two major inorganic N forms shape root system architecture in a complementary manner. When N is evenly distributed in the substrate, root system architecture responds to a limiting dose of N in a dual manner 9 . Being exposed to very low external N, plants adopt a “survival strategy,” in which the elongation of both primary and lateral roots, as well as the emergence of new lateral roots is inhibited 9 , 12 . Besides the involvement of NRT1.1-dependent auxin removal from lateral root primordia 13 , this root architectural modification also depends on a regulatory module consisting of CLE-type signaling peptides and their receptor protein CLV1 14 , 15 . In N-deficient roots, CLE1 , CLE3 , CLE4 , and CLE7 are upregulated and their corresponding peptides are suggested to move from root pericycle cells to phloem companion cells, where they interact with CLV1 to inhibit the outgrowth and emergence of lateral roots 14 . In contrast to severe N limitation, external N levels that induce only mild deficiency stimulate the emergence of lateral roots 16 and especially the elongation of primary and lateral roots 9 , 12 . Although this stimulatory response is of particular interest as it reflects a “systemic foraging strategy” that increases the soil volume explored by the root system, it is the least understood N-dependent architectural adjustment. Also here auxin appears to play an active role, as the auxin biosynthesis gene TAR2 is upregulated by low N and the tar2 mutant displays inhibited lateral root emergence under mild N deficiency 16 . However, as the length of primary and lateral roots in tar2 mutants remained unaffected, TAR2-dependent auxin biosynthesis alone cannot explain how mild N deficiency stimulates root elongation. Here we assess the natural variation in root growth under mild N deficiency in 200 accessions of A . thaliana . By performing a genome-wide association study (GWAS), we identify BSK3 (brassinosteroid signaling kinase 3), which mediates brassinosteroid (BR) signaling downstream of the BR receptors, as a major determinant for primary root length adjustment to low N. Furthermore, we demonstrate that low N activates BR signaling by upregulating the transcription of BAK1 , and that allelic variation of BSK3 coordinates the signaling amplitude that tunes the root growth to external N availability. Results GWAS maps primary root length variation at low N to BSK3 We set out to identify genetic components that modulate root growth under mild N deficiency by genome-wide association (GWA) mapping. For this purpose, we used a diverse panel of 200 accessions of A . thaliana reflecting a wide geographic distribution (Supplementary Fig. 1 ). After 1 week of pre-culture with sufficient N, plants were transferred to either 11.4 mM N (high N, HN) or 0.55 mM N (low N, LN), a concentration that induces a strong systemic root foraging response in the accession Col-0 9 . After 9 days on treatments, we measured the primary root length of all accessions and observed a high degree of natural variation with primary root lengths ranging from 3 to 10.8 cm at HN and from 3.5 to 12.5 cm at LN (Fig. 1a , Supplementary Data 1 ). On average, primary roots of all examined accessions were 16% longer at LN than at HN ( P < 2.2e − 16; Fig. 1a ). The broad-sense heritability ( h 2 ) for primary root length was estimated to be 88.8% and 85.7% for HN and LN, respectively. Fig. 1 Genetic variation and GWAS of primary root length grown under low N. a Reaction norms and phenotypic variation of primary root length of 200 natural accessions of A . thaliana grown under HN vs. LN for 9 days. Purple diamonds represent means of primary root length for 200 accessions under each N treatment. b Manhattan plot for the SNP associations to primary root length under LN. Negative log 10 -transformed P -values from a genome-wide scan were plotted against positions on each of the five chromosomes of A .", "role": "user" }, { "content": "As sessile organisms, plants rely on their ability to adapt the development and growth of their roots in response to changing nutrient conditions. One such response, known to be displayed by plants grown in low nitrogen conditions, is the elongation of primary and lateral roots to explore the surrounding soil. This adaption to the lack of the essential element nitrogen is of particular interest, as it reflects a \"foraging strategy,\" by which the root system can exploit nutrients from a larger soil volume. Until recently, this was the least understood nitrogen-dependent root response. Scientists from the IPK in Gatersleben have now identified the hormone pathway regulating root foraging under low nitrogen conditions and a signalling component that modulates the intensity of this response. These findings open up the possibility of breeding crops with root systems enabling more efficient nitrogen uptake. The amount and form of plant-available nutrients fluctuates in soils, for example in dependence of soil moisture or microbial transformation processes of nutrients. Plants sense changes in their nutritional status and respond to these by tailoring the growth and development of their roots. These responses express in an altered degree of branching, extension, placement, and growth direction of individual parts of the root system. Nitrogen is an essential mineral element and nutrient for plants. When nitrogen availability is low, plant roots preferentially grow into nitrogen-enriched soil patches by locally expanding their lateral roots. As soon as plants run into nitrogen deficiency, they immediately induce a foraging response, in which roots elongate to explore a larger soil volume. The regulatory mechanisms underlying this nitrogen-dependent root response were previously unknown. Researchers from the IPK in Gatersleben have now discovered that a class of steroid hormones modulate root foraging under low nitrogen conditions and thereby determine the extent of this response. The findings were published in Nature Communications. In this study, scientists from the research group \"Molecular Plant Nutrition,\" led by Prof. N. von Wirén, assessed the natural variation in root growth under mild nitrogen deficiency in 200 accessions of the model plant Arabidopsis thaliana. Employing genome-wide association mapping with support of the \"Heterosis\" group led by Prof. T. Altmann, the researchers were able to show that BSK3, a brassinosteroid signaling kinase, is modulating the extent of root elongation under low nitrogen. Further, they demonstrated that mild nitrogen deficiency activates brassinosteroid signaling by upregulating the transcript levels of the brassinosteroid co-receptor BAK1 that enhances the sensitivity of root cells to brassinosteroids. The results reveal a previously unknown role of brassinosteroid-type plant hormones in shaping root systems in response to nutrient deficiencies. This novel insight allows a deeper understanding of the regulation behind adaptive responses of plants to changes in nitrogen availability, but also provides a perspective for practical application in agriculture. As a \"major driver of plant growth,\" nitrogen is an indispensable element in agricultural plant production. However, nitrogen fertilizers must be used with care, as a surplus of nitrogen in the soil can have a detrimental impact on the environment, for example by leading to soil acidification or to eutrophication of waterbodies. Therefore, the breeding of crops, which better exploit the soil for nutrients, is highly desirable as they may require less fertilizer. The researchers of this study see their discovery of the regulatory role of BSK3 as novel opportunity to approach this matter. By exploiting naturally occurring allelic versions of BSK3 or by the generation of de-novo variants by precise genome editing, plant breeders could develop new crop cultivars with larger root systems, giving crop species the sought-after mechanisms to perform better at low nitrogen fertilizer inputs. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Developmental plasticity of root system architecture is crucial for plant performance in nutrient-poor soils. Roots of plants grown under mild nitrogen (N) deficiency show a foraging response characterized by increased root length but mechanisms underlying this developmental plasticity are still elusive. By employing natural variation in Arabidopsis accessions, we show that the brassinosteroid (BR) signaling kinase BSK3 modulates root elongation under mild N deficiency. In particular, a proline to leucine substitution in the predicted kinase domain of BSK3 enhances BR sensitivity and signaling to increase the extent of root elongation. We further show that low N specifically upregulates transcript levels of the BR co-receptor BAK1 to activate BR signaling and stimulate root elongation. Altogether, our results uncover a role of BR signaling in root elongation under low N. The BSK3 alleles identified here provide targets for improving root growth of crops growing under limited N conditions. Introduction In quantitative terms, nitrogen (N) is the mineral element required in largest amounts by plants. However, soils in natural or agro-ecosystems often do not provide sufficient levels of N to sustain optimal plant growth and development. As soil N constantly undergoes transformation processes, pool sizes of different inorganic and organic N forms change frequently, so that plant-available N pools can vary largely over time and within very short horizontal and vertical distances 1 . Thus, to optimize access to N under limiting conditions, root systems must continuously sense and respond to local or temporal fluctuations in N availability 2 , 3 , 4 . Previous experiments with Arabidopsis thaliana have shown that specific root architectural modifications can be induced by nutrient-derived signals that act locally 5 , 6 , 7 , 8 or systemically 9 , 10 . In growth substrates with heterogeneous N availability, plant roots preferentially colonize N-enriched patches by targeted lateral root development. Whereas nitrate (NO 3 − ) mainly stimulates lateral root elongation 5 , 6 , 11 , ammonium (NH 4 + ) induces lateral root branching 7 , supporting the view that these two major inorganic N forms shape root system architecture in a complementary manner. When N is evenly distributed in the substrate, root system architecture responds to a limiting dose of N in a dual manner 9 . Being exposed to very low external N, plants adopt a “survival strategy,” in which the elongation of both primary and lateral roots, as well as the emergence of new lateral roots is inhibited 9 , 12 . Besides the involvement of NRT1.1-dependent auxin removal from lateral root primordia 13 , this root architectural modification also depends on a regulatory module consisting of CLE-type signaling peptides and their receptor protein CLV1 14 , 15 . In N-deficient roots, CLE1 , CLE3 , CLE4 , and CLE7 are upregulated and their corresponding peptides are suggested to move from root pericycle cells to phloem companion cells, where they interact with CLV1 to inhibit the outgrowth and emergence of lateral roots 14 . In contrast to severe N limitation, external N levels that induce only mild deficiency stimulate the emergence of lateral roots 16 and especially the elongation of primary and lateral roots 9 , 12 . Although this stimulatory response is of particular interest as it reflects a “systemic foraging strategy” that increases the soil volume explored by the root system, it is the least understood N-dependent architectural adjustment. Also here auxin appears to play an active role, as the auxin biosynthesis gene TAR2 is upregulated by low N and the tar2 mutant displays inhibited lateral root emergence under mild N deficiency 16 . However, as the length of primary and lateral roots in tar2 mutants remained unaffected, TAR2-dependent auxin biosynthesis alone cannot explain how mild N deficiency stimulates root elongation. Here we assess the natural variation in root growth under mild N deficiency in 200 accessions of A . thaliana . By performing a genome-wide association study (GWAS), we identify BSK3 (brassinosteroid signaling kinase 3), which mediates brassinosteroid (BR) signaling downstream of the BR receptors, as a major determinant for primary root length adjustment to low N. Furthermore, we demonstrate that low N activates BR signaling by upregulating the transcription of BAK1 , and that allelic variation of BSK3 coordinates the signaling amplitude that tunes the root growth to external N availability. Results GWAS maps primary root length variation at low N to BSK3 We set out to identify genetic components that modulate root growth under mild N deficiency by genome-wide association (GWA) mapping. For this purpose, we used a diverse panel of 200 accessions of A . thaliana reflecting a wide geographic distribution (Supplementary Fig. 1 ). After 1 week of pre-culture with sufficient N, plants were transferred to either 11.4 mM N (high N, HN) or 0.55 mM N (low N, LN), a concentration that induces a strong systemic root foraging response in the accession Col-0 9 . After 9 days on treatments, we measured the primary root length of all accessions and observed a high degree of natural variation with primary root lengths ranging from 3 to 10.8 cm at HN and from 3.5 to 12.5 cm at LN (Fig. 1a , Supplementary Data 1 ). On average, primary roots of all examined accessions were 16% longer at LN than at HN ( P < 2.2e − 16; Fig. 1a ). The broad-sense heritability ( h 2 ) for primary root length was estimated to be 88.8% and 85.7% for HN and LN, respectively. Fig. 1 Genetic variation and GWAS of primary root length grown under low N. a Reaction norms and phenotypic variation of primary root length of 200 natural accessions of A . thaliana grown under HN vs. LN for 9 days. Purple diamonds represent means of primary root length for 200 accessions under each N treatment. b Manhattan plot for the SNP associations to primary root length under LN. Negative log 10 -transformed P -values from a genome-wide scan were plotted against positions on each of the five chromosomes of A .<|im_end|> <|im_start|>assistant As sessile organisms, plants rely on their ability to adapt the development and growth of their roots in response to changing nutrient conditions. One such response, known to be displayed by plants grown in low nitrogen conditions, is the elongation of primary and lateral roots to explore the surrounding soil. This adaption to the lack of the essential element nitrogen is of particular interest, as it reflects a "foraging strategy," by which the root system can exploit nutrients from a larger soil volume. Until recently, this was the least understood nitrogen-dependent root response. Scientists from the IPK in Gatersleben have now identified the hormone pathway regulating root foraging under low nitrogen conditions and a signalling component that modulates the intensity of this response. These findings open up the possibility of breeding crops with root systems enabling more efficient nitrogen uptake. The amount and form of plant-available nutrients fluctuates in soils, for example in dependence of soil moisture or microbial transformation processes of nutrients. Plants sense changes in their nutritional status and respond to these by tailoring the growth and development of their roots. These responses express in an altered degree of branching, extension, placement, and growth direction of individual parts of the root system. Nitrogen is an essential mineral element and nutrient for plants. When nitrogen availability is low, plant roots preferentially grow into nitrogen-enriched soil patches by locally expanding their lateral roots. As soon as plants run into nitrogen deficiency, they immediately induce a foraging response, in which roots elongate to explore a larger soil volume. The regulatory mechanisms underlying this nitrogen-dependent root response were previously unknown. Researchers from the IPK in Gatersleben have now discovered that a class of steroid hormones modulate root foraging under low nitrogen conditions and thereby determine the extent of this response. The findings were published in Nature Communications. In this study, scientists from the research group "Molecular Plant Nutrition," led by Prof. N. von Wirén, assessed the natural variation in root growth under mild nitrogen deficiency in 200 accessions of the model plant Arabidopsis thaliana. Employing genome-wide association mapping with support of the "Heterosis" group led by Prof. T. Altmann, the researchers were able to show that BSK3, a brassinosteroid signaling kinase, is modulating the extent of root elongation under low nitrogen. Further, they demonstrated that mild nitrogen deficiency activates brassinosteroid signaling by upregulating the transcript levels of the brassinosteroid co-receptor BAK1 that enhances the sensitivity of root cells to brassinosteroids. The results reveal a previously unknown role of brassinosteroid-type plant hormones in shaping root systems in response to nutrient deficiencies. This novel insight allows a deeper understanding of the regulation behind adaptive responses of plants to changes in nitrogen availability, but also provides a perspective for practical application in agriculture. As a "major driver of plant growth," nitrogen is an indispensable element in agricultural plant production. However, nitrogen fertilizers must be used with care, as a surplus of nitrogen in the soil can have a detrimental impact on the environment, for example by leading to soil acidification or to eutrophication of waterbodies. Therefore, the breeding of crops, which better exploit the soil for nutrients, is highly desirable as they may require less fertilizer. The researchers of this study see their discovery of the regulatory role of BSK3 as novel opportunity to approach this matter. By exploiting naturally occurring allelic versions of BSK3 or by the generation of de-novo variants by precise genome editing, plant breeders could develop new crop cultivars with larger root systems, giving crop species the sought-after mechanisms to perform better at low nitrogen fertilizer inputs. <|im_end|>

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2804, 2731, 520, 3428, 47503, 65391, 11374, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract PARP3 is a member of the ADP-ribosyl transferase superfamily that we show accelerates the repair of chromosomal DNA single-strand breaks in avian DT40 cells. Two-dimensional nuclear magnetic resonance experiments reveal that PARP3 employs a conserved DNA-binding interface to detect and stably bind DNA breaks and to accumulate at sites of chromosome damage. PARP3 preferentially binds to and is activated by mononucleosomes containing nicked DNA and which target PARP3 trans-ribosylation activity to a single-histone substrate. Although nicks in naked DNA stimulate PARP3 autoribosylation, nicks in mononucleosomes promote the trans-ribosylation of histone H2B specifically at Glu2. These data identify PARP3 as a molecular sensor of nicked nucleosomes and demonstrate, for the first time, the ribosylation of chromatin at a site-specific DNA single-strand break. Introduction Chromosomal single-strand breaks (SSBs) are the most common DNA lesions arising in cells, arising at a frequency of tens-of-thousands per cell per day 1 , 2 . SSBs can arise directly as a result of oxidative attack of deoxyribose or indirectly as products of topoisomerase activity or DNA base excision repair. The threat posed by unrepaired SSBs is illustrated by the neurological dysfunction observed in individuals in which SSB repair (SSBR) is attenuated 1 , 3 . The detection of at least a subset of SSBs is accelerated by a family of enzymes known as (ADP-ribosyl) transferases (ARTs) that catalyse mono- or poly-ADP-ribosylation; a post-translational modification in which proteins are covalently modified with single or multiple units of ADP-ribose 4 , 5 . Two such enzymes are so far implicated in SSB detection and repair; PARP1 (ADPRT1/ART1), and PARP2 (ADPRT2/ART2). PARP1 is the archetypal SSB sensor and is responsible for most of the cellular poly (ADP-ribosylation) activity following DNA strand breakage 6 , 7 , with PARP2 accounting for 5–15% of this activity and fulfilling a partially overlapping role with PARP1 (refs 8 , 9 ). More recently PARP3 (ADPRT3/ART3) was also implicated in SSB detection by experiments in which nicked oligonucleotide substrates were shown to stimulate PARP3 autoribosylation activity 10 , 11 , 12 , 13 . However, it is not yet known whether PARP3 is involved in sensing SSBs in cells and whether it plays a role in the repair of these lesions. In addition, there is little or no understanding of whether or how chromatin structure affects SSB detection and signalling by ADPRT enzymes. For example, it was established more than 30 years ago that all of the histones in chromatin are ribosylated in permeabilised rat liver nuclei, with histones H1 and H2B the primary targets. However, the identity of the ADPRT enzyme/s responsible for these modifications remains unclear 14 , 15 . Here, we identify the importance, mechanism and role of PARP3 at SSBs and identify for the first time the selective ribosylation of a specific histone at a site-specific DNA break. Results PARP1 and PARP3 accelerate chromosomal SSBR in DT40 cells PARP3 is stimulated by DNA double-strand breaks (DSBs) in vitro and accelerates the repair of chromosomal DSBs at early times following γ-irradiation by promoting the final step of DNA ligation 10 , 12 . More recently, it was shown that PARP3 is also stimulated by SSBs in vitro to a greater extent than DSBs 16 . Since PARP1 is considered the primary SSB sensor protein, we wished to examine whether PARP3 stimulation by SSBs is physiologically relevant by examining the importance of PARP3 for chromosomal SSBR in cells. To do this, we deleted PARP3 in chicken DT40 cells by targeted gene disruption ( Supplementary Fig. 1a ). PARP3 −/− DT40 cells were hypersensitive to γ-rays and, similar to PARP1 −/− cells, repaired ionizing radiation-induced DNA-strand breaks more slowly than wild-type cells ( Fig. 1a,b ). Importantly, both of these phenotypes were corrected by expression of recombinant human PARP3 ( Fig. 1a,c ). Given that >95% of γ-rays induced DNA breaks are SSBs 17 these experiments suggest that SSBR is slower in the absence of PARP3. Consistent with this, neither Ku70 −/− or XRCC3 −/− DSB repair-defective DT40 cells 18 , 19 exhibited significantly slower DNA repair kinetics in alkaline comet assays, suggesting that the level of DSBs induced by γ-irradiation, relative to SSBs, is too low to affect this assay under the conditions employed ( Fig. 1d ). Collectively, these data suggest that both PARP1 and PARP3 accelerate chromosomal SSBR in avian DT40 cells. Figure 1: PARP3 promotes chromosomal SSBR and is stimulated by SSBs with canonical termini. ( a ) Wild-type (WT) DT40 cells, PARP3 −/− (PARP3 KO) DT40 cells, and PARP3 −/− DT40 cells stably transfected with either empty vector (vector) or vector encoding human recombinant PARP3 (hPARP3) were treated with the indicated doses of γ-rays and survival calculated in clonogenic assays. Data are the mean (±s.e.m.) of three independent experiments. Where not visible, error bars are smaller than the symbols. ( b ) WT, PARP1 −/− , or PARP3 −/− DT40 cells were treated on ice with γ-rays (20 Gy) and incubated for the indicated times to allow repair. DNA strand breaks were quantified (tail moment) by alkaline comet assays. Data are the average tail moment of >50 cells per sample and are the mean of three independent experiments (±s.e.m.). ( c ) WT, PARP3 −/− , or derivatives of PARP3 −/− DT40 cells complemented with empty vector or hPARP3 were treated on ice with γ-rays (20 Gy) and incubated for the indicated times to allow repair. DNA strand breaks were quantified as above. ( d ) WT, KU70 −/− , or XRCC3 −/− DT40 cells were treated on ice with γ-rays (20 Gy) and incubated for the indicated times to allow repair. DNA strand breaks were quantified as above. ANOVA was employed to compare mutant DT40 for significant differences with WT (** P <0.01. ‘ns’; not significant). Data are the mean (±s.e.m.) of three independent experiments. ( e ) hPARP1 and/or hPARP3 (50 nM) was incubated with 12.5 μM biotin-NAD + and 200 ng uncut or nicked plasmid (nicked with Nt.BsmA1; nick concentration of 32 nM) that", "role": "user" }, { "content": "Scientists from the University of Sussex have discovered how an enzyme, known as PARP3, helps to accelerate the repair of DNA. In the body, mutations can arise from DNA damage that is not repaired properly, leading to disease, including cancer and neurodegenerative disease. New research funded by the MRC and Cancer Research UK, led by the laboratories of Professor Keith Caldecott and Professor Laurence Pearl at the University of Sussex's Genome Damage and Stability Centre, has identified how the enzyme PARP3, short for poly(ADP-ribose) polymerase 3, recognises and signals the presence of broken DNA strands. Research has shown that the PARP3 enzyme is involved in the DNA repair process and helps to maintain the integrity of the genetic code, but until now the precise DNA repair activation mechanism triggered by the enzyme was unclear. Using multi-disciplinary expertise, Sussex scientists have identified the specific steps involved in activating the DNA repair process. When the PARP3 enzyme locates a specific site of DNA damage, it 'marks' the damaged DNA with a molecular signal. This signal is created via a chemical change, involving the addition of a molecule called 'ADP-ribose' to the DNA. The DNA is packaged up in a complex called 'chromatin' which contains proteins; the team found that the PARP3 enzyme adds the 'ADP-ribose' molecule to one of these proteins – 'histone H2B'. By marking the precise site of damage the enzyme flags the problem up to specialised DNA repair enzymes that will move in to repair the damage, protecting the cell from potentially dangerous DNA breaks. The researchers believe this is a vital step towards understanding how DNA breaks are detected, signalled, and repaired, which could in the future enable scientists to create drugs which can better target certain cancers. PARP3 is one of a superfamily of enzymes that are targeted by PARP inhibitor drugs, a new class drugs used to treat hereditary cancer, including ovarian and breast cancer. Knowledge of how the PARP3 enzyme activates DNA repair will also contribute to improving the understanding, and targeting, of PARP inhibitor drugs. The research, which took place over four years, also involved nuclear magnetic resonance expertise in Professor Steve Matthews' group at Imperial College, London, proteomics in the lab of Dr Steve Sweet in Sussex and chromatin biology in the lab of Dr Alan Thorne at the University of Portsmouth. Professor Keith Caldecott, who led the study, said: \"This discovery highlights the value of multi-disciplinary collaborations, combining molecular and cellular biology with biochemistry and structural biology. As a result of working together, we have been able to identify how PARP3 recognises and flags the presence of broken DNA. \"This will be important for our understanding of how cells protect themselves from potentially dangerous DNA breaks. It will also help to provide insight into the mechanisms of action of a new class of PARP inhibitory anti-cancer drugs.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract PARP3 is a member of the ADP-ribosyl transferase superfamily that we show accelerates the repair of chromosomal DNA single-strand breaks in avian DT40 cells. Two-dimensional nuclear magnetic resonance experiments reveal that PARP3 employs a conserved DNA-binding interface to detect and stably bind DNA breaks and to accumulate at sites of chromosome damage. PARP3 preferentially binds to and is activated by mononucleosomes containing nicked DNA and which target PARP3 trans-ribosylation activity to a single-histone substrate. Although nicks in naked DNA stimulate PARP3 autoribosylation, nicks in mononucleosomes promote the trans-ribosylation of histone H2B specifically at Glu2. These data identify PARP3 as a molecular sensor of nicked nucleosomes and demonstrate, for the first time, the ribosylation of chromatin at a site-specific DNA single-strand break. Introduction Chromosomal single-strand breaks (SSBs) are the most common DNA lesions arising in cells, arising at a frequency of tens-of-thousands per cell per day 1 , 2 . SSBs can arise directly as a result of oxidative attack of deoxyribose or indirectly as products of topoisomerase activity or DNA base excision repair. The threat posed by unrepaired SSBs is illustrated by the neurological dysfunction observed in individuals in which SSB repair (SSBR) is attenuated 1 , 3 . The detection of at least a subset of SSBs is accelerated by a family of enzymes known as (ADP-ribosyl) transferases (ARTs) that catalyse mono- or poly-ADP-ribosylation; a post-translational modification in which proteins are covalently modified with single or multiple units of ADP-ribose 4 , 5 . Two such enzymes are so far implicated in SSB detection and repair; PARP1 (ADPRT1/ART1), and PARP2 (ADPRT2/ART2). PARP1 is the archetypal SSB sensor and is responsible for most of the cellular poly (ADP-ribosylation) activity following DNA strand breakage 6 , 7 , with PARP2 accounting for 5–15% of this activity and fulfilling a partially overlapping role with PARP1 (refs 8 , 9 ). More recently PARP3 (ADPRT3/ART3) was also implicated in SSB detection by experiments in which nicked oligonucleotide substrates were shown to stimulate PARP3 autoribosylation activity 10 , 11 , 12 , 13 . However, it is not yet known whether PARP3 is involved in sensing SSBs in cells and whether it plays a role in the repair of these lesions. In addition, there is little or no understanding of whether or how chromatin structure affects SSB detection and signalling by ADPRT enzymes. For example, it was established more than 30 years ago that all of the histones in chromatin are ribosylated in permeabilised rat liver nuclei, with histones H1 and H2B the primary targets. However, the identity of the ADPRT enzyme/s responsible for these modifications remains unclear 14 , 15 . Here, we identify the importance, mechanism and role of PARP3 at SSBs and identify for the first time the selective ribosylation of a specific histone at a site-specific DNA break. Results PARP1 and PARP3 accelerate chromosomal SSBR in DT40 cells PARP3 is stimulated by DNA double-strand breaks (DSBs) in vitro and accelerates the repair of chromosomal DSBs at early times following γ-irradiation by promoting the final step of DNA ligation 10 , 12 . More recently, it was shown that PARP3 is also stimulated by SSBs in vitro to a greater extent than DSBs 16 . Since PARP1 is considered the primary SSB sensor protein, we wished to examine whether PARP3 stimulation by SSBs is physiologically relevant by examining the importance of PARP3 for chromosomal SSBR in cells. To do this, we deleted PARP3 in chicken DT40 cells by targeted gene disruption ( Supplementary Fig. 1a ). PARP3 −/− DT40 cells were hypersensitive to γ-rays and, similar to PARP1 −/− cells, repaired ionizing radiation-induced DNA-strand breaks more slowly than wild-type cells ( Fig. 1a,b ). Importantly, both of these phenotypes were corrected by expression of recombinant human PARP3 ( Fig. 1a,c ). Given that >95% of γ-rays induced DNA breaks are SSBs 17 these experiments suggest that SSBR is slower in the absence of PARP3. Consistent with this, neither Ku70 −/− or XRCC3 −/− DSB repair-defective DT40 cells 18 , 19 exhibited significantly slower DNA repair kinetics in alkaline comet assays, suggesting that the level of DSBs induced by γ-irradiation, relative to SSBs, is too low to affect this assay under the conditions employed ( Fig. 1d ). Collectively, these data suggest that both PARP1 and PARP3 accelerate chromosomal SSBR in avian DT40 cells. Figure 1: PARP3 promotes chromosomal SSBR and is stimulated by SSBs with canonical termini. ( a ) Wild-type (WT) DT40 cells, PARP3 −/− (PARP3 KO) DT40 cells, and PARP3 −/− DT40 cells stably transfected with either empty vector (vector) or vector encoding human recombinant PARP3 (hPARP3) were treated with the indicated doses of γ-rays and survival calculated in clonogenic assays. Data are the mean (±s.e.m.) of three independent experiments. Where not visible, error bars are smaller than the symbols. ( b ) WT, PARP1 −/− , or PARP3 −/− DT40 cells were treated on ice with γ-rays (20 Gy) and incubated for the indicated times to allow repair. DNA strand breaks were quantified (tail moment) by alkaline comet assays. Data are the average tail moment of >50 cells per sample and are the mean of three independent experiments (±s.e.m.). ( c ) WT, PARP3 −/− , or derivatives of PARP3 −/− DT40 cells complemented with empty vector or hPARP3 were treated on ice with γ-rays (20 Gy) and incubated for the indicated times to allow repair. DNA strand breaks were quantified as above. ( d ) WT, KU70 −/− , or XRCC3 −/− DT40 cells were treated on ice with γ-rays (20 Gy) and incubated for the indicated times to allow repair. DNA strand breaks were quantified as above. ANOVA was employed to compare mutant DT40 for significant differences with WT (** P <0.01. ‘ns’; not significant). Data are the mean (±s.e.m.) of three independent experiments. ( e ) hPARP1 and/or hPARP3 (50 nM) was incubated with 12.5 μM biotin-NAD + and 200 ng uncut or nicked plasmid (nicked with Nt.BsmA1; nick concentration of 32 nM) that<|im_end|> <|im_start|>assistant Scientists from the University of Sussex have discovered how an enzyme, known as PARP3, helps to accelerate the repair of DNA. In the body, mutations can arise from DNA damage that is not repaired properly, leading to disease, including cancer and neurodegenerative disease. New research funded by the MRC and Cancer Research UK, led by the laboratories of Professor Keith Caldecott and Professor Laurence Pearl at the University of Sussex's Genome Damage and Stability Centre, has identified how the enzyme PARP3, short for poly(ADP-ribose) polymerase 3, recognises and signals the presence of broken DNA strands. Research has shown that the PARP3 enzyme is involved in the DNA repair process and helps to maintain the integrity of the genetic code, but until now the precise DNA repair activation mechanism triggered by the enzyme was unclear. Using multi-disciplinary expertise, Sussex scientists have identified the specific steps involved in activating the DNA repair process. When the PARP3 enzyme locates a specific site of DNA damage, it 'marks' the damaged DNA with a molecular signal. This signal is created via a chemical change, involving the addition of a molecule called 'ADP-ribose' to the DNA. The DNA is packaged up in a complex called 'chromatin' which contains proteins; the team found that the PARP3 enzyme adds the 'ADP-ribose' molecule to one of these proteins – 'histone H2B'. By marking the precise site of damage the enzyme flags the problem up to specialised DNA repair enzymes that will move in to repair the damage, protecting the cell from potentially dangerous DNA breaks. The researchers believe this is a vital step towards understanding how DNA breaks are detected, signalled, and repaired, which could in the future enable scientists to create drugs which can better target certain cancers. PARP3 is one of a superfamily of enzymes that are targeted by PARP inhibitor drugs, a new class drugs used to treat hereditary cancer, including ovarian and breast cancer. Knowledge of how the PARP3 enzyme activates DNA repair will also contribute to improving the understanding, and targeting, of PARP inhibitor drugs. The research, which took place over four years, also involved nuclear magnetic resonance expertise in Professor Steve Matthews' group at Imperial College, London, proteomics in the lab of Dr Steve Sweet in Sussex and chromatin biology in the lab of Dr Alan Thorne at the University of Portsmouth. Professor Keith Caldecott, who led the study, said: "This discovery highlights the value of multi-disciplinary collaborations, combining molecular and cellular biology with biochemistry and structural biology. As a result of working together, we have been able to identify how PARP3 recognises and flags the presence of broken DNA. "This will be important for our understanding of how cells protect themselves from potentially dangerous DNA breaks. It will also help to provide insight into the mechanisms of action of a new class of PARP inhibitory anti-cancer drugs." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bell's theorem proves the existence of entangled quantum states with no classical counterpart 1 . An experimental violation of Bell's inequality demands simultaneously high fidelities in the preparation, manipulation and measurement of multipartite quantum entangled states, and provides a single-number benchmark for the performance of devices that use such states for quantum computing 2 , 3 , 4 . We demonstrate a Bell/ Clauser–Horne–Shimony–Holt inequality 5 violation with Bell signals up to 2.70(9), using the electron and the nuclear spins of a single phosphorus atom embedded in a silicon nanoelectronic device. Two-qubit state tomography reveals that our prepared states match the target maximally entangled Bell states with >96% fidelity. These experiments demonstrate complete control of the two-qubit Hilbert space of a phosphorus atom and highlight the important function of the nuclear qubit to expand the computational basis and maximize the readout fidelity. Main Bell's theorem provides a boundary to the strength of correlation that a pair of quantum two-level systems (qubits) can display, under the assumption that physical systems cannot be instantly affected by distant objects (‘locality’) and that their properties exist before they are observed (‘realism’). Certain quantum entangled states are predicted to violate Bell's theorem and therefore invalidate local realistic interpretations of quantum mechanics. The most profound implications of Bell's theorem arise when observing entangled pairs of particles that are separated in space–time, such as photons travelling at the speed of light in different directions 6 , 7 . Even for physical systems where space–time separation is not achievable, the Bell test carries an important message when placed in the context of using such systems for quantum information processing 8 . It is, in principle, possible to produce and observe quantum entanglement without violating Bell's inequality, as is the case in a wide range of experiments, particularly in the solid state 9 , 10 , 11 , 12 , 13 , 14 . However, a Bell's inequality violation constitutes an even stronger measure of the ability to faithfully produce, control and read out non-classical states of pairs of qubits 2 , 3 , 4 . This maps directly onto the ability to perform high-fidelity entangling operations 15 , which, together with single-qubit operations, can fully access the two-qubit Hilbert space. Experimental access to Bell's theorem takes the form of the Clauser–Horne–Shimony–Holt (CHSH) inequality 5 . This involves the joint measurement of a two-qubit system along measurement axes α and β . The binary measurement outcomes (0/1) produce a correlation where P is the probability of detecting the subscripted measurement outcome. In its standard form, the inequality is tested by measuring each qubit along two axes, α , α ′ and β , β ′ respectively, and extracting E in all four possible combinations of axes. If the measurement set-up does not allow for physically rotating the measurement axes, equivalent outcomes are obtained by rotating the qubit before a measurement along a fixed axis. The Bell signal is then Bell's theorem states that, within local realistic theories, | S | ≤ 2. Conversely, quantum mechanics predicts for a maximally entangled state and an appropriately chosen sets of axes. In the present experiment, we use as qubits the electron (↓,↑) and nuclear ( ⇓ , ⇑ ) spins of a single substitutional 31 P donor, implanted 16 in an isotopically enriched 28 Si epilayer 17 , 18 . The qubits are coupled by the hyperfine interaction A ≈ 96.9 MHz (shifted from the bulk value of 117 MHz due to the strong electric fields in the nanostructure 19 ). A static magnetic field B 0 ≈ 1.55 T induces a Zeeman splitting on the electron ( γ e B 0 , with γ e ≈ 27.97 GHz T –1 ) and nuclear ( γ N B 0 , with γ N ≈ 17.23 MHz T –1 ) spins, resulting in the two-qubit energy level diagram depicted in the inset of Fig. 1a . Manipulation of the full two-qubit Hilbert space requires access to at least three eigenstate transitions. Our experimental set-up includes three microwave sources, which deliver signals to a nanoscale broadband antenna 20 , providing access to both electron spin resonance (ESR) transitions at microwave (MW) frequencies v MW1,2 = γ e B 0 ∓ A /2 and one nuclear magnetic resonance (NMR) transition at radiofrequency (RF) v RF = γ N B 0 + A /2. Coherent qubit rotations are denoted as α s , where α is the rotation angle in radians and the subscript identifies the transition. The 31 P donor is located in the vicinity ( ∼ 25 nm) of the large electron island of a single-electron transistor (SET), formed by biasing a metal–oxide–semiconductor (MOS) gate stack above a SiO 2 layer. An additional set of gates (DG) controls the (spin-dependent) electrochemical potential of the donor, μ ↑,↓ , with respect to the SET potential μ SET ( Fig. 1a ) 17 . The SET island acts as a quasi-continuum electron reservoir for spin-dependent electron tunnelling to and from the donor, which is the key step for single-shot readout and electrical initialization of the electron qubit state 21 . Figure 1: Device operation and state preparation protocols. a , Coloured scanning electron microscope image of a device similar to the one used in the experiments. The gates in red make up the single electron transistor (SET), used to perform sensitive charge sensing for electron spin readout; the donor gates (DG, in blue) control the donor potential; the gate in yellow is a broadband antenna used to drive the nuclear magnetic resonance and electron spin resonance (NMR/ESR) transitions. Inset: Schematic four-level energy diagram of the two-spin electron–nuclear system under a static magnetic field. The colour coding of the three accessible transitions (MW1, MW 2 , RF) will be used in the pulse sequences throughout the figures. b , Bottom: electron |↓〉 initialization is achieved by setting the donor potential such that μ ↑ > μ SET > μ ↓ . Because γ e B 0", "role": "user" }, { "content": "A team of Australian engineers has proven—with the highest score ever obtained—that a quantum version of computer code can be written, and manipulated, using two quantum bits in a silicon microchip. The advance removes lingering doubts that such operations can be made reliably enough to allow powerful quantum computers to become a reality. The result, obtained by a team at Australia's University of New South Wales (UNSW) in Sydney, appears today in the international journal, Nature Nanotechnology. The quantum code written at UNSW is built upon a class of phenomena called quantum entanglement, which allows for seemingly counterintuitive phenomena such as the measurement of one particle instantly affecting another - even if they are at opposite ends of the universe. \"This effect is famous for puzzling some of the deepest thinkers in the field, including Albert Einstein, who called it 'spooky action at a distance',\" said Professor Andrea Morello, of the School of Electrical Engineering & Telecommunications at UNSW and Program Manager in the Centre for Quantum Computation & Communication Technology, who led the research. \"Einstein was sceptical about entanglement, because it appears to contradict the principles of 'locality', which means that objects cannot be instantly influenced from a distance.\" Physicists have since struggled to establish a clear boundary between our everyday world—which is governed by classical physics—and this strangeness of the quantum world. For the past 50 years, the best guide to that boundary has been a theorem called Bell's Inequality, which states that no local description of the world can reproduce all of the predictions of quantum mechanics. Bell's Inequality demands a very stringent test to verify if two particles are actually entangled, known as the 'Bell test', named for the British physicist who devised the theorem in 1964. \"The key aspect of the Bell test is that it is extremely unforgiving: any imperfection in the preparation, manipulation and read-out protocol will cause the particles to fail the test,\" said Dr Juan Pablo Dehollain, a UNSW Research Associate who with Dr Stephanie Simmons was a lead author of the Nature Nanotechnology paper. \"Nevertheless, we have succeeded in passing the test, and we have done so with the highest 'score' ever recorded in an experiment,\" he added. Project leader Andrea Morello (left) with lead authors Stephanie Simmons (middle) and Juan Pablo Dehollain (right) in the UNSW laboratory where the experiments were performed. Credit: Paul Henderson-Kelly/UNSW In the UNSW experiment, the two quantum particles involved are an electron and the nucleus of a single phosphorus atom, placed inside a silicon microchip. These particles are, literally, on top of each other—the electron orbits around the nucleus. Therefore, there is no complication arising from the spookiness of action at a distance. However, the significance of the UNSW experiment is that creating these two-particle entangled states is tantamount to writing a type of computer code that does not exist in everyday computers. It therefore demonstrates the ability to write a purely quantum version of computer code, using two quantum bits in a silicon microchip—a key plank in the quest super-powerful quantum computers of the future. \"Passing the Bell test with such a high score is the strongest possible proof that we have the operation of a quantum computer entirely under control,\" said Morello. \"In particular, we can access the purely-quantum type of code that requires the use of the delicate quantum entanglement between two particles.\" In a normal computer, using two bits one, could write four possible code words: 00, 01, 10 and 11. In a quantum computer, instead, one can also write and use 'superpositions' of the classical code words, such as (01 + 10), or (00 + 11). This requires the creation of quantum entanglement between two particles. \"These codes are perfectly legitimate in a quantum computer, but don't exist in a classical one,\" said UNSW Research Fellow Stephanie Simmons, the paper's co-author. \"This is, in some sense, the reason why quantum computers can be so much more powerful: with the same number of bits, they allow us to write a computer code that contains many more words, and we can use those extra words to run a different algorithm that reaches the result in a smaller number of steps.\" Morello highlighted the importance of achieving the breakthrough using a silicon chip: \"What I find mesmerising about this experiment is that this seemingly innocuous 'quantum computer code' - (01 + 10) and (00 + 11) - has puzzled, confused and infuriated generations of physicists over the past 80 years. \"Now, we have shown beyond any doubt that we can write this code inside a device that resembles the silicon microchips you have on your laptop or your mobile phone. It's a real triumph of electrical engineering,\" he added. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Bell's theorem proves the existence of entangled quantum states with no classical counterpart 1 . An experimental violation of Bell's inequality demands simultaneously high fidelities in the preparation, manipulation and measurement of multipartite quantum entangled states, and provides a single-number benchmark for the performance of devices that use such states for quantum computing 2 , 3 , 4 . We demonstrate a Bell/ Clauser–Horne–Shimony–Holt inequality 5 violation with Bell signals up to 2.70(9), using the electron and the nuclear spins of a single phosphorus atom embedded in a silicon nanoelectronic device. Two-qubit state tomography reveals that our prepared states match the target maximally entangled Bell states with >96% fidelity. These experiments demonstrate complete control of the two-qubit Hilbert space of a phosphorus atom and highlight the important function of the nuclear qubit to expand the computational basis and maximize the readout fidelity. Main Bell's theorem provides a boundary to the strength of correlation that a pair of quantum two-level systems (qubits) can display, under the assumption that physical systems cannot be instantly affected by distant objects (‘locality’) and that their properties exist before they are observed (‘realism’). Certain quantum entangled states are predicted to violate Bell's theorem and therefore invalidate local realistic interpretations of quantum mechanics. The most profound implications of Bell's theorem arise when observing entangled pairs of particles that are separated in space–time, such as photons travelling at the speed of light in different directions 6 , 7 . Even for physical systems where space–time separation is not achievable, the Bell test carries an important message when placed in the context of using such systems for quantum information processing 8 . It is, in principle, possible to produce and observe quantum entanglement without violating Bell's inequality, as is the case in a wide range of experiments, particularly in the solid state 9 , 10 , 11 , 12 , 13 , 14 . However, a Bell's inequality violation constitutes an even stronger measure of the ability to faithfully produce, control and read out non-classical states of pairs of qubits 2 , 3 , 4 . This maps directly onto the ability to perform high-fidelity entangling operations 15 , which, together with single-qubit operations, can fully access the two-qubit Hilbert space. Experimental access to Bell's theorem takes the form of the Clauser–Horne–Shimony–Holt (CHSH) inequality 5 . This involves the joint measurement of a two-qubit system along measurement axes α and β . The binary measurement outcomes (0/1) produce a correlation where P is the probability of detecting the subscripted measurement outcome. In its standard form, the inequality is tested by measuring each qubit along two axes, α , α ′ and β , β ′ respectively, and extracting E in all four possible combinations of axes. If the measurement set-up does not allow for physically rotating the measurement axes, equivalent outcomes are obtained by rotating the qubit before a measurement along a fixed axis. The Bell signal is then Bell's theorem states that, within local realistic theories, | S | ≤ 2. Conversely, quantum mechanics predicts for a maximally entangled state and an appropriately chosen sets of axes. In the present experiment, we use as qubits the electron (↓,↑) and nuclear ( ⇓ , ⇑ ) spins of a single substitutional 31 P donor, implanted 16 in an isotopically enriched 28 Si epilayer 17 , 18 . The qubits are coupled by the hyperfine interaction A ≈ 96.9 MHz (shifted from the bulk value of 117 MHz due to the strong electric fields in the nanostructure 19 ). A static magnetic field B 0 ≈ 1.55 T induces a Zeeman splitting on the electron ( γ e B 0 , with γ e ≈ 27.97 GHz T –1 ) and nuclear ( γ N B 0 , with γ N ≈ 17.23 MHz T –1 ) spins, resulting in the two-qubit energy level diagram depicted in the inset of Fig. 1a . Manipulation of the full two-qubit Hilbert space requires access to at least three eigenstate transitions. Our experimental set-up includes three microwave sources, which deliver signals to a nanoscale broadband antenna 20 , providing access to both electron spin resonance (ESR) transitions at microwave (MW) frequencies v MW1,2 = γ e B 0 ∓ A /2 and one nuclear magnetic resonance (NMR) transition at radiofrequency (RF) v RF = γ N B 0 + A /2. Coherent qubit rotations are denoted as α s , where α is the rotation angle in radians and the subscript identifies the transition. The 31 P donor is located in the vicinity ( ∼ 25 nm) of the large electron island of a single-electron transistor (SET), formed by biasing a metal–oxide–semiconductor (MOS) gate stack above a SiO 2 layer. An additional set of gates (DG) controls the (spin-dependent) electrochemical potential of the donor, μ ↑,↓ , with respect to the SET potential μ SET ( Fig. 1a ) 17 . The SET island acts as a quasi-continuum electron reservoir for spin-dependent electron tunnelling to and from the donor, which is the key step for single-shot readout and electrical initialization of the electron qubit state 21 . Figure 1: Device operation and state preparation protocols. a , Coloured scanning electron microscope image of a device similar to the one used in the experiments. The gates in red make up the single electron transistor (SET), used to perform sensitive charge sensing for electron spin readout; the donor gates (DG, in blue) control the donor potential; the gate in yellow is a broadband antenna used to drive the nuclear magnetic resonance and electron spin resonance (NMR/ESR) transitions. Inset: Schematic four-level energy diagram of the two-spin electron–nuclear system under a static magnetic field. The colour coding of the three accessible transitions (MW1, MW 2 , RF) will be used in the pulse sequences throughout the figures. b , Bottom: electron |↓〉 initialization is achieved by setting the donor potential such that μ ↑ > μ SET > μ ↓ . Because γ e B 0<|im_end|> <|im_start|>assistant A team of Australian engineers has proven—with the highest score ever obtained—that a quantum version of computer code can be written, and manipulated, using two quantum bits in a silicon microchip. The advance removes lingering doubts that such operations can be made reliably enough to allow powerful quantum computers to become a reality. The result, obtained by a team at Australia's University of New South Wales (UNSW) in Sydney, appears today in the international journal, Nature Nanotechnology. The quantum code written at UNSW is built upon a class of phenomena called quantum entanglement, which allows for seemingly counterintuitive phenomena such as the measurement of one particle instantly affecting another - even if they are at opposite ends of the universe. "This effect is famous for puzzling some of the deepest thinkers in the field, including Albert Einstein, who called it 'spooky action at a distance'," said Professor Andrea Morello, of the School of Electrical Engineering & Telecommunications at UNSW and Program Manager in the Centre for Quantum Computation & Communication Technology, who led the research. "Einstein was sceptical about entanglement, because it appears to contradict the principles of 'locality', which means that objects cannot be instantly influenced from a distance." Physicists have since struggled to establish a clear boundary between our everyday world—which is governed by classical physics—and this strangeness of the quantum world. For the past 50 years, the best guide to that boundary has been a theorem called Bell's Inequality, which states that no local description of the world can reproduce all of the predictions of quantum mechanics. Bell's Inequality demands a very stringent test to verify if two particles are actually entangled, known as the 'Bell test', named for the British physicist who devised the theorem in 1964. "The key aspect of the Bell test is that it is extremely unforgiving: any imperfection in the preparation, manipulation and read-out protocol will cause the particles to fail the test," said Dr Juan Pablo Dehollain, a UNSW Research Associate who with Dr Stephanie Simmons was a lead author of the Nature Nanotechnology paper. "Nevertheless, we have succeeded in passing the test, and we have done so with the highest 'score' ever recorded in an experiment," he added. Project leader Andrea Morello (left) with lead authors Stephanie Simmons (middle) and Juan Pablo Dehollain (right) in the UNSW laboratory where the experiments were performed. Credit: Paul Henderson-Kelly/UNSW In the UNSW experiment, the two quantum particles involved are an electron and the nucleus of a single phosphorus atom, placed inside a silicon microchip. These particles are, literally, on top of each other—the electron orbits around the nucleus. Therefore, there is no complication arising from the spookiness of action at a distance. However, the significance of the UNSW experiment is that creating these two-particle entangled states is tantamount to writing a type of computer code that does not exist in everyday computers. It therefore demonstrates the ability to write a purely quantum version of computer code, using two quantum bits in a silicon microchip—a key plank in the quest super-powerful quantum computers of the future. "Passing the Bell test with such a high score is the strongest possible proof that we have the operation of a quantum computer entirely under control," said Morello. "In particular, we can access the purely-quantum type of code that requires the use of the delicate quantum entanglement between two particles." In a normal computer, using two bits one, could write four possible code words: 00, 01, 10 and 11. In a quantum computer, instead, one can also write and use 'superpositions' of the classical code words, such as (01 + 10), or (00 + 11). This requires the creation of quantum entanglement between two particles. "These codes are perfectly legitimate in a quantum computer, but don't exist in a classical one," said UNSW Research Fellow Stephanie Simmons, the paper's co-author. "This is, in some sense, the reason why quantum computers can be so much more powerful: with the same number of bits, they allow us to write a computer code that contains many more words, and we can use those extra words to run a different algorithm that reaches the result in a smaller number of steps." Morello highlighted the importance of achieving the breakthrough using a silicon chip: "What I find mesmerising about this experiment is that this seemingly innocuous 'quantum computer code' - (01 + 10) and (00 + 11) - has puzzled, confused and infuriated generations of physicists over the past 80 years. "Now, we have shown beyond any doubt that we can write this code inside a device that resembles the silicon microchips you have on your laptop or your mobile phone. It's a real triumph of electrical engineering," he added. <|im_end|>

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2,371

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The assessment of greenhouse gases (GHGs) and air pollutants emitted to and removed from the atmosphere ranks high on international political and scientific agendas. Growing international concern and cooperation regarding the climate change problem have increased the need to consider the uncertainty in inventories of GHG emissions. The approaches to address uncertainty discussed in this special issue reflect attempts to improve national inventories, not only for their own sake but also from a wider, system analytic perspective. They seek to strengthen the usefulness of national emission inventories under a compliance and/or global monitoring and reporting framework. The papers in this special issue demonstrate the benefits of including inventory uncertainty in policy analyses. The issues raised by the authors and featured in their papers, along with the role that uncertainty analysis plays in many of their arguments, highlight the challenges and the importance of dealing with uncertainty. While the Intergovernmental Panel on Climate Change (IPCC) clearly stresses the value of conducting uncertainty analyses and offers guidance on executing them, the arguments made here in favor of performing these studies go well beyond any suggestions made by the IPCC to date. Improving and conducting uncertainty analyses are needed to develop a clear understanding and informed policy. Uncertainty matters and is key to many issues related to inventorying and reducing emissions. Considering uncertainty helps to avoid situations that can create a false sense of certainty or lead to invalid views of subsystems. Dealing proactively with uncertainty allows for the generation of useful knowledge that the international community should have to hand while strengthening the 2015 Paris Agreement, which had been agreed at the 21st Conference of the Parties to the United Nations Framework Convention on Climate Change (UNFCCC). However, considering uncertainty does not come free. Proper treatment of uncertainty is demanding because it forces us to take the step from “simple to complex” and to grasp a holistic system view. Only, thereafter, can we consider potential simplifications. That is, comprehensive treatment of uncertainty does not necessarily offer quick or easy solutions for policymakers. This special issue brings together 13 papers that resulted from the 2015 (4th) International Workshop on Uncertainty in Atmospheric Emissions, in Cracow, Poland. While they deal with many different aspects of the uncertainty in emission estimates, they are guided by the same principal question: “What GHGs shall be verified at what spatio-temporal scale to support conducive legislation at local and national scales, while ensuring effective governance at the global scale?” This question is at the heart of mitigation and adaptation. It requires an understanding of the entire system of GHG sources and sinks, their spatial characteristics and the temporal scales at which they react and interact, the uncertainty (accuracy and/or precision) with which fluxes can be measured, and last but not least, the consequences that follow from all of the aforementioned aspects, for policy actors to frame compliance and/or global monitoring and reporting agreements. This bigger system context serves as a reference for the papers in the special issue, irrespective of their spatio-temporal focus, and is used as a guide for the reader. Working on a manuscript? Avoid the common mistakes 1 Introduction This special issue has been compiled to enhance understanding of the uncertainty in estimating greenhouse gas (GHG) emissions and to provide guidance on dealing with the challenges resulting from those uncertainties. Such challenges include, but are not limited to the following: (i) accurately and precisely accounting for emissions in space and time (and their verification); (ii) complying with emission reduction commitments under uncertainty; (iii) dealing with the risk of exceeding future temperature targets; (iv) evaluating mitigation—both domestic and in other countries—versus adaptation in the presence of uncertainty; and (v) trading inherently uncertain emission permits. The special issue brings together 13 contributions that originated as short papers presented at the 2015 (4th) International Workshop on Uncertainty in Atmospheric Emissions, in Cracow, Poland. Their common concern is to highlight issues where our understanding of uncertainty still falls short. With the momentum of that Workshop, these short papers have been developed further and expanded considerably. All have undergone two to three rounds of improvement, and the short papers have matured into the longer, peer-reviewed papers that are presented here. 1.1 The rationale for estimating GHG emissions and removals The assessment of GHGs and air pollutants (indirect GHGs) emitted to and removed from the atmosphere ranks high on scientific and political agendas, which is steered internationally by the Intergovernmental Panel on Climate Change (IPCC) on the one hand, and the United Nations Framework Convention on Climate Change (UNFCCC) on the other. The UNFCCC provides the foundation for multilateral action to combat climate change and its impacts on humanity and ecosystems. Its objective is to “stabilize greenhouse gas concentrations in the atmosphere at a level that would prevent dangerous anthropogenic interference with the climate system.” In pursuit of this objective, the UNFCCC established a framework with broad principles, general obligations, basic institutional arrangements, and an intergovernmental process for agreeing to specific actions over time, supported by international instruments such as the 1997 Kyoto Protocol (in force until 2020) and its successor, the 2015 Paris Agreement (in force as of 2016). The Paris Agreement aims to keep this century’s mean global temperature rise well below 2 °C above pre-industrial levels and to pursue efforts to limit the temperature increase to 1.5 °C. The Agreement requires all signatory countries to employ their best efforts to achieve this goal through nationally determined contributions and to strengthen their efforts in the years ahead (see also Tollefson 2018a , b ). The Agreement includes the requirement that all signatory countries report regularly on their emissions and implementation efforts. A global stock-take will be carried out every five years to assess collective progress toward achieving the aims of the Agreement and to inform further actions by individual countries (UNFCCC 2018 ). GHG emissions are rarely measured directly. To assist countries in compiling comprehensive emission inventories and conducting quantitative uncertainty analyses under the UNFCCC, the IPCC has put", "role": "user" }, { "content": "National or other emissions inventories of greenhouse gases that are used to develop strategies and track progress in terms of emissions reductions for climate mitigation contain a certain amount of uncertainty, which inevitably has an impact on the decisions they inform. IIASA researchers contributed to several studies in a recently published volume that aims to enhance understanding of uncertainty in emissions inventories. Estimates of greenhouse gas (GHG) emissions are important for many reasons, but it is crucial to acknowledge that these values have a certain level of uncertainty that has to be taken into account. If, for example, two estimates of emissions from a country are different, it does not necessarily imply that one or both are wrong—it simply means that there is an uncertainty that needs to be recognized and dealt with. A special issue of the Springer journal Mitigation and Adaptation Strategies for Global Change, aims to enhance understanding of uncertainty in estimating GHG emissions and to provide guidance on dealing with the resulting challenges. IIASA researchers and colleagues from other international institutions including the Lviv Polytechnic National University in Ukraine, the Systems Research Institute at the Polish Academy of Sciences, and Appalachian State University in the US, contributed to the 13 papers featured in the publication, addressing questions such as the size of the uncertainty dealt with, how to deal with this, and how uncertainty might be decreased. According to the researchers, there are ways to decrease uncertainty but these are often difficult and ultimately expensive. In their respective papers, they point out that there are seven important issues that currently dominate our understanding of uncertainty. These include 1) verification; 2) avoidance of systemic surprises; 3) uncertainty informing policy; 4) minimizing the impact of uncertainty; 5) full GHG accounting; 6) compliance versus reporting; and 7) changes in emissions versus changes in the atmosphere. In terms of how uncertainty in observations and modeling results can influence policy decisions on climate change mitigation, some of the papers also looked at how decision-making procedures can be improved to produce more fair rules for checking compliance and how information around emission inventories can be communicated to make it more transparent and easier to understand. The authors explain that understanding the uncertainties is very important both for those who do the calculations or modeling and for the consumers of this information, like policymakers or consultants, as it provides an indication of how much they can rely on the data, in other words, how \"strong\" the conclusions are and how sure the decisions derived from the data can be. \"Uncertainty is higher for some GHGs and some sectors of an inventory than for others. This raises the option that, when future policy agreements are being designed, some components of a GHG inventory could be treated differently from others. The approach of treating subsystems individually and differently would allow emissions and uncertainty to be looked at simultaneously and would thus allow for differentiated emission reduction policies,\" explains Matthias Jonas, an IIASA researcher in the Advanced Systems Analysis Program and one of the editors of the special issue. \"The current policy approach of ignoring inventory uncertainty altogether (inventory uncertainty was monitored, but not regulated, under the Kyoto Protocol) is problematic. Being aware of the uncertainties involved, including those resulting from our systems views, will help to strengthen future political decision making.\" The authors all agree that dealing with uncertainty is often not a quick exercise but rather involves a commitment that is painstaking and long-term. Proper treatment of uncertainty can be costly in terms of both time and effort because it necessitates taking the step from \"simple\" to \"complex\" in order to grasp a wider and more holistic systems view. Only after that step has been taken, is it possible to consider simplifications that may be warranted. \"Decision makers want certainty, the public wants certainty, but certainty is not achievable. We can work with the best information available and we have to keep moving forward and learning. I think that we need to convince data users such as policymakers or the public that uncertainty in these kinds of numbers is normal and expected and does not mean that the numbers are not useful,\" says study author Gregg Marland from Appalachian State University in the US. Special edition co-editor Rostyslav Bun from Lviv Polytechnic National University in Ukraine confirms this sentiment and in conclusion adds: \"The presence of uncertainties in estimates of GHG emissions may suggest that we have to devote more energy to decreasing uncertainties or it may simply mean that we need to be prepared to deal with a future that includes a certain measure of uncertainty.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The assessment of greenhouse gases (GHGs) and air pollutants emitted to and removed from the atmosphere ranks high on international political and scientific agendas. Growing international concern and cooperation regarding the climate change problem have increased the need to consider the uncertainty in inventories of GHG emissions. The approaches to address uncertainty discussed in this special issue reflect attempts to improve national inventories, not only for their own sake but also from a wider, system analytic perspective. They seek to strengthen the usefulness of national emission inventories under a compliance and/or global monitoring and reporting framework. The papers in this special issue demonstrate the benefits of including inventory uncertainty in policy analyses. The issues raised by the authors and featured in their papers, along with the role that uncertainty analysis plays in many of their arguments, highlight the challenges and the importance of dealing with uncertainty. While the Intergovernmental Panel on Climate Change (IPCC) clearly stresses the value of conducting uncertainty analyses and offers guidance on executing them, the arguments made here in favor of performing these studies go well beyond any suggestions made by the IPCC to date. Improving and conducting uncertainty analyses are needed to develop a clear understanding and informed policy. Uncertainty matters and is key to many issues related to inventorying and reducing emissions. Considering uncertainty helps to avoid situations that can create a false sense of certainty or lead to invalid views of subsystems. Dealing proactively with uncertainty allows for the generation of useful knowledge that the international community should have to hand while strengthening the 2015 Paris Agreement, which had been agreed at the 21st Conference of the Parties to the United Nations Framework Convention on Climate Change (UNFCCC). However, considering uncertainty does not come free. Proper treatment of uncertainty is demanding because it forces us to take the step from “simple to complex” and to grasp a holistic system view. Only, thereafter, can we consider potential simplifications. That is, comprehensive treatment of uncertainty does not necessarily offer quick or easy solutions for policymakers. This special issue brings together 13 papers that resulted from the 2015 (4th) International Workshop on Uncertainty in Atmospheric Emissions, in Cracow, Poland. While they deal with many different aspects of the uncertainty in emission estimates, they are guided by the same principal question: “What GHGs shall be verified at what spatio-temporal scale to support conducive legislation at local and national scales, while ensuring effective governance at the global scale?” This question is at the heart of mitigation and adaptation. It requires an understanding of the entire system of GHG sources and sinks, their spatial characteristics and the temporal scales at which they react and interact, the uncertainty (accuracy and/or precision) with which fluxes can be measured, and last but not least, the consequences that follow from all of the aforementioned aspects, for policy actors to frame compliance and/or global monitoring and reporting agreements. This bigger system context serves as a reference for the papers in the special issue, irrespective of their spatio-temporal focus, and is used as a guide for the reader. Working on a manuscript? Avoid the common mistakes 1 Introduction This special issue has been compiled to enhance understanding of the uncertainty in estimating greenhouse gas (GHG) emissions and to provide guidance on dealing with the challenges resulting from those uncertainties. Such challenges include, but are not limited to the following: (i) accurately and precisely accounting for emissions in space and time (and their verification); (ii) complying with emission reduction commitments under uncertainty; (iii) dealing with the risk of exceeding future temperature targets; (iv) evaluating mitigation—both domestic and in other countries—versus adaptation in the presence of uncertainty; and (v) trading inherently uncertain emission permits. The special issue brings together 13 contributions that originated as short papers presented at the 2015 (4th) International Workshop on Uncertainty in Atmospheric Emissions, in Cracow, Poland. Their common concern is to highlight issues where our understanding of uncertainty still falls short. With the momentum of that Workshop, these short papers have been developed further and expanded considerably. All have undergone two to three rounds of improvement, and the short papers have matured into the longer, peer-reviewed papers that are presented here. 1.1 The rationale for estimating GHG emissions and removals The assessment of GHGs and air pollutants (indirect GHGs) emitted to and removed from the atmosphere ranks high on scientific and political agendas, which is steered internationally by the Intergovernmental Panel on Climate Change (IPCC) on the one hand, and the United Nations Framework Convention on Climate Change (UNFCCC) on the other. The UNFCCC provides the foundation for multilateral action to combat climate change and its impacts on humanity and ecosystems. Its objective is to “stabilize greenhouse gas concentrations in the atmosphere at a level that would prevent dangerous anthropogenic interference with the climate system.” In pursuit of this objective, the UNFCCC established a framework with broad principles, general obligations, basic institutional arrangements, and an intergovernmental process for agreeing to specific actions over time, supported by international instruments such as the 1997 Kyoto Protocol (in force until 2020) and its successor, the 2015 Paris Agreement (in force as of 2016). The Paris Agreement aims to keep this century’s mean global temperature rise well below 2 °C above pre-industrial levels and to pursue efforts to limit the temperature increase to 1.5 °C. The Agreement requires all signatory countries to employ their best efforts to achieve this goal through nationally determined contributions and to strengthen their efforts in the years ahead (see also Tollefson 2018a , b ). The Agreement includes the requirement that all signatory countries report regularly on their emissions and implementation efforts. A global stock-take will be carried out every five years to assess collective progress toward achieving the aims of the Agreement and to inform further actions by individual countries (UNFCCC 2018 ). GHG emissions are rarely measured directly. To assist countries in compiling comprehensive emission inventories and conducting quantitative uncertainty analyses under the UNFCCC, the IPCC has put<|im_end|> <|im_start|>assistant National or other emissions inventories of greenhouse gases that are used to develop strategies and track progress in terms of emissions reductions for climate mitigation contain a certain amount of uncertainty, which inevitably has an impact on the decisions they inform. IIASA researchers contributed to several studies in a recently published volume that aims to enhance understanding of uncertainty in emissions inventories. Estimates of greenhouse gas (GHG) emissions are important for many reasons, but it is crucial to acknowledge that these values have a certain level of uncertainty that has to be taken into account. If, for example, two estimates of emissions from a country are different, it does not necessarily imply that one or both are wrong—it simply means that there is an uncertainty that needs to be recognized and dealt with. A special issue of the Springer journal Mitigation and Adaptation Strategies for Global Change, aims to enhance understanding of uncertainty in estimating GHG emissions and to provide guidance on dealing with the resulting challenges. IIASA researchers and colleagues from other international institutions including the Lviv Polytechnic National University in Ukraine, the Systems Research Institute at the Polish Academy of Sciences, and Appalachian State University in the US, contributed to the 13 papers featured in the publication, addressing questions such as the size of the uncertainty dealt with, how to deal with this, and how uncertainty might be decreased. According to the researchers, there are ways to decrease uncertainty but these are often difficult and ultimately expensive. In their respective papers, they point out that there are seven important issues that currently dominate our understanding of uncertainty. These include 1) verification; 2) avoidance of systemic surprises; 3) uncertainty informing policy; 4) minimizing the impact of uncertainty; 5) full GHG accounting; 6) compliance versus reporting; and 7) changes in emissions versus changes in the atmosphere. In terms of how uncertainty in observations and modeling results can influence policy decisions on climate change mitigation, some of the papers also looked at how decision-making procedures can be improved to produce more fair rules for checking compliance and how information around emission inventories can be communicated to make it more transparent and easier to understand. The authors explain that understanding the uncertainties is very important both for those who do the calculations or modeling and for the consumers of this information, like policymakers or consultants, as it provides an indication of how much they can rely on the data, in other words, how "strong" the conclusions are and how sure the decisions derived from the data can be. "Uncertainty is higher for some GHGs and some sectors of an inventory than for others. This raises the option that, when future policy agreements are being designed, some components of a GHG inventory could be treated differently from others. The approach of treating subsystems individually and differently would allow emissions and uncertainty to be looked at simultaneously and would thus allow for differentiated emission reduction policies," explains Matthias Jonas, an IIASA researcher in the Advanced Systems Analysis Program and one of the editors of the special issue. "The current policy approach of ignoring inventory uncertainty altogether (inventory uncertainty was monitored, but not regulated, under the Kyoto Protocol) is problematic. Being aware of the uncertainties involved, including those resulting from our systems views, will help to strengthen future political decision making." The authors all agree that dealing with uncertainty is often not a quick exercise but rather involves a commitment that is painstaking and long-term. Proper treatment of uncertainty can be costly in terms of both time and effort because it necessitates taking the step from "simple" to "complex" in order to grasp a wider and more holistic systems view. Only after that step has been taken, is it possible to consider simplifications that may be warranted. "Decision makers want certainty, the public wants certainty, but certainty is not achievable. We can work with the best information available and we have to keep moving forward and learning. I think that we need to convince data users such as policymakers or the public that uncertainty in these kinds of numbers is normal and expected and does not mean that the numbers are not useful," says study author Gregg Marland from Appalachian State University in the US. Special edition co-editor Rostyslav Bun from Lviv Polytechnic National University in Ukraine confirms this sentiment and in conclusion adds: "The presence of uncertainties in estimates of GHG emissions may suggest that we have to devote more energy to decreasing uncertainties or it may simply mean that we need to be prepared to deal with a future that includes a certain measure of uncertainty." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin, we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β- catenin level in human myeloid leukemia. Introduction Canonical Wnt signaling is an evolutionary conserved signal transduction pathway strictly controlled during normal development but frequently dysregulated in cancer. 1 In the absence of a Wnt ligand, the central mediator of this signaling pathway, β-catenin, is constitutively phosphorylated by a destruction complex (DC) consisting of GSK3β, CK1, Axin and APC, priming it for subsequent degradation by the proteasome. Upon Wnt ligand binding to the Wnt receptors (Frizzled and LRP5/6), the DC becomes saturated with phosphorylated β-catenin (which cannot be degraded) resulting in cytosolic accumulation of non-phosphorylated β-catenin. 2 Following nuclear translocation, β-catenin complexes with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcriptional regulators and promotes activation of proto-oncogenic Wnt target genes, like c-myc, cyclinD1 and survivin ( ). Thus, Wnt signaling activation is dependent on the movement of β-catenin into the nucleus, yet this remains a poorly understood process in blood cells. β-Catenin lacks canonical nuclear-localization or -export sequences and its subcellular distribution has instead been associated with multiple factors in context-dependent settings. 3 β-Catenin is frequently over-expressed in acute myeloid leukemia (AML) 4 where its expression correlates with inferior patient survival. 5 β-Catenin has been shown to play a key role in the initiation of AML and chronic myeloid leukemia (CML). 7 6 Furthermore, frequent chromosomal aberrations driving AML and CML are known to co-operate with β-catenin. 9 8 Key to the activation of Wnt signaling is the movement of β-catenin into the nucleus and this is frequently observed in AML. 10 We have previously demonstrated that approximately 10% of primary AML patient blast samples exhibit little nuclear β-catenin expression, despite substantial cytosolic levels, a phenomenon replicated in 10-20% of myeloid leukemia cell lines upon Wnt stimulation. 11 3 In fact, this is characteristic of normal human hematopoietic stem/progenitor cells (HSPC) which similarly limit β-catenin nuclear-localization, possibly to protect normal HSC from detrimental levels of Wnt signaling. 12 The permissive nuclear-localization of β-catenin observed in myeloid leukemias is therefore aberrant and warrants further investigation. To better understand β-catenin nuclear-localization mechanisms in myeloid leukemia cells, we generated the first β-catenin interactomes in hematopoietic cells. These analyses have shown that LEF-1, a β-catenin-dependent transcription factor, can also regulate the level of nuclear β-catenin in myeloid leukemia cells. The relative level of nuclear LEF-1 expression correlates with relative nuclear levels of β-catenin in primary AML patient blasts indicating this axis has clinical relevance. Furthermore, the nuclear-localization of β-catenin can be promoted by LEF-1 overexpression and conversely is reduced by LEF-1 knockdown. Finally, we demonstrate LEF-1 expression is suppressed in Wnt-unresponsive cells through rapid proteolytic degradation that is not observed in Wnt-responsive cells. Overall, this study characterizes β-catenin interactions within a hematopoietic context and identifies LEF-1 as a regulator of nuclear β-catenin localization in human leukemia. Methods Patient samples, cell culture and β-catenin stabilization Bone marrow, peripheral blood or leukapheresis samples from patients diagnosed with AML/myelodysplastic syndromes (MDS) (for clinical information see Online Supplementary Table S1 ) were collected in accordance with the Declaration of Helsinki and with approval of University Hospitals Bristol NHS Trust and London Brent Research Ethics Committee. Mononuclear cells were separated using Ficoll-Hypaque (Sigmα-Aldrich, Poole, UK) and samples with ≥80% viability included in the study. K562, HEL, ML-1, U937, THP1 and PLB-985 cell lines (ECACC, Salisbury, UK) were cultured as previously described. 11 For proliferation assays, cell lines were seeded in triplicate at 1×10/mL into 24-well plates within medium containing 10, 5, 1 or 0.5% fetal bovine serum (Labtech, East Sussex, UK) and cellular density counted using a hemocytometer at 24, 48 and 72 hours (h). For Wnt signaling activation, cell lines were treated with 5 μM of the GSK-3β inhibitor CHIR99021 (Sigmα-Aldrich) or 1 μg/mL recombinant murine Wnt3a (Peprotech, London, UK) for 16 h (unless otherwise stated) at 37°C. Nuclear/cytoplasmic fractionation 2-8×10 cells were washed in PBS and resuspended in 250 μL cytoplasmic lysis buffer (10 mM Tris-HCl (pH8), 10 mM NaCl, 1.5 mM MgCl2, 0.5% Igepal-CA630/NP40) containing complete™ Mini Protease-Inhibitor Cocktail (PIC; Sigmα-Aldrich) for 10 minutes (min) at 4°C. The supernatant (cytosolic fraction) was recovered following centrifugation at 800 g for 5 min, and the nuclear pellet washed twice with PBS. Nuclear pellets were resuspended in lysis buffer (Cell Signaling Technology, Leiden, the Netherlands) containing PIC and incubated for 45 min with sonication to maximize nuclear lysis. Insoluble material was removed at 21,000 g for 10 min and solubilized nuclear fractions stored at −80°C. Lentiviral transduction K562 and HEL cells were lentivirally-transduced with the β-catenin-activated reporter (BAR) or mutant ‘found unresponsive’ control (fuBAR) system as previously. 11 For LEF-1 knockdown/overexpression, cells were lentivirally-transduced with human LEF-1 shRNA (TRCN0000-020163, -413476, -418104, -428178 and -428355, MISSION® Sigma), or LEF-1 overexpression vector (pLV-EGFP:T2A:Puro-EF1A>hLEF-1 VectorBuilder, Neu-Isenburg, Germany). Cells transduced with scrambled shRNA/empty vector served as controls. β-catenin co-immunoprecipitation and immunoblotting For co-immunoprecipitation (co-IP), 8 μg of crosslinked β-catenin (Clone-14) or IgG", "role": "user" }, { "content": "A mechanism which drives leukaemia cell growth has been discovered by researchers at the University of Sussex, who believe their findings could help to inform new strategies when it comes to treating the cancer. Acute myeloid leukaemia (AML) is a devastating blood cancer with around 3,000 new cases annually in the UK. Despite considerable improvement in patient survival over the last 50 years, the prognosis remains poor for many subsets of adults and children who suffer from the disease. Current chemotherapies are highly toxic, and often fail to induce a long-term cure resulting in an urgent clinical need for the design of better tolerated and highly targeted therapies that induce durable remissions. Leukaemia cells are known to have an overactive level of a protein called β-catenin, which can drive cancer development. Once this protein moves into the nucleus of cells, where DNA is stored, it can assist the activation of genes important for leukaemia development. The activity of β-catenin is highly dependent upon the interactions it forms with other proteins in the cell. Up until now, the movement of β-catenin into the nucleus of leukaemia cells has been a poorly understood process in blood cells. But researchers from the University of Sussex, Bristol and Cardiff using funding from the Kay Kendall Leukaemia Fund (KKLF) and Bloodwise have now discovered a protein partner that promotes this process and therefore helps leukaemia cells to grow. Their findings could lead to the development of new therapeutic strategies to treat AML. In a paper published in the journal Haematologica, Dr. Rhys Morgan, Lecturer in Biomedical Science, observed that protein LEF-1 can actively control the level of β-catenin in the nucleus of myeloid leukaemia cells. This is the first study to reveal such a mechanism is active in leukaemia cells, and also the first to reveal β-catenin's interaction partners in blood cells. Dr. Rhys Morgan, from the University of Sussex, said: \"Whilst scientists have long been aware of the involvement of β-catenin in cancer progression, drugs directly targeting the protein or its partners haven't yet reached the clinic. From our research findings we'd suggest that pharmacological targeting of β-catenin's movement into the nucleus, through a partner like LEF-1, could be a viable treatment strategy in leukaemia.\" He explained further: \"This research is at a very early stage and targeting the activity of β-catenin won't be a solution for all leukaemia cases and subtypes. \"However data suggests that anywhere between 20-80% of AML cases display elevated levels of this molecule which justifies further investigation in this setting.\" Dr. Morgan and his team are now working to further understand the biological significance of many of the new interacting proteins discovered in the study, with the belief that others could be worth targeting to inhibit β-catenin level and activity in leukaemia. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin, we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β- catenin level in human myeloid leukemia. Introduction Canonical Wnt signaling is an evolutionary conserved signal transduction pathway strictly controlled during normal development but frequently dysregulated in cancer. 1 In the absence of a Wnt ligand, the central mediator of this signaling pathway, β-catenin, is constitutively phosphorylated by a destruction complex (DC) consisting of GSK3β, CK1, Axin and APC, priming it for subsequent degradation by the proteasome. Upon Wnt ligand binding to the Wnt receptors (Frizzled and LRP5/6), the DC becomes saturated with phosphorylated β-catenin (which cannot be degraded) resulting in cytosolic accumulation of non-phosphorylated β-catenin. 2 Following nuclear translocation, β-catenin complexes with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcriptional regulators and promotes activation of proto-oncogenic Wnt target genes, like c-myc, cyclinD1 and survivin ( ). Thus, Wnt signaling activation is dependent on the movement of β-catenin into the nucleus, yet this remains a poorly understood process in blood cells. β-Catenin lacks canonical nuclear-localization or -export sequences and its subcellular distribution has instead been associated with multiple factors in context-dependent settings. 3 β-Catenin is frequently over-expressed in acute myeloid leukemia (AML) 4 where its expression correlates with inferior patient survival. 5 β-Catenin has been shown to play a key role in the initiation of AML and chronic myeloid leukemia (CML). 7 6 Furthermore, frequent chromosomal aberrations driving AML and CML are known to co-operate with β-catenin. 9 8 Key to the activation of Wnt signaling is the movement of β-catenin into the nucleus and this is frequently observed in AML. 10 We have previously demonstrated that approximately 10% of primary AML patient blast samples exhibit little nuclear β-catenin expression, despite substantial cytosolic levels, a phenomenon replicated in 10-20% of myeloid leukemia cell lines upon Wnt stimulation. 11 3 In fact, this is characteristic of normal human hematopoietic stem/progenitor cells (HSPC) which similarly limit β-catenin nuclear-localization, possibly to protect normal HSC from detrimental levels of Wnt signaling. 12 The permissive nuclear-localization of β-catenin observed in myeloid leukemias is therefore aberrant and warrants further investigation. To better understand β-catenin nuclear-localization mechanisms in myeloid leukemia cells, we generated the first β-catenin interactomes in hematopoietic cells. These analyses have shown that LEF-1, a β-catenin-dependent transcription factor, can also regulate the level of nuclear β-catenin in myeloid leukemia cells. The relative level of nuclear LEF-1 expression correlates with relative nuclear levels of β-catenin in primary AML patient blasts indicating this axis has clinical relevance. Furthermore, the nuclear-localization of β-catenin can be promoted by LEF-1 overexpression and conversely is reduced by LEF-1 knockdown. Finally, we demonstrate LEF-1 expression is suppressed in Wnt-unresponsive cells through rapid proteolytic degradation that is not observed in Wnt-responsive cells. Overall, this study characterizes β-catenin interactions within a hematopoietic context and identifies LEF-1 as a regulator of nuclear β-catenin localization in human leukemia. Methods Patient samples, cell culture and β-catenin stabilization Bone marrow, peripheral blood or leukapheresis samples from patients diagnosed with AML/myelodysplastic syndromes (MDS) (for clinical information see Online Supplementary Table S1 ) were collected in accordance with the Declaration of Helsinki and with approval of University Hospitals Bristol NHS Trust and London Brent Research Ethics Committee. Mononuclear cells were separated using Ficoll-Hypaque (Sigmα-Aldrich, Poole, UK) and samples with ≥80% viability included in the study. K562, HEL, ML-1, U937, THP1 and PLB-985 cell lines (ECACC, Salisbury, UK) were cultured as previously described. 11 For proliferation assays, cell lines were seeded in triplicate at 1×10/mL into 24-well plates within medium containing 10, 5, 1 or 0.5% fetal bovine serum (Labtech, East Sussex, UK) and cellular density counted using a hemocytometer at 24, 48 and 72 hours (h). For Wnt signaling activation, cell lines were treated with 5 μM of the GSK-3β inhibitor CHIR99021 (Sigmα-Aldrich) or 1 μg/mL recombinant murine Wnt3a (Peprotech, London, UK) for 16 h (unless otherwise stated) at 37°C. Nuclear/cytoplasmic fractionation 2-8×10 cells were washed in PBS and resuspended in 250 μL cytoplasmic lysis buffer (10 mM Tris-HCl (pH8), 10 mM NaCl, 1.5 mM MgCl2, 0.5% Igepal-CA630/NP40) containing complete™ Mini Protease-Inhibitor Cocktail (PIC; Sigmα-Aldrich) for 10 minutes (min) at 4°C. The supernatant (cytosolic fraction) was recovered following centrifugation at 800 g for 5 min, and the nuclear pellet washed twice with PBS. Nuclear pellets were resuspended in lysis buffer (Cell Signaling Technology, Leiden, the Netherlands) containing PIC and incubated for 45 min with sonication to maximize nuclear lysis. Insoluble material was removed at 21,000 g for 10 min and solubilized nuclear fractions stored at −80°C. Lentiviral transduction K562 and HEL cells were lentivirally-transduced with the β-catenin-activated reporter (BAR) or mutant ‘found unresponsive’ control (fuBAR) system as previously. 11 For LEF-1 knockdown/overexpression, cells were lentivirally-transduced with human LEF-1 shRNA (TRCN0000-020163, -413476, -418104, -428178 and -428355, MISSION® Sigma), or LEF-1 overexpression vector (pLV-EGFP:T2A:Puro-EF1A>hLEF-1 VectorBuilder, Neu-Isenburg, Germany). Cells transduced with scrambled shRNA/empty vector served as controls. β-catenin co-immunoprecipitation and immunoblotting For co-immunoprecipitation (co-IP), 8 μg of crosslinked β-catenin (Clone-14) or IgG<|im_end|> <|im_start|>assistant A mechanism which drives leukaemia cell growth has been discovered by researchers at the University of Sussex, who believe their findings could help to inform new strategies when it comes to treating the cancer. Acute myeloid leukaemia (AML) is a devastating blood cancer with around 3,000 new cases annually in the UK. Despite considerable improvement in patient survival over the last 50 years, the prognosis remains poor for many subsets of adults and children who suffer from the disease. Current chemotherapies are highly toxic, and often fail to induce a long-term cure resulting in an urgent clinical need for the design of better tolerated and highly targeted therapies that induce durable remissions. Leukaemia cells are known to have an overactive level of a protein called β-catenin, which can drive cancer development. Once this protein moves into the nucleus of cells, where DNA is stored, it can assist the activation of genes important for leukaemia development. The activity of β-catenin is highly dependent upon the interactions it forms with other proteins in the cell. Up until now, the movement of β-catenin into the nucleus of leukaemia cells has been a poorly understood process in blood cells. But researchers from the University of Sussex, Bristol and Cardiff using funding from the Kay Kendall Leukaemia Fund (KKLF) and Bloodwise have now discovered a protein partner that promotes this process and therefore helps leukaemia cells to grow. Their findings could lead to the development of new therapeutic strategies to treat AML. In a paper published in the journal Haematologica, Dr. Rhys Morgan, Lecturer in Biomedical Science, observed that protein LEF-1 can actively control the level of β-catenin in the nucleus of myeloid leukaemia cells. This is the first study to reveal such a mechanism is active in leukaemia cells, and also the first to reveal β-catenin's interaction partners in blood cells. Dr. Rhys Morgan, from the University of Sussex, said: "Whilst scientists have long been aware of the involvement of β-catenin in cancer progression, drugs directly targeting the protein or its partners haven't yet reached the clinic. From our research findings we'd suggest that pharmacological targeting of β-catenin's movement into the nucleus, through a partner like LEF-1, could be a viable treatment strategy in leukaemia." He explained further: "This research is at a very early stage and targeting the activity of β-catenin won't be a solution for all leukaemia cases and subtypes. "However data suggests that anywhere between 20-80% of AML cases display elevated levels of this molecule which justifies further investigation in this setting." Dr. Morgan and his team are now working to further understand the biological significance of many of the new interacting proteins discovered in the study, with the belief that others could be worth targeting to inhibit β-catenin level and activity in leukaemia. <|im_end|>

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2,453

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Methane (CH 4 ) emission by carbon-rich cryosols at the high latitudes in Northern Hemisphere has been studied extensively. In contrast, data on the CH 4 emission potential of carbon-poor cryosols is limited, despite their spatial predominance. This work employs CH 4 flux measurements in the field and under laboratory conditions to show that the mineral cryosols at Axel Heiberg Island in the Canadian high Arctic consistently consume atmospheric CH 4 . Omics analyses present the first molecular evidence of active atmospheric CH 4 -oxidizing bacteria (atmMOB) in permafrost-affected cryosols, with the prevalent atmMOB genotype in our acidic mineral cryosols being closely related to Upland Soil Cluster α. The atmospheric (atm) CH 4 uptake at the study site increases with ground temperature between 0 °C and 18 °C. Consequently, the atm CH 4 sink strength is predicted to increase by a factor of 5–30 as the Arctic warms by 5–15 °C over a century. We demonstrate that acidic mineral cryosols are a previously unrecognized potential of CH 4 sink that requires further investigation to determine its potential impact on larger scales. This study also calls attention to the poleward distribution of atmMOB, as well as to the potential influence of microbial atm CH 4 oxidation, in the context of regional CH 4 flux models and global warming. Introduction After 7 years of a steady-state concentration between 1999 and 2006, atmospheric (atm) CH 4 has been increasing steadily at 5 p.p.b. year −1 ( Dlugokencky et al., 2009 ). At 1.80 p.p.m.v. in 2011, the atm CH 4 concentration is 217 times lower than that of carbon dioxide (CO 2 ); however, it accounts for 18% of the total radiative forcing by long-lived greenhouse gases ( IPCC, 2013 ) and has a global warming potential 75 times greater than CO 2 over a 20-year timescale ( Shindell et al., 2009 ). Although cost-effective strategies could be applied to mitigate CH 4 production due to anthropogenic activities (~64% of current global total CH 4 emissions), future global CH 4 emissions will depend greatly on the uncertain responses of natural ecosystems to climate change, especially in wetlands and permafrost-affected areas in the Arctic and sub-Arctic regions ( Dlugokencky et al., 2011 ; Graham et al., 2012 ). Permafrost, defined as ‘ground that remains ⩽ 0 °C for at least 2 consecutive years’ ( Van Everdingen, 1998 ), is overlain by an active layer that thaws seasonally. By 2100, it is projected that the mean annual air temperature in the Arctic will have increased by up to 10 °C ( IPCC, 2013 ), which would result in warming of the 17.8–22.8 × 10 6 km 2 of permafrost ( Zhang et al., 2008 ; Hugelius et al., 2014 ) that contains 1034±183 or 1104±133 Pg of soil organic carbon in the top 3 m ( Hugelius et al., 2014 ). If 20–59% of the permafrost has thawed down to 0.5–1 m by 2200 as predicted ( Schaefer et al., 2011 ), this large carbon pool would become available for microbial mineralization into greenhouse gases and may amplify warming. As a result of the concern about this positive feedback response that further intensifies warming, the transition of carbon-rich permafrost into CH 4 -emitting wetlands has been the focus of considerable research (1–9 in Figure 1 ; Supplementary Table S1 ), even though the majority (87%) of Arctic permafrost is comprised of mineral (that is, carbon-poor) cryosols ( Hugelius et al., 2014 ). Observations of atm CH 4 uptake were first reported in Alaskan permafrost sites in early 1990 s ( Whalen and Reeburgh, 1990 ). Since then, atm CH 4 uptake has occasionally been reported in other permafrost-affected sites (a–k in Figure 1 ; Supplementary Table S1 ), including cryosols of high organic carbon and water saturation levels where CH 4 emission was expected. Recently reported CH 4 fluxes of polar desert mineral cryosols at Ellesmere Island, Canada over five consecutive summers also indicate consumption of atm CH 4 (a in Figure 1 ; Emmerton et al., 2014 ). In the present study, we investigated the CH 4 feedback response of mineral cryosols on Axel Heiberg Island (AHI) in the Canadian high Arctic by both in situ flux measurements and laboratory experiments, identified the active functional groups responsible for the feedback process and evaluated how these cryosols would respond to changing climate. Figure 1 CH 4 field fluxes in the Northern Circumpolar permafrost region. Sites that showed net CH 4 release are sources (numbers) whereas those showed net atm CH 4 consumption are sinks (letters). The CH 4 fluxes are rounded up to the first decimal place except for values <0.1 mg CH 4 -C m −2 day −1 . Purple outline indicates that the presence of atmMOB is supported by microbial data. Information of soil characteristics is provided in Supplementary Table S1 . Background map was generated using the interactive tool ‘The Atlas of the Cryosphere’ ( Maurer, 2007 ) available at the National Snow and Ice Data Center website ( ). Full size image Materials and methods Site description The study site, characterized by high-centered ice-wedge polygons of acidic tundra, is located at an upland polygonal terrain in proximity to the McGill Arctic Research Station at Expedition Fjord (79°24’57\"N, 90°45’46\"W), AHI, Nunavut, Canada. The average depth of the active layer varied between 60 and 73 cm (mid-summer 2009–2011; Allan et al., 2014 ). The mean soil temperatures in mid-summer (14 July 2013) at both the polygon interior and the ice wedge trough were 9±0.8 °C at 5-cm depth and decreased to 3±1.4 °C at 20-cm depth. Soil temperatures were measured by LiCOR thermistor (Maxim Integrated Products, San Jose, CA, USA). The polygon (16 × 16 m 2 ) from which cryosols were collected for incubation and molecular studies was sparsely vegetated but root materials were present to 15-cm depth (Stackhouse et al. , submitted). Soil characteristics and pore water chemistry has been analyzed by Stackhouse et al. (submitted). Briefly, the cryosols were", "role": "user" }, { "content": "In addition to melting icecaps and imperiled wildlife, a significant concern among scientists is that higher Arctic temperatures brought about by climate change could result in the release of massive amounts of carbon locked in the region's frozen soil in the form of carbon dioxide and methane. Arctic permafrost is estimated to contain about a trillion tons of carbon, which would potentially accelerate global warming. Carbon emissions in the form of methane have been of particular concern because on a 100-year scale methane is about 25-times more potent than carbon dioxide at trapping heat. However, new research led by Princeton University researchers and published in The ISME Journal in August suggests that, thanks to methane-hungry bacteria, the majority of Arctic soil might actually be able to absorb methane from the atmosphere rather than release it. Furthermore, that ability seems to become greater as temperatures rise. The researchers found that Arctic soils containing low carbon content—which make up 87 percent of the soil in permafrost regions globally—not only remove methane from the atmosphere, but also become more efficient as temperatures increase. During a three-year period, a carbon-poor site on Axel Heiberg Island in Canada's Arctic region consistently took up more methane as the ground temperature rose from 0 to 18 degrees Celsius (32 to 64.4 degrees Fahrenheit). The researchers project that should Arctic temperatures rise by 5 to 15 degrees Celsius over the next 100 years, the methane-absorbing capacity of \"carbon-poor\" soil could increase by five to 30 times. The researchers found that this ability stems from an as-yet unknown species of bacteria in carbon-poor Arctic soil that consume methane in the atmosphere. The bacteria are related to a bacterial group known as Upland Soil Cluster Alpha, the dominant methane-consuming bacteria in carbon-poor Arctic soil. The bacteria the researchers studied remove the carbon from methane to produce methanol, a simple alcohol the bacteria process immediately. The carbon is used for growth or respiration, meaning that it either remains in bacterial cells or is released as carbon dioxide. First author Chui Yim \"Maggie\" Lau, an associate research scholar in Princeton's Department of Geosciences, said that although it's too early to claim that the entire Arctic will be a massive methane \"sink\" in a warmer world, the study's results do suggest that the Arctic could help mitigate the warming effect that would be caused by a rising amount of methane in the atmosphere. In immediate terms, climate models that project conditions on a warmer Earth could use this study to more accurately calculate the future methane content of the atmosphere, Lau said. \"At our study sites, we are more confident that these soils will continue to be a sink under future warming. In the future, the Arctic may not have atmospheric methane increase as much as the rest of the world,\" Lau said. \"We don't have a direct answer as to whether these Arctic soils will offset global atmospheric methane or not, but they will certainly help the situation.\" The researchers want to study the bacteria's physiology as well as test the upper temperature threshold and methane concentrations at which they can still efficiently process methane, Lau said. Field observations showed that the bacteria are still effective up to 18 degrees Celsius (64.4 degrees Fahrenheit) and can remove methane down to one-quarter of the methane level in the atmosphere, which is around 0.5 parts-per-million. \"If these bacteria can still work in a future warmer climate and are widespread in other Arctic permafrost areas, maybe they could regulate methane for the whole globe,\" Lau said. \"These regions may seem isolated from the world, but they may have been doing things to help the world.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Methane (CH 4 ) emission by carbon-rich cryosols at the high latitudes in Northern Hemisphere has been studied extensively. In contrast, data on the CH 4 emission potential of carbon-poor cryosols is limited, despite their spatial predominance. This work employs CH 4 flux measurements in the field and under laboratory conditions to show that the mineral cryosols at Axel Heiberg Island in the Canadian high Arctic consistently consume atmospheric CH 4 . Omics analyses present the first molecular evidence of active atmospheric CH 4 -oxidizing bacteria (atmMOB) in permafrost-affected cryosols, with the prevalent atmMOB genotype in our acidic mineral cryosols being closely related to Upland Soil Cluster α. The atmospheric (atm) CH 4 uptake at the study site increases with ground temperature between 0 °C and 18 °C. Consequently, the atm CH 4 sink strength is predicted to increase by a factor of 5–30 as the Arctic warms by 5–15 °C over a century. We demonstrate that acidic mineral cryosols are a previously unrecognized potential of CH 4 sink that requires further investigation to determine its potential impact on larger scales. This study also calls attention to the poleward distribution of atmMOB, as well as to the potential influence of microbial atm CH 4 oxidation, in the context of regional CH 4 flux models and global warming. Introduction After 7 years of a steady-state concentration between 1999 and 2006, atmospheric (atm) CH 4 has been increasing steadily at 5 p.p.b. year −1 ( Dlugokencky et al., 2009 ). At 1.80 p.p.m.v. in 2011, the atm CH 4 concentration is 217 times lower than that of carbon dioxide (CO 2 ); however, it accounts for 18% of the total radiative forcing by long-lived greenhouse gases ( IPCC, 2013 ) and has a global warming potential 75 times greater than CO 2 over a 20-year timescale ( Shindell et al., 2009 ). Although cost-effective strategies could be applied to mitigate CH 4 production due to anthropogenic activities (~64% of current global total CH 4 emissions), future global CH 4 emissions will depend greatly on the uncertain responses of natural ecosystems to climate change, especially in wetlands and permafrost-affected areas in the Arctic and sub-Arctic regions ( Dlugokencky et al., 2011 ; Graham et al., 2012 ). Permafrost, defined as ‘ground that remains ⩽ 0 °C for at least 2 consecutive years’ ( Van Everdingen, 1998 ), is overlain by an active layer that thaws seasonally. By 2100, it is projected that the mean annual air temperature in the Arctic will have increased by up to 10 °C ( IPCC, 2013 ), which would result in warming of the 17.8–22.8 × 10 6 km 2 of permafrost ( Zhang et al., 2008 ; Hugelius et al., 2014 ) that contains 1034±183 or 1104±133 Pg of soil organic carbon in the top 3 m ( Hugelius et al., 2014 ). If 20–59% of the permafrost has thawed down to 0.5–1 m by 2200 as predicted ( Schaefer et al., 2011 ), this large carbon pool would become available for microbial mineralization into greenhouse gases and may amplify warming. As a result of the concern about this positive feedback response that further intensifies warming, the transition of carbon-rich permafrost into CH 4 -emitting wetlands has been the focus of considerable research (1–9 in Figure 1 ; Supplementary Table S1 ), even though the majority (87%) of Arctic permafrost is comprised of mineral (that is, carbon-poor) cryosols ( Hugelius et al., 2014 ). Observations of atm CH 4 uptake were first reported in Alaskan permafrost sites in early 1990 s ( Whalen and Reeburgh, 1990 ). Since then, atm CH 4 uptake has occasionally been reported in other permafrost-affected sites (a–k in Figure 1 ; Supplementary Table S1 ), including cryosols of high organic carbon and water saturation levels where CH 4 emission was expected. Recently reported CH 4 fluxes of polar desert mineral cryosols at Ellesmere Island, Canada over five consecutive summers also indicate consumption of atm CH 4 (a in Figure 1 ; Emmerton et al., 2014 ). In the present study, we investigated the CH 4 feedback response of mineral cryosols on Axel Heiberg Island (AHI) in the Canadian high Arctic by both in situ flux measurements and laboratory experiments, identified the active functional groups responsible for the feedback process and evaluated how these cryosols would respond to changing climate. Figure 1 CH 4 field fluxes in the Northern Circumpolar permafrost region. Sites that showed net CH 4 release are sources (numbers) whereas those showed net atm CH 4 consumption are sinks (letters). The CH 4 fluxes are rounded up to the first decimal place except for values <0.1 mg CH 4 -C m −2 day −1 . Purple outline indicates that the presence of atmMOB is supported by microbial data. Information of soil characteristics is provided in Supplementary Table S1 . Background map was generated using the interactive tool ‘The Atlas of the Cryosphere’ ( Maurer, 2007 ) available at the National Snow and Ice Data Center website ( ). Full size image Materials and methods Site description The study site, characterized by high-centered ice-wedge polygons of acidic tundra, is located at an upland polygonal terrain in proximity to the McGill Arctic Research Station at Expedition Fjord (79°24’57"N, 90°45’46"W), AHI, Nunavut, Canada. The average depth of the active layer varied between 60 and 73 cm (mid-summer 2009–2011; Allan et al., 2014 ). The mean soil temperatures in mid-summer (14 July 2013) at both the polygon interior and the ice wedge trough were 9±0.8 °C at 5-cm depth and decreased to 3±1.4 °C at 20-cm depth. Soil temperatures were measured by LiCOR thermistor (Maxim Integrated Products, San Jose, CA, USA). The polygon (16 × 16 m 2 ) from which cryosols were collected for incubation and molecular studies was sparsely vegetated but root materials were present to 15-cm depth (Stackhouse et al. , submitted). Soil characteristics and pore water chemistry has been analyzed by Stackhouse et al. (submitted). Briefly, the cryosols were<|im_end|> <|im_start|>assistant In addition to melting icecaps and imperiled wildlife, a significant concern among scientists is that higher Arctic temperatures brought about by climate change could result in the release of massive amounts of carbon locked in the region's frozen soil in the form of carbon dioxide and methane. Arctic permafrost is estimated to contain about a trillion tons of carbon, which would potentially accelerate global warming. Carbon emissions in the form of methane have been of particular concern because on a 100-year scale methane is about 25-times more potent than carbon dioxide at trapping heat. However, new research led by Princeton University researchers and published in The ISME Journal in August suggests that, thanks to methane-hungry bacteria, the majority of Arctic soil might actually be able to absorb methane from the atmosphere rather than release it. Furthermore, that ability seems to become greater as temperatures rise. The researchers found that Arctic soils containing low carbon content—which make up 87 percent of the soil in permafrost regions globally—not only remove methane from the atmosphere, but also become more efficient as temperatures increase. During a three-year period, a carbon-poor site on Axel Heiberg Island in Canada's Arctic region consistently took up more methane as the ground temperature rose from 0 to 18 degrees Celsius (32 to 64.4 degrees Fahrenheit). The researchers project that should Arctic temperatures rise by 5 to 15 degrees Celsius over the next 100 years, the methane-absorbing capacity of "carbon-poor" soil could increase by five to 30 times. The researchers found that this ability stems from an as-yet unknown species of bacteria in carbon-poor Arctic soil that consume methane in the atmosphere. The bacteria are related to a bacterial group known as Upland Soil Cluster Alpha, the dominant methane-consuming bacteria in carbon-poor Arctic soil. The bacteria the researchers studied remove the carbon from methane to produce methanol, a simple alcohol the bacteria process immediately. The carbon is used for growth or respiration, meaning that it either remains in bacterial cells or is released as carbon dioxide. First author Chui Yim "Maggie" Lau, an associate research scholar in Princeton's Department of Geosciences, said that although it's too early to claim that the entire Arctic will be a massive methane "sink" in a warmer world, the study's results do suggest that the Arctic could help mitigate the warming effect that would be caused by a rising amount of methane in the atmosphere. In immediate terms, climate models that project conditions on a warmer Earth could use this study to more accurately calculate the future methane content of the atmosphere, Lau said. "At our study sites, we are more confident that these soils will continue to be a sink under future warming. In the future, the Arctic may not have atmospheric methane increase as much as the rest of the world," Lau said. "We don't have a direct answer as to whether these Arctic soils will offset global atmospheric methane or not, but they will certainly help the situation." The researchers want to study the bacteria's physiology as well as test the upper temperature threshold and methane concentrations at which they can still efficiently process methane, Lau said. Field observations showed that the bacteria are still effective up to 18 degrees Celsius (64.4 degrees Fahrenheit) and can remove methane down to one-quarter of the methane level in the atmosphere, which is around 0.5 parts-per-million. "If these bacteria can still work in a future warmer climate and are widespread in other Arctic permafrost areas, maybe they could regulate methane for the whole globe," Lau said. "These regions may seem isolated from the world, but they may have been doing things to help the world." <|im_end|>

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1176, 5068, 304, 1708, 79451, 824, 99161, 42602, 6732, 304, 4216, 220, 2550, 15, 274, 320, 1254, 36749, 323, 1050, 3141, 324, 876, 11, 220, 2550, 15, 7609, 8876, 1243, 11, 70887, 6969, 220, 19, 69575, 706, 23781, 1027, 5068, 304, 1023, 824, 99161, 42602, 12, 32157, 6732, 320, 64, 4235, 74, 304, 19575, 220, 16, 2652, 99371, 6771, 328, 16, 7026, 2737, 16106, 437, 3145, 315, 1579, 17808, 12782, 323, 3090, 50843, 5990, 1405, 6969, 220, 19, 41353, 574, 3685, 13, 42096, 5068, 6969, 220, 19, 31405, 288, 315, 25685, 24521, 25107, 16106, 437, 3145, 520, 4072, 645, 61031, 10951, 11, 7008, 927, 4330, 24871, 80769, 1101, 13519, 15652, 315, 70887, 6969, 220, 19, 320, 64, 304, 19575, 220, 16, 2652, 66555, 37733, 1880, 453, 2637, 220, 679, 19, 7609, 763, 279, 3118, 4007, 11, 584, 27313, 279, 6969, 220, 19, 11302, 2077, 315, 25107, 16106, 437, 3145, 389, 87779, 1283, 581, 2431, 10951, 320, 32, 24860, 8, 304, 279, 12152, 1579, 37518, 555, 2225, 304, 10109, 31405, 22323, 323, 27692, 21896, 11, 11054, 279, 4642, 16003, 5315, 8647, 369, 279, 11302, 1920, 323, 26126, 1268, 1521, 16106, 437, 3145, 1053, 6013, 311, 10223, 10182, 13, 19575, 220, 16, 6969, 220, 19, 2115, 31405, 288, 304, 279, 17355, 16741, 1538, 7569, 824, 99161, 42602, 5654, 13, 33038, 430, 8710, 4272, 6969, 220, 19, 4984, 527, 8336, 320, 38478, 8, 20444, 1884, 8710, 4272, 70887, 6969, 220, 19, 15652, 527, 58052, 320, 21731, 570, 578, 6969, 220, 19, 31405, 288, 527, 18460, 709, 311, 279, 1176, 12395, 2035, 3734, 369, 2819, 366, 15, 13, 16, 14060, 6969, 220, 19, 482, 34, 296, 25173, 17, 1938, 25173, 16, 662, 41489, 21782, 15151, 430, 279, 9546, 315, 70887, 10754, 33, 374, 7396, 555, 75418, 828, 13, 8245, 315, 17614, 17910, 374, 3984, 304, 99371, 6771, 328, 16, 662, 25837, 2472, 574, 8066, 1701, 279, 21416, 5507, 3451, 791, 43443, 315, 279, 43805, 66222, 529, 320, 34492, 261, 11, 220, 1049, 22, 883, 2561, 520, 279, 5165, 19435, 323, 20534, 2956, 5955, 3997, 320, 7609, 8797, 1404, 2217, 32009, 323, 5528, 13207, 4096, 578, 4007, 2816, 11, 32971, 555, 1579, 50482, 10054, 2695, 7334, 69259, 315, 84903, 259, 79830, 11, 374, 7559, 520, 459, 709, 1974, 30472, 278, 25911, 304, 37843, 311, 279, 94076, 37518, 8483, 17040, 520, 84874, 435, 73, 541, 320, 4643, 11877, 1187, 529, 3226, 93466, 11, 220, 1954, 11877, 1774, 529, 2790, 61067, 705, 362, 24860, 11, 64778, 402, 332, 11, 7008, 13, 578, 5578, 8149, 315, 279, 4642, 6324, 28830, 1990, 220, 1399, 323, 220, 5958, 10166, 320, 16497, 12, 63666, 220, 1049, 24, 4235, 679, 16, 26, 61325, 1880, 453, 2637, 220, 679, 19, 7609, 578, 3152, 17614, 20472, 304, 5209, 12, 63666, 320, 975, 5887, 220, 679, 18, 8, 520, 2225, 279, 30472, 15135, 323, 279, 10054, 64785, 79065, 1051, 220, 24, 38121, 15, 13, 23, 37386, 34, 520, 220, 20, 1824, 76, 8149, 323, 25983, 311, 220, 18, 38121, 16, 13, 19, 37386, 34, 520, 220, 508, 1824, 76, 8149, 13, 76619, 20472, 1051, 17303, 555, 14851, 53420, 30945, 5436, 320, 6102, 318, 50521, 15899, 11, 5960, 11097, 11, 9362, 11, 7427, 570, 578, 30472, 320, 845, 25800, 220, 845, 296, 220, 17, 883, 505, 902, 16106, 437, 3145, 1051, 14890, 369, 49727, 367, 323, 31206, 7978, 574, 993, 1590, 989, 13294, 660, 719, 3789, 7384, 1051, 3118, 311, 220, 868, 1824, 76, 8149, 320, 4434, 7830, 1880, 453, 13, 1174, 14976, 570, 76619, 17910, 323, 97551, 3090, 30903, 706, 1027, 30239, 555, 14619, 7830, 1880, 453, 13, 320, 73563, 570, 37618, 398, 11, 279, 16106, 437, 3145, 1051, 128257, 198, 128256, 78191, 198, 644, 5369, 311, 50684, 10054, 49333, 323, 17190, 2230, 30405, 11, 264, 5199, 4747, 4315, 14248, 374, 430, 5190, 37518, 20472, 7263, 922, 555, 10182, 2349, 1436, 1121, 304, 279, 4984, 315, 11191, 15055, 315, 12782, 16447, 304, 279, 5654, 596, 20268, 17614, 304, 279, 1376, 315, 12782, 40589, 323, 61083, 13, 37518, 824, 99161, 42602, 374, 13240, 311, 6782, 922, 264, 32610, 20181, 315, 12782, 11, 902, 1053, 13893, 43880, 3728, 24808, 13, 22208, 20748, 304, 279, 1376, 315, 61083, 617, 1027, 315, 4040, 4747, 1606, 389, 264, 220, 1041, 4771, 5569, 61083, 374, 922, 220, 914, 45548, 810, 36875, 1109, 12782, 40589, 520, 93669, 8798, 13, 4452, 11, 502, 3495, 6197, 555, 50421, 3907, 12074, 323, 4756, 304, 578, 3507, 7614, 10139, 304, 6287, 13533, 430, 11, 9523, 311, 61083, 2902, 2234, 894, 24032, 11, 279, 8857, 315, 37518, 17614, 2643, 3604, 387, 3025, 311, 35406, 61083, 505, 279, 16975, 4856, 1109, 4984, 433, 13, 24296, 11, 430, 5845, 5084, 311, 3719, 7191, 439, 20472, 10205, 13, 578, 12074, 1766, 430, 37518, 69561, 8649, 3428, 12782, 2262, 50004, 1304, 709, 220, 4044, 3346, 315, 279, 17614, 304, 824, 99161, 42602, 13918, 31550, 63938, 1193, 4148, 61083, 505, 279, 16975, 11, 719, 1101, 3719, 810, 11297, 439, 20472, 5376, 13, 12220, 264, 2380, 4771, 4261, 11, 264, 12782, 2320, 10922, 2816, 389, 87779, 1283, 581, 2431, 10951, 304, 7008, 596, 37518, 5654, 21356, 3952, 709, 810, 61083, 439, 279, 5015, 9499, 16392, 505, 220, 15, 311, 220, 972, 12628, 62447, 320, 843, 311, 220, 1227, 13, 19, 12628, 69823, 570, 578, 12074, 2447, 430, 1288, 37518, 20472, 10205, 555, 220, 20, 311, 220, 868, 12628, 62447, 927, 279, 1828, 220, 1041, 1667, 11, 279, 61083, 97510, 269, 7278, 8824, 315, 330, 74441, 2320, 10922, 1, 17614, 1436, 5376, 555, 4330, 311, 220, 966, 3115, 13, 578, 12074, 1766, 430, 420, 5845, 44814, 505, 459, 439, 12303, 295, 9987, 9606, 315, 24032, 304, 12782, 2320, 10922, 37518, 17614, 430, 25024, 61083, 304, 279, 16975, 13, 578, 24032, 527, 5552, 311, 264, 45964, 1912, 3967, 439, 549, 501, 438, 76619, 36480, 25737, 11, 279, 25462, 61083, 70840, 24032, 304, 12782, 2320, 10922, 37518, 17614, 13, 578, 24032, 279, 12074, 20041, 4148, 279, 12782, 505, 61083, 311, 8356, 21747, 39710, 11, 264, 4382, 13200, 279, 24032, 1920, 7214, 13, 578, 12782, 374, 1511, 369, 6650, 477, 594, 29579, 11, 7438, 430, 433, 3060, 8625, 304, 45964, 7917, 477, 374, 6004, 439, 12782, 40589, 13, 5629, 3229, 921, 2005, 816, 318, 330, 44, 16094, 648, 1, 86091, 11, 459, 22712, 3495, 18640, 304, 50421, 596, 6011, 315, 4323, 85728, 2436, 11, 1071, 430, 8051, 433, 596, 2288, 4216, 311, 3802, 430, 279, 4553, 37518, 690, 387, 264, 11191, 61083, 330, 67838, 1, 304, 264, 46039, 1917, 11, 279, 4007, 596, 3135, 656, 4284, 430, 279, 37518, 1436, 1520, 50460, 279, 24808, 2515, 430, 1053, 387, 9057, 555, 264, 16448, 3392, 315, 61083, 304, 279, 16975, 13, 763, 14247, 3878, 11, 10182, 4211, 430, 2447, 4787, 389, 264, 46039, 9420, 1436, 1005, 420, 4007, 311, 810, 30357, 11294, 279, 3938, 61083, 2262, 315, 279, 16975, 11, 86091, 1071, 13, 330, 1688, 1057, 4007, 6732, 11, 584, 527, 810, 16913, 430, 1521, 69561, 690, 3136, 311, 387, 264, 19868, 1234, 3938, 24808, 13, 763, 279, 3938, 11, 279, 37518, 1253, 539, 617, 45475, 61083, 5376, 439, 1790, 439, 279, 2800, 315, 279, 1917, 1359, 86091, 1071, 13, 330, 1687, 1541, 956, 617, 264, 2167, 4320, 439, 311, 3508, 1521, 37518, 69561, 690, 4445, 3728, 45475, 61083, 477, 539, 11, 719, 814, 690, 7995, 1520, 279, 6671, 1210, 578, 12074, 1390, 311, 4007, 279, 24032, 596, 78152, 439, 1664, 439, 1296, 279, 8582, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 + T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Main Chronic viral infections and cancer exhibit accumulating changes in antigen-specific CD8 + T cells, termed T cell exhaustion 1 , 2 . T cell exhaustion is initiated and maintained by extended exposure to cognate antigen and inflammatory signals 2 , 3 . Exhausted T (T EX ) cells characteristically express inhibitory receptors such as programmed cell death 1 (PD-1) or 2B4 (refs. 4 , 5 , 6 ), increasingly lose key functions such as cytokine secretion and proliferation 3 , 7 , and do not differentiate into memory T (T MEM ) cells as occurs after acute infection 8 . T EX cells also lack antigen-independent self-renewal 9 , 10 and cannot mount a swift recall response. At the end of the exhaustion spectrum, antigen-specific T cells even get physically deleted 9 , 11 . T cell exhaustion is reversable, for example, with checkpoint inhibitor therapies targeting PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4; refs. 12 , 13 ). However, these cancer immunotherapies are effective only for some cancers and, within a disease category, only for select patient subsets—indicating that the molecular mechanisms underlying T cell exhaustion are complex and heterogeneous 14 . Additionally, immune recovery is not long lasting 15 . Other treatment modalities aimed at invigorating T cell responses, such as therapeutic vaccines 16 , 17 and immunomodulatory or antigen-lowering drugs in chronic viral infection 18 , similarly aim at overcoming the dysfunctionality of T EX cells. Understanding the cellular pathways driving T cell exhaustion and the road to sustained T cell recovery is critical for developing more effective and targeted therapies 14 . While the major clinical breakthroughs in reversing T cell exhaustion have been achieved in cancer, much of our understanding of the molecular mechanisms of T cell exhaustion stems from studies of chronic viral infection, most notably with strains of the lymphocytic choriomeningitis virus (LCMV) in mice 19 . The major advantage of studying viral infection is that it readily allows analysis of T cell exhaustion in antigen-specific T cells and within the critical context of antigen burden, both of which are more difficult to define in cancer. Emerging tools to study small populations of immune cells from clinical samples enable studies of T cell exhaustion directly in humans, especially in chronic infections with human immunodeficiency virus (HIV) 20 , hepatitis B virus (HBV) 21 , 22 and HCV 4 , 23 . HCV infection is particularly suited to elucidating differences in the regulation of of T cell differentiation. HCV is the only chronic viral infection with a complete dichotomy in natural outcome 24 : an estimated 20–30% of infected individuals completely clear the virus, typically within 6 months, allowing direct comparison of T cell memory and exhaustion within the same pathogen and host framework 25 . Additionally, HCV is the first, and so far only, chronic viral infection that can be completely terminated using direct-acting antivirals (DAAs) 26 , enabling the study of whether termination of antigen exposure enables the redifferentiation of T EX cell populations into effective T cell memory. Such work has revealed important insights, including T cell proliferation recovery after antigen clearance in parallel to the expansion of preexisting CD127 + PD-1 + TCF-1 + memory-like T cells 27 , 28 . Nevertheless, these memory-like CD8 + T cells are partially different from actual T MEM cells after acute infection 27 , 29 , 30 , indicating the need for more detailed analyses to understand the molecular trajectories of T EX cells after antigen removal and the hurdles to achieving full memory potential. In this study, we used the paradigm of chronic HCV infection and DAA treatment to further define the features of T cell exhaustion in humans, and the potential for reversion of exhaustion after antigen removal. A specifically designed clinical DAA trial that incorporated leukapheresis collection at specified time points allowed us to perform broad and deep T cell studies from the same peripheral blood mononuclear cell (PBMC) collections in the context of a well-defined clinical perturbation. After cure, we documented pervasive phenotypic changes in clonally stable T EX cell populations suggesting differentiation toward memory-like cells, but function and critical transcriptional regulators were mostly fixed in the T EX cell state. We also provide evidence that T cell dysregulation solidifies with the duration of exhaustion, indicating a limited window of opportunity early in chronic infection. Results DAA treatment trial for immunological studies of viral cure To determine the impact of antigen removal in a state of chronic viral infection, we designed a DAA treatment trial for HCV infection, generating optimal samples for immunological studies. We were able to study 20 of 25 long-term HCV-infected patients who received 12 weeks of paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin 31 (Supplementary Table 1 ). PBMC collections were scheduled at structured intervals before, during and after therapy, including at least two leukapheresis collections at weeks 0 and 24. A typical yield of 10 10 PBMCs per leukapheresis procedure allowed us to perform all CD8 + T cell assays reported in this paper on cells from the same", "role": "user" }, { "content": "Chronic viral infections and cancer can cause \"killer\" T cells in the immune system to take on a state of dysfunction or exhaustion whereby they can no longer react to infectious invaders or abnormal cells like normal \"memory\" T cells. Two new studies led by investigators at Massachusetts General Hospital (MGH) and published in Nature Immunology provide insights into T cell exhaustion, which could lead to potential strategies to overcome it. One study, which was led by Georg M. Lauer, MD, Ph.D., of the Division of Gastroenterology at MGH, focused on differences between memory and exhausted T cells in individuals with human hepatitis C virus (HCV) infection before and after treatment. After patients were treated and cured, their exhausted T cells tended to take on some properties of memory T cells but did not function as well as memory T cells. \"We saw some cosmetic improvement of the T cells that in a more superficial study could have been interpreted as real recovery, whereas in reality the key parameters determining the efficacy of a T cell were unchanged,\" says Lauer. \"A significant number of molecules that were altered were normalized after treatment, but others were stuck, and these were clearly the ones associated with T cell function.\" This lack of recovery was especially prominent with a long duration of T cell stimulation by the virus; a shorter stimulation allowed the cells to revert to functional memory T cells. \"We are currently studying whether treating HCV with direct acting antiviral therapy in the acute phase of infection, instead of many years later, will result in full memory differentiation of T cells. If correct, this could indicate a short window of opportunity early during chronic infections to protect T cell function,\" says Lauer. Also, the molecules that the researchers found to be expressed in severely exhausted T cells might be targeted to rescue these cells. A complementary study in the same issue of Nature Immunology that was led by Debattama Sen, Ph.D., at the Center for Cancer Research at MGH, and W. Nicholas Haining, BM, BCh, at Merck found that these exhausted T cells in chronic HCV infection were regulated epigenetically, or through physical changes in the cells' chromosomes that affect the expression of genes. The investigators discovered that after clearing the virus, the epigenetic landscape of exhausted T cells was partially remodeled, but maintained many exhaustion-specific alterations, which the authors termed \"epigenetic scars\". The epigenetic patterns paralleled the findings of the first paper on the protein and transcriptional level, indicating a key role for epigenetic control in determining the fate of the T cells. \"These scars might be locking the exhausted T cells and preventing return to proper function even if the chronic infection in the patient is cured,\" notes Sen. \"Thus, restoring the function of these cells will likely require directly removing or inactivating these scarred regions to unlock the cells' functionality.\" By comparing T cell responses across a range of viruses that are either effectively cleared (like influenza) or become chronic (like HCV and HIV), the scientists produced a map of where these exhaustion-specific scars occur. \"This will enable precision editing and allow us to target the specific regions relevant to exhausted T cells and minimize off-target effects in other T cell populations,\" says Sen. The two studies were performed within an NIH/NIAID-funded U19 Cooperative Center on Human Immunology (CCHI) located at MGH. A third study on exhausted T cells, which was conducted by MGH CCHI investigators at the University of Pennsylvania, accompanies these two articles in Nature Immunology. A News & Views article in the journal provides additional perspectives on the implications of the studies' findings. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 + T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Main Chronic viral infections and cancer exhibit accumulating changes in antigen-specific CD8 + T cells, termed T cell exhaustion 1 , 2 . T cell exhaustion is initiated and maintained by extended exposure to cognate antigen and inflammatory signals 2 , 3 . Exhausted T (T EX ) cells characteristically express inhibitory receptors such as programmed cell death 1 (PD-1) or 2B4 (refs. 4 , 5 , 6 ), increasingly lose key functions such as cytokine secretion and proliferation 3 , 7 , and do not differentiate into memory T (T MEM ) cells as occurs after acute infection 8 . T EX cells also lack antigen-independent self-renewal 9 , 10 and cannot mount a swift recall response. At the end of the exhaustion spectrum, antigen-specific T cells even get physically deleted 9 , 11 . T cell exhaustion is reversable, for example, with checkpoint inhibitor therapies targeting PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4; refs. 12 , 13 ). However, these cancer immunotherapies are effective only for some cancers and, within a disease category, only for select patient subsets—indicating that the molecular mechanisms underlying T cell exhaustion are complex and heterogeneous 14 . Additionally, immune recovery is not long lasting 15 . Other treatment modalities aimed at invigorating T cell responses, such as therapeutic vaccines 16 , 17 and immunomodulatory or antigen-lowering drugs in chronic viral infection 18 , similarly aim at overcoming the dysfunctionality of T EX cells. Understanding the cellular pathways driving T cell exhaustion and the road to sustained T cell recovery is critical for developing more effective and targeted therapies 14 . While the major clinical breakthroughs in reversing T cell exhaustion have been achieved in cancer, much of our understanding of the molecular mechanisms of T cell exhaustion stems from studies of chronic viral infection, most notably with strains of the lymphocytic choriomeningitis virus (LCMV) in mice 19 . The major advantage of studying viral infection is that it readily allows analysis of T cell exhaustion in antigen-specific T cells and within the critical context of antigen burden, both of which are more difficult to define in cancer. Emerging tools to study small populations of immune cells from clinical samples enable studies of T cell exhaustion directly in humans, especially in chronic infections with human immunodeficiency virus (HIV) 20 , hepatitis B virus (HBV) 21 , 22 and HCV 4 , 23 . HCV infection is particularly suited to elucidating differences in the regulation of of T cell differentiation. HCV is the only chronic viral infection with a complete dichotomy in natural outcome 24 : an estimated 20–30% of infected individuals completely clear the virus, typically within 6 months, allowing direct comparison of T cell memory and exhaustion within the same pathogen and host framework 25 . Additionally, HCV is the first, and so far only, chronic viral infection that can be completely terminated using direct-acting antivirals (DAAs) 26 , enabling the study of whether termination of antigen exposure enables the redifferentiation of T EX cell populations into effective T cell memory. Such work has revealed important insights, including T cell proliferation recovery after antigen clearance in parallel to the expansion of preexisting CD127 + PD-1 + TCF-1 + memory-like T cells 27 , 28 . Nevertheless, these memory-like CD8 + T cells are partially different from actual T MEM cells after acute infection 27 , 29 , 30 , indicating the need for more detailed analyses to understand the molecular trajectories of T EX cells after antigen removal and the hurdles to achieving full memory potential. In this study, we used the paradigm of chronic HCV infection and DAA treatment to further define the features of T cell exhaustion in humans, and the potential for reversion of exhaustion after antigen removal. A specifically designed clinical DAA trial that incorporated leukapheresis collection at specified time points allowed us to perform broad and deep T cell studies from the same peripheral blood mononuclear cell (PBMC) collections in the context of a well-defined clinical perturbation. After cure, we documented pervasive phenotypic changes in clonally stable T EX cell populations suggesting differentiation toward memory-like cells, but function and critical transcriptional regulators were mostly fixed in the T EX cell state. We also provide evidence that T cell dysregulation solidifies with the duration of exhaustion, indicating a limited window of opportunity early in chronic infection. Results DAA treatment trial for immunological studies of viral cure To determine the impact of antigen removal in a state of chronic viral infection, we designed a DAA treatment trial for HCV infection, generating optimal samples for immunological studies. We were able to study 20 of 25 long-term HCV-infected patients who received 12 weeks of paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin 31 (Supplementary Table 1 ). PBMC collections were scheduled at structured intervals before, during and after therapy, including at least two leukapheresis collections at weeks 0 and 24. A typical yield of 10 10 PBMCs per leukapheresis procedure allowed us to perform all CD8 + T cell assays reported in this paper on cells from the same<|im_end|> <|im_start|>assistant Chronic viral infections and cancer can cause "killer" T cells in the immune system to take on a state of dysfunction or exhaustion whereby they can no longer react to infectious invaders or abnormal cells like normal "memory" T cells. Two new studies led by investigators at Massachusetts General Hospital (MGH) and published in Nature Immunology provide insights into T cell exhaustion, which could lead to potential strategies to overcome it. One study, which was led by Georg M. Lauer, MD, Ph.D., of the Division of Gastroenterology at MGH, focused on differences between memory and exhausted T cells in individuals with human hepatitis C virus (HCV) infection before and after treatment. After patients were treated and cured, their exhausted T cells tended to take on some properties of memory T cells but did not function as well as memory T cells. "We saw some cosmetic improvement of the T cells that in a more superficial study could have been interpreted as real recovery, whereas in reality the key parameters determining the efficacy of a T cell were unchanged," says Lauer. "A significant number of molecules that were altered were normalized after treatment, but others were stuck, and these were clearly the ones associated with T cell function." This lack of recovery was especially prominent with a long duration of T cell stimulation by the virus; a shorter stimulation allowed the cells to revert to functional memory T cells. "We are currently studying whether treating HCV with direct acting antiviral therapy in the acute phase of infection, instead of many years later, will result in full memory differentiation of T cells. If correct, this could indicate a short window of opportunity early during chronic infections to protect T cell function," says Lauer. Also, the molecules that the researchers found to be expressed in severely exhausted T cells might be targeted to rescue these cells. A complementary study in the same issue of Nature Immunology that was led by Debattama Sen, Ph.D., at the Center for Cancer Research at MGH, and W. Nicholas Haining, BM, BCh, at Merck found that these exhausted T cells in chronic HCV infection were regulated epigenetically, or through physical changes in the cells' chromosomes that affect the expression of genes. The investigators discovered that after clearing the virus, the epigenetic landscape of exhausted T cells was partially remodeled, but maintained many exhaustion-specific alterations, which the authors termed "epigenetic scars". The epigenetic patterns paralleled the findings of the first paper on the protein and transcriptional level, indicating a key role for epigenetic control in determining the fate of the T cells. "These scars might be locking the exhausted T cells and preventing return to proper function even if the chronic infection in the patient is cured," notes Sen. "Thus, restoring the function of these cells will likely require directly removing or inactivating these scarred regions to unlock the cells' functionality." By comparing T cell responses across a range of viruses that are either effectively cleared (like influenza) or become chronic (like HCV and HIV), the scientists produced a map of where these exhaustion-specific scars occur. "This will enable precision editing and allow us to target the specific regions relevant to exhausted T cells and minimize off-target effects in other T cell populations," says Sen. The two studies were performed within an NIH/NIAID-funded U19 Cooperative Center on Human Immunology (CCHI) located at MGH. A third study on exhausted T cells, which was conducted by MGH CCHI investigators at the University of Pennsylvania, accompanies these two articles in Nature Immunology. A News & Views article in the journal provides additional perspectives on the implications of the studies' findings. <|im_end|>

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2,076

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The neural mechanisms mediating sensory-guided decision-making have received considerable attention, but animals often pursue behaviors for which there is currently no sensory evidence. Such behaviors are guided by internal representations of choice values that have to be maintained even when these choices are unavailable. We investigated how four macaque monkeys maintained representations of the value of counterfactual choices—choices that could not be taken at the current moment but which could be taken in the future. Using functional magnetic resonance imaging, we found two different patterns of activity co-varying with values of counterfactual choices in a circuit spanning the hippocampus, the anterior lateral prefrontal cortex and the anterior cingulate cortex. Anterior cingulate cortex activity also reflected whether the internal value representations would be translated into actual behavioral change. To establish the causal importance of the anterior cingulate cortex for this translation process, we used a novel technique, transcranial focused ultrasound stimulation, to reversibly disrupt anterior cingulate cortex activity. Main Every day, chacma baboons, an old world primate, navigate to and from the safety of their sleeping post and distant foraging or watering sites 1 . The decision to move to alternative locations is not simply guided by accumulation of sensory evidence for that choice but by internal representation or memory of the alternative choice’s value. The same is true when they move back toward the sleeping post in the evening. While sensory and associative decision-making have been well-studied 2 , less is known about how representations of counterfactual choices—choices not currently taken but which may be taken in the future—are held in memory and guide behavior. In humans, the lateral frontal polar cortex (lFPC) holds counterfactual information 3 , 4 , 5 . This may underlie its role in exploratory behavior 6 . However, many questions remain. First, some of the same studies report a similar pattern of activity in the anterior cingulate cortex (ACC) 3 , 5 , 6 . Other studies have emphasized a related role for the ACC in encoding the value of switching behavior and rejection of the default choice 7 , 8 . Here we introduce a simple paradigm that makes separation of the roles of the areas possible and distinguishes them from a third region: the hippocampus. Within the hippocampal formation, the subiculum projects monosynaptically to the ACC 9 . Information held in memory in such medial temporal structures may guide decision-making 2 . Although little is known about whether or how activity in the hippocampus encodes counterfactual choices, it is clear that hippocampal lesions disrupt switching between choices in other tasks 10 . We also address a second issue: whether macaques possess a brain region with a functional role corresponding to that of the human lFPC. The human frontal polar cortex can be subdivided into the lateral and medial sub-regions, lFPC and mFPC 11 , 12 . While resting state connectivity patterns exhibited by the human mFPC and the macaque FPC are similar, human lFPCs more closely resemble the macaque lateral prefrontal cortex (lPFC). It is therefore unclear if macaques hold counterfactual information as humans do and, if they can, whether it is mediated by the macaque FPC or lPFC. We know that when macaques are given feedback about what would have happened had another choice been made, they use it to guide their next choice 13 , 14 . However, how information about the multiple counterfactual choices that typically exist in natural environments is retained while another choice is actually made is unknown. Finally, our experiment allowed comparison of two fundamentally different ways in which counterfactual choice information might influence behavior. On the one hand, information about currently unavailable choices must be held if future behavior is to be accurate when that choice once again becomes available. This might be mediated by some combination of ACC, lPFC and lFPC. On the other hand, holding information about currently unavailable choices may impact on the current decision being made. We show that the second influence of counterfactual choice is mediated by a distinct neural circuit centered on ventromedial prefrontal cortex (vmPFC) and/or medial orbitofrontal cortex (mOFC). Four macaques chose between pairs of abstract visual stimuli while in the magnetic resonance imaging (MRI) scanner (Fig. 1a,b ). On each trial, the two stimuli available for choice (available options) were drawn from a set of three, each associated with distinct reward probabilities (Fig. 1a ). The rewards were delivered probabilistically in a manner that fluctuated across the session, with two of the options reversing toward the middle of a session (Fig. 1c ). Each stimulus’ reward probability was uncorrelated from that of the others (<22% mean shared variance). On each trial one of the two available options was chosen by the monkey, the other was unchosen and a third option was invisible and unavailable for choice. Both the unchosen option and the unavailable option can be considered counterfactual choices—although these choices were not made on the current trial, they might be made on a future occasion. Fig. 1: Schematic view of the task, behavioral results and hypothesized neural schemes. a , On each trial, animals could choose between two symbols presented on the screen and had to keep in mind a third option, unavailable to them. The position of each symbol on the left or right part of the screen and the combination of available or unavailable options were fully and pseudorandomized, respectively. b , Each trial began with a random delay followed by the presentation of two abstract symbols for a period ending when the animals made a choice. During this time, monkeys pressed one of two touch sensors to indicate which of the two symbols (right or left) they believed was more likely to lead to a reward. Finally, the decision outcome was revealed for 1.5 s. The selected symbol was kept on the screen (or not) to inform the monkeys of a reward delivery (or no reward). c , The plots show the probability of receiving a reward for choosing option 1 (light", "role": "user" }, { "content": "Imagine working in your office while the sun is shining outside. Thinking about what you could be doing instead of working is an example of \"counterfactual thinking\". New research in primates has shown for the first time that counterfactual thinking is causally related to a frontal part of the brain, called the anterior cingulate cortex. And scientists have proven that the process can be changed by targeting neurons (nerve cells) in this region using low-intensity ultrasound. The study was led by Dr. Elsa Fouragnan at the University of Plymouth and published Monday 15 April in Nature Neuroscience. Counterfactual thinking is an important cognitive process by which humans and animals make decisions—not only based on what they are currently experiencing, but by comparing their present experience with potential alternatives. In typical circumstances, should these alternatives become available in the near future, one would adaptively switch to them. For example, if the sun was shining while working, one would go out and enjoy the sun as soon as work is done. If neurons in the anterior cingulate cortex are not working properly, then it would not be possible to switch to alternative options, even when these alternatives are the best available. Scientists believe that this is what happens in some psychiatric conditions where people are stuck in dysfunctional habits. The study showed for the first time how low-intensity ultrasonic waves can be used to non-invasively, and with pinpoint accuracy, modulate normal brain function—affecting counterfactual thinking and the ability to switch to better alternative. The research, conducted in macaques monkeys, follows previous work highlighting the safeness of the non-invasive ultrasound technique and its effect on the brain. In the study, the macaques were tasked with finding a treat from a variety of options. They quickly learned which one was best, but the 'best' option was not always available to choose. Thus, they had to keep it in mind for when it became available again. After showing that the cingulate cortex was linked with remembering which option was best, researchers used low intensity ultrasound to modulate the activity in this brain region and see its effect on behaviours. When the neurons were stimulated, their counterfactual thinking was impaired. Dr. Fouragnan explained why the findings were so significant and what it could mean for future treatment: \"This is a really exciting study for two main reasons—firstly because we discovered that the cingulate cortex is crucial to help switch to better alternatives, and secondly because low-intensity ultrasound can be used to reversibly change brain activity in very precise part of the brain,\" she said. Ultrasound is well known as an imaging tool—in pregnancy, for example—but it can also be used as a therapeutic method, particularly for safely modulating brain activity. This is possible because the mechanical vibrations caused by ultrasonic waves can cause the generation or suppression of electrical signals in the brain, which in turn can be used to restore normal brain function. Dr. Fouragnan continued: \"Ultrasound neurostimulation is an early-stage, non-invasive therapeutic technology that has the potential to improve the lives of millions of patients with mental health conditions by stimulating brain tissues with millimetre accuracy. Presently, neuromodulation techniques do exist for humans, to help people with conditions such as major depression or Parkinson's. But there are no techniques that have this level of accuracy while remaining non-invasive. \"It's still early stages and the next stage is for further trials to be conducted in humans, but the potential is very exciting.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The neural mechanisms mediating sensory-guided decision-making have received considerable attention, but animals often pursue behaviors for which there is currently no sensory evidence. Such behaviors are guided by internal representations of choice values that have to be maintained even when these choices are unavailable. We investigated how four macaque monkeys maintained representations of the value of counterfactual choices—choices that could not be taken at the current moment but which could be taken in the future. Using functional magnetic resonance imaging, we found two different patterns of activity co-varying with values of counterfactual choices in a circuit spanning the hippocampus, the anterior lateral prefrontal cortex and the anterior cingulate cortex. Anterior cingulate cortex activity also reflected whether the internal value representations would be translated into actual behavioral change. To establish the causal importance of the anterior cingulate cortex for this translation process, we used a novel technique, transcranial focused ultrasound stimulation, to reversibly disrupt anterior cingulate cortex activity. Main Every day, chacma baboons, an old world primate, navigate to and from the safety of their sleeping post and distant foraging or watering sites 1 . The decision to move to alternative locations is not simply guided by accumulation of sensory evidence for that choice but by internal representation or memory of the alternative choice’s value. The same is true when they move back toward the sleeping post in the evening. While sensory and associative decision-making have been well-studied 2 , less is known about how representations of counterfactual choices—choices not currently taken but which may be taken in the future—are held in memory and guide behavior. In humans, the lateral frontal polar cortex (lFPC) holds counterfactual information 3 , 4 , 5 . This may underlie its role in exploratory behavior 6 . However, many questions remain. First, some of the same studies report a similar pattern of activity in the anterior cingulate cortex (ACC) 3 , 5 , 6 . Other studies have emphasized a related role for the ACC in encoding the value of switching behavior and rejection of the default choice 7 , 8 . Here we introduce a simple paradigm that makes separation of the roles of the areas possible and distinguishes them from a third region: the hippocampus. Within the hippocampal formation, the subiculum projects monosynaptically to the ACC 9 . Information held in memory in such medial temporal structures may guide decision-making 2 . Although little is known about whether or how activity in the hippocampus encodes counterfactual choices, it is clear that hippocampal lesions disrupt switching between choices in other tasks 10 . We also address a second issue: whether macaques possess a brain region with a functional role corresponding to that of the human lFPC. The human frontal polar cortex can be subdivided into the lateral and medial sub-regions, lFPC and mFPC 11 , 12 . While resting state connectivity patterns exhibited by the human mFPC and the macaque FPC are similar, human lFPCs more closely resemble the macaque lateral prefrontal cortex (lPFC). It is therefore unclear if macaques hold counterfactual information as humans do and, if they can, whether it is mediated by the macaque FPC or lPFC. We know that when macaques are given feedback about what would have happened had another choice been made, they use it to guide their next choice 13 , 14 . However, how information about the multiple counterfactual choices that typically exist in natural environments is retained while another choice is actually made is unknown. Finally, our experiment allowed comparison of two fundamentally different ways in which counterfactual choice information might influence behavior. On the one hand, information about currently unavailable choices must be held if future behavior is to be accurate when that choice once again becomes available. This might be mediated by some combination of ACC, lPFC and lFPC. On the other hand, holding information about currently unavailable choices may impact on the current decision being made. We show that the second influence of counterfactual choice is mediated by a distinct neural circuit centered on ventromedial prefrontal cortex (vmPFC) and/or medial orbitofrontal cortex (mOFC). Four macaques chose between pairs of abstract visual stimuli while in the magnetic resonance imaging (MRI) scanner (Fig. 1a,b ). On each trial, the two stimuli available for choice (available options) were drawn from a set of three, each associated with distinct reward probabilities (Fig. 1a ). The rewards were delivered probabilistically in a manner that fluctuated across the session, with two of the options reversing toward the middle of a session (Fig. 1c ). Each stimulus’ reward probability was uncorrelated from that of the others (<22% mean shared variance). On each trial one of the two available options was chosen by the monkey, the other was unchosen and a third option was invisible and unavailable for choice. Both the unchosen option and the unavailable option can be considered counterfactual choices—although these choices were not made on the current trial, they might be made on a future occasion. Fig. 1: Schematic view of the task, behavioral results and hypothesized neural schemes. a , On each trial, animals could choose between two symbols presented on the screen and had to keep in mind a third option, unavailable to them. The position of each symbol on the left or right part of the screen and the combination of available or unavailable options were fully and pseudorandomized, respectively. b , Each trial began with a random delay followed by the presentation of two abstract symbols for a period ending when the animals made a choice. During this time, monkeys pressed one of two touch sensors to indicate which of the two symbols (right or left) they believed was more likely to lead to a reward. Finally, the decision outcome was revealed for 1.5 s. The selected symbol was kept on the screen (or not) to inform the monkeys of a reward delivery (or no reward). c , The plots show the probability of receiving a reward for choosing option 1 (light<|im_end|> <|im_start|>assistant Imagine working in your office while the sun is shining outside. Thinking about what you could be doing instead of working is an example of "counterfactual thinking". New research in primates has shown for the first time that counterfactual thinking is causally related to a frontal part of the brain, called the anterior cingulate cortex. And scientists have proven that the process can be changed by targeting neurons (nerve cells) in this region using low-intensity ultrasound. The study was led by Dr. Elsa Fouragnan at the University of Plymouth and published Monday 15 April in Nature Neuroscience. Counterfactual thinking is an important cognitive process by which humans and animals make decisions—not only based on what they are currently experiencing, but by comparing their present experience with potential alternatives. In typical circumstances, should these alternatives become available in the near future, one would adaptively switch to them. For example, if the sun was shining while working, one would go out and enjoy the sun as soon as work is done. If neurons in the anterior cingulate cortex are not working properly, then it would not be possible to switch to alternative options, even when these alternatives are the best available. Scientists believe that this is what happens in some psychiatric conditions where people are stuck in dysfunctional habits. The study showed for the first time how low-intensity ultrasonic waves can be used to non-invasively, and with pinpoint accuracy, modulate normal brain function—affecting counterfactual thinking and the ability to switch to better alternative. The research, conducted in macaques monkeys, follows previous work highlighting the safeness of the non-invasive ultrasound technique and its effect on the brain. In the study, the macaques were tasked with finding a treat from a variety of options. They quickly learned which one was best, but the 'best' option was not always available to choose. Thus, they had to keep it in mind for when it became available again. After showing that the cingulate cortex was linked with remembering which option was best, researchers used low intensity ultrasound to modulate the activity in this brain region and see its effect on behaviours. When the neurons were stimulated, their counterfactual thinking was impaired. Dr. Fouragnan explained why the findings were so significant and what it could mean for future treatment: "This is a really exciting study for two main reasons—firstly because we discovered that the cingulate cortex is crucial to help switch to better alternatives, and secondly because low-intensity ultrasound can be used to reversibly change brain activity in very precise part of the brain," she said. Ultrasound is well known as an imaging tool—in pregnancy, for example—but it can also be used as a therapeutic method, particularly for safely modulating brain activity. This is possible because the mechanical vibrations caused by ultrasonic waves can cause the generation or suppression of electrical signals in the brain, which in turn can be used to restore normal brain function. Dr. Fouragnan continued: "Ultrasound neurostimulation is an early-stage, non-invasive therapeutic technology that has the potential to improve the lives of millions of patients with mental health conditions by stimulating brain tissues with millimetre accuracy. Presently, neuromodulation techniques do exist for humans, to help people with conditions such as major depression or Parkinson's. But there are no techniques that have this level of accuracy while remaining non-invasive. "It's still early stages and the next stage is for further trials to be conducted in humans, but the potential is very exciting." <|im_end|>

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2,026

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Invertebrates are dominant species in primary tropical rainforests, where their abundance and diversity contributes to the functioning and resilience of these globally important ecosystems. However, more than one-third of tropical forests have been logged, with dramatic impacts on rainforest biodiversity that may disrupt key ecosystem processes. We find that the contribution of invertebrates to three ecosystem processes operating at three trophic levels (litter decomposition, seed predation and removal, and invertebrate predation) is reduced by up to one-half following logging. These changes are associated with decreased abundance of key functional groups of termites, ants, beetles and earthworms, and an increase in the abundance of small mammals, amphibians and insectivorous birds in logged relative to primary forest. Our results suggest that ecosystem processes themselves have considerable resilience to logging, but the consistent decline of invertebrate functional importance is indicative of a human-induced shift in how these ecological processes operate in tropical rainforests. Introduction Invertebrates are ‘the little things that run the world’ 1 , and nowhere is this more evident than in tropical rainforests. Invertebrates are dominant prey 2 , predators of seeds 3 and other invertebrates 2 , 4 , herbivores 5 and pollinators 6 , 7 in rainforest ecosystems, and are among the most important organisms for breaking down dead organic matter 8 . Tropical rainforests are estimated to host around six million invertebrate species 9 , 10 , and over 18,000 species can be present in a single hectare 11 . This diversity is expected to confer substantial redundancy to ecosystem processes. Differences in environmental sensitivity among functionally similar species give stability to ecosystem processes in the face of environmental change, as the loss of environmentally sensitive species will be compensated for by more robust species 12 . Such functional resistance to disturbance would indicate a resilient ecosystem 13 , and understanding the resilience of natural habitats represents one of the great challenges for predicting the future impacts of human-caused global change on biodiversity 14 . We conducted a set of experiments to quantify the resistance to intensive logging of three ecosystem processes that operate at three different trophic levels in the tropical rainforests of Borneo. The logged forest had been logged twice 15 , the second time a salvage logging rotation that ended <10 years before data collection, and was conducted under a regime in which any sized tree could be cut. In total, a cumulative amount of 179 m 3 ha −1 timber was removed 16 , placing our sites among the most heavily logged forests in the tropics 17 . Overall, we find that ecosystem processes are remarkably resilient to very heavy logging, but the taxa performing those processes change. Ecosystem processes in primary forest are dominated by the actions of invertebrates such as ants, termites, beetles and earthworms. In logged forest, however, invertebrates are much less dominant and we find the actions of vertebrate taxa, such as birds, amphibians and small mammals, increase in importance. Our results are consistent with those expected in a resilient ecosystem, with that resilience conferred through functional similarity between invertebrates and vertebrates. Results Resilience of ecosystem processes We found a 15% decrease in the rate of leaf litter decomposition (likelihood ratio test, χ 2 (1) =5.90, P =0.015, N =25) in logged compared with primary forest, a 13% increase in the rate at which seeds were removed and/or predated (likelihood ratio test, χ 2 (1) =3.98, P =0.047, N =194), and no difference in invertebrate predation rate ( Fig. 1 ; likelihood ratio test, χ 2 (1) =1.03, P =0.310, N =51; Supplementary Table 1 ). In combination, this indicates considerable resilience of ecosystem processes to the biodiversity changes caused by logging. However, experimental manipulations demonstrated that invertebrates contributed significantly less to delivering all three ecosystem processes in logged relative to primary forest ( Fig. 1 ). Figure 1: Ecosystem process rates in primary (green) and logged (orange) forest in response to experimental removal of invertebrates, fungi or vertebrates. Ecosystem processes were quantified at three trophic levels represented by ( a , b ) leaf litter decomposition rate, ( c , d ) seed disturbance, defined as the combined removal and/or predation rate; and ( e , f ) invertebrate predation rate. Symbols indicate the taxa that contributed to the rates displayed. Absolute values (mean±95% CI) of the ecosystem process rates are presented in the left-hand column and are measured as ( a ) the slope of a linear regression model relating log e -transformed litter mass (g) as a function of log e -transformed time (number of days), ( c ) the proportion of experimental seeds removed or predated per day, and ( e ) the proportion of experimental mealworm larvae predated per day. Letters indicate habitat × treatment categories that did not significantly differ from each other ( P <0.05). There was a significant treatment × habitat interaction for all three ecosystem processes, demonstrating that the role of invertebrates was stronger in primary than logged forests. In the right-hand column (panels b , d , f ), values represent the proportional change in ecosystem process rates relative to control sites (calculated from data presented in the left-hand column). Values <1 (dashed line) indicate functions whose rate is reduced following the exclusion of a taxon; smaller values indicate larger reductions in the rate and hence a stronger contribution of that taxon to delivering the ecosystem process. Posthoc significance tests were used to examine the treatment × habitat interaction effects. For example, in panel b , the asterisk indicates that the effect on decomposition of excluding invertebrates was significantly ( P <0.05) larger in primary forest than in logged forest. NS indicates nonsignificant interactions. Full size image Invertebrate contributions to ecosystem processes We quantified the rate of decomposition of Macaranga sp. leaves, a common genus of early successional trees in southeast Asian rainforests found in both primary and logged forest. When invertebrates were excluded from leaf litter, decomposition rates were reduced by 39% in primary forest but by just", "role": "user" }, { "content": "Invertebrates perform essential functions for the smooth running of the ecosystems in tropical forests. For example, creatures such as termites and millipedes help dead leaves decompose and release their nutrients back into the soil, and carnivorous ants and spiders act as predators of herbivorous invertebrates that would otherwise munch through all the foliage. Nearly a half of all tropical rainforests worldwide have been logged, and this often causes heavy changes to the number and type of invertebrates, with many species being lost from the ecosystem. New research led by biologists from Imperial College London, published in Nature Communications, has discovered that when invertebrate diversity declines, their vital functions can be carried out by other members of the ecosystem. The result shows that rainforest ecosystems have a remarkable resilience to change. \"Invertebrates are often thought of as the controllers of tropical forests, so it's surprising that people can upset their dominance to this level,\" said lead author Dr Robert Ewers from the Department of Life Sciences at Imperial. Although the ecosystem can continue to function with vertebrates taking more of a leading role, Dr Ewers says the situation leaves rainforests vulnerable: \"The forest will keep maintaining itself, but it will be much more susceptible to further change. Relying on vertebrates is a bad tactic - they are less diverse and vulnerable to new challenges such as land use change.\" For example, the switch to agricultural plots such as palm plantations would cause biodiversity to drop faster. \"Knocking out one or two invertebrates might not be too bad, as there are many others to take their place, but knocking out one or two vertebrates could now be disastrous,\" said Dr Ewers. Polyrhachis sp ant with prey. Ants like this keep invertebrate numbers down. Credit: Tom Fayle By excluding certain organisms from patches of both natural and logged tropical rainforest in Borneo, the team were able to determine their contribution to the ecosystem. They found that in logged forests, the essential activities were still carried out at approximately the same speed, but that invertebrates contributed much less. For example, the overall rate of invertebrate predation in natural and logged rainforests was the same. However, invertebrates were responsible for only around 60 percent of the activity in logged forests, compared to nearly all of it in natural forests. Instead, birds and bats were responsible for preying on many more invertebrates in logged forests. The same trend was seen for seed disturbance, a vital function that helps maintain tree diversity, which was taken up by small mammals such as mice and treeshrews. The decomposition of leaf litter also seemed to be unaffected by the lack of invertebrates, although this was not a function picked up by vertebrates. Instead, the researchers think the litter may have continued to decompose thanks to a changing microclimate or the activities of soil bacteria. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Invertebrates are dominant species in primary tropical rainforests, where their abundance and diversity contributes to the functioning and resilience of these globally important ecosystems. However, more than one-third of tropical forests have been logged, with dramatic impacts on rainforest biodiversity that may disrupt key ecosystem processes. We find that the contribution of invertebrates to three ecosystem processes operating at three trophic levels (litter decomposition, seed predation and removal, and invertebrate predation) is reduced by up to one-half following logging. These changes are associated with decreased abundance of key functional groups of termites, ants, beetles and earthworms, and an increase in the abundance of small mammals, amphibians and insectivorous birds in logged relative to primary forest. Our results suggest that ecosystem processes themselves have considerable resilience to logging, but the consistent decline of invertebrate functional importance is indicative of a human-induced shift in how these ecological processes operate in tropical rainforests. Introduction Invertebrates are ‘the little things that run the world’ 1 , and nowhere is this more evident than in tropical rainforests. Invertebrates are dominant prey 2 , predators of seeds 3 and other invertebrates 2 , 4 , herbivores 5 and pollinators 6 , 7 in rainforest ecosystems, and are among the most important organisms for breaking down dead organic matter 8 . Tropical rainforests are estimated to host around six million invertebrate species 9 , 10 , and over 18,000 species can be present in a single hectare 11 . This diversity is expected to confer substantial redundancy to ecosystem processes. Differences in environmental sensitivity among functionally similar species give stability to ecosystem processes in the face of environmental change, as the loss of environmentally sensitive species will be compensated for by more robust species 12 . Such functional resistance to disturbance would indicate a resilient ecosystem 13 , and understanding the resilience of natural habitats represents one of the great challenges for predicting the future impacts of human-caused global change on biodiversity 14 . We conducted a set of experiments to quantify the resistance to intensive logging of three ecosystem processes that operate at three different trophic levels in the tropical rainforests of Borneo. The logged forest had been logged twice 15 , the second time a salvage logging rotation that ended <10 years before data collection, and was conducted under a regime in which any sized tree could be cut. In total, a cumulative amount of 179 m 3 ha −1 timber was removed 16 , placing our sites among the most heavily logged forests in the tropics 17 . Overall, we find that ecosystem processes are remarkably resilient to very heavy logging, but the taxa performing those processes change. Ecosystem processes in primary forest are dominated by the actions of invertebrates such as ants, termites, beetles and earthworms. In logged forest, however, invertebrates are much less dominant and we find the actions of vertebrate taxa, such as birds, amphibians and small mammals, increase in importance. Our results are consistent with those expected in a resilient ecosystem, with that resilience conferred through functional similarity between invertebrates and vertebrates. Results Resilience of ecosystem processes We found a 15% decrease in the rate of leaf litter decomposition (likelihood ratio test, χ 2 (1) =5.90, P =0.015, N =25) in logged compared with primary forest, a 13% increase in the rate at which seeds were removed and/or predated (likelihood ratio test, χ 2 (1) =3.98, P =0.047, N =194), and no difference in invertebrate predation rate ( Fig. 1 ; likelihood ratio test, χ 2 (1) =1.03, P =0.310, N =51; Supplementary Table 1 ). In combination, this indicates considerable resilience of ecosystem processes to the biodiversity changes caused by logging. However, experimental manipulations demonstrated that invertebrates contributed significantly less to delivering all three ecosystem processes in logged relative to primary forest ( Fig. 1 ). Figure 1: Ecosystem process rates in primary (green) and logged (orange) forest in response to experimental removal of invertebrates, fungi or vertebrates. Ecosystem processes were quantified at three trophic levels represented by ( a , b ) leaf litter decomposition rate, ( c , d ) seed disturbance, defined as the combined removal and/or predation rate; and ( e , f ) invertebrate predation rate. Symbols indicate the taxa that contributed to the rates displayed. Absolute values (mean±95% CI) of the ecosystem process rates are presented in the left-hand column and are measured as ( a ) the slope of a linear regression model relating log e -transformed litter mass (g) as a function of log e -transformed time (number of days), ( c ) the proportion of experimental seeds removed or predated per day, and ( e ) the proportion of experimental mealworm larvae predated per day. Letters indicate habitat × treatment categories that did not significantly differ from each other ( P <0.05). There was a significant treatment × habitat interaction for all three ecosystem processes, demonstrating that the role of invertebrates was stronger in primary than logged forests. In the right-hand column (panels b , d , f ), values represent the proportional change in ecosystem process rates relative to control sites (calculated from data presented in the left-hand column). Values <1 (dashed line) indicate functions whose rate is reduced following the exclusion of a taxon; smaller values indicate larger reductions in the rate and hence a stronger contribution of that taxon to delivering the ecosystem process. Posthoc significance tests were used to examine the treatment × habitat interaction effects. For example, in panel b , the asterisk indicates that the effect on decomposition of excluding invertebrates was significantly ( P <0.05) larger in primary forest than in logged forest. NS indicates nonsignificant interactions. Full size image Invertebrate contributions to ecosystem processes We quantified the rate of decomposition of Macaranga sp. leaves, a common genus of early successional trees in southeast Asian rainforests found in both primary and logged forest. When invertebrates were excluded from leaf litter, decomposition rates were reduced by 39% in primary forest but by just<|im_end|> <|im_start|>assistant Invertebrates perform essential functions for the smooth running of the ecosystems in tropical forests. For example, creatures such as termites and millipedes help dead leaves decompose and release their nutrients back into the soil, and carnivorous ants and spiders act as predators of herbivorous invertebrates that would otherwise munch through all the foliage. Nearly a half of all tropical rainforests worldwide have been logged, and this often causes heavy changes to the number and type of invertebrates, with many species being lost from the ecosystem. New research led by biologists from Imperial College London, published in Nature Communications, has discovered that when invertebrate diversity declines, their vital functions can be carried out by other members of the ecosystem. The result shows that rainforest ecosystems have a remarkable resilience to change. "Invertebrates are often thought of as the controllers of tropical forests, so it's surprising that people can upset their dominance to this level," said lead author Dr Robert Ewers from the Department of Life Sciences at Imperial. Although the ecosystem can continue to function with vertebrates taking more of a leading role, Dr Ewers says the situation leaves rainforests vulnerable: "The forest will keep maintaining itself, but it will be much more susceptible to further change. Relying on vertebrates is a bad tactic - they are less diverse and vulnerable to new challenges such as land use change." For example, the switch to agricultural plots such as palm plantations would cause biodiversity to drop faster. "Knocking out one or two invertebrates might not be too bad, as there are many others to take their place, but knocking out one or two vertebrates could now be disastrous," said Dr Ewers. Polyrhachis sp ant with prey. Ants like this keep invertebrate numbers down. Credit: Tom Fayle By excluding certain organisms from patches of both natural and logged tropical rainforest in Borneo, the team were able to determine their contribution to the ecosystem. They found that in logged forests, the essential activities were still carried out at approximately the same speed, but that invertebrates contributed much less. For example, the overall rate of invertebrate predation in natural and logged rainforests was the same. However, invertebrates were responsible for only around 60 percent of the activity in logged forests, compared to nearly all of it in natural forests. Instead, birds and bats were responsible for preying on many more invertebrates in logged forests. The same trend was seen for seed disturbance, a vital function that helps maintain tree diversity, which was taken up by small mammals such as mice and treeshrews. The decomposition of leaf litter also seemed to be unaffected by the lack of invertebrates, although this was not a function picked up by vertebrates. Instead, the researchers think the litter may have continued to decompose thanks to a changing microclimate or the activities of soil bacteria. <|im_end|>

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9523, 311, 264, 10223, 8162, 94874, 477, 279, 7640, 315, 17614, 24032, 13, 220, 128257, 198 ]

1,934

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although the role of Earth’s orbital variations in driving global climate cycles has long been recognized, their effect on evolution is hitherto unknown. The fossil remains of coccolithophores, a key calcifying phytoplankton group, enable a detailed assessment of the effect of cyclic orbital-scale climate changes on evolution because of their abundance in marine sediments and the preservation of their morphological adaptation to the changing environment 1 , 2 . Evolutionary genetic analyses have linked broad changes in Pleistocene fossil coccolith morphology to species radiation events 3 . Here, using high-resolution coccolith data, we show that during the last 2.8 million years the morphological evolution of coccolithophores was forced by Earth’s orbital eccentricity with rhythms of around 100,000 years and 405,000 years—a distinct spectral signature to that of coeval global climate cycles 4 . Simulations with an Earth System Model 5 coupled with an ocean biogeochemical model 6 show a strong eccentricity modulation of the seasonal cycle, which we suggest directly affects the diversity of ecological niches that occur over the annual cycle in the tropical ocean. Reduced seasonality in surface ocean conditions favours species with mid-size coccoliths, increasing coccolith carbonate export and burial; whereas enhanced seasonality favours a larger range of coccolith sizes and reduced carbonate export. We posit that eccentricity pacing of phytoplankton evolution contributed to the strong 405,000-year cyclicity that is seen in global carbon cycle records. Main Coccolithophores precipitate half of the biogenic CaCO 3 that is exported from the open ocean 7 and their fossil platelets (coccoliths) first appeared in sediments during the Upper Triassic, around 215 million years ago (Ma). Thereafter, coccolithophores rose to dominance 8 and became a key biological modulator of the global carbon cycle through photosynthesis and calcification 9 . In the dominant Cenozoic Noelaerhabdaceae family (including Emiliania huxleyi and Gephyrocapsa ), species are defined by the morphological characteristics of their coccoliths, with size being a key criterion 10 that is related to cell size 11 . For Gephyrocapsa and Emiliania , phylogenies reconstructed from gene sequences indicate that morphology-based definitions correspond to biological species 3 , 12 . Within a given Noelaerhabdaceae population—which is typically dominated by one species but includes several—interspecific and intraspecific changes in coccolith length and mass occur in response to environmental parameters such as carbonate chemistry 1 and temperature 2 . Studies of coccolithophore evolution have focused on geological-timescale changes in species richness and turnover 13 , coccolith carbonate accumulation 8 , 14 or calcification potentially driven by carbon cycle changes 15 . In addition, climate changes induced by orbital cycles (on timescales of tens to hundreds of thousands of years) strongly influence the composition of nannofossil assemblages 16 , 17 , 18 . However, so far the effects of orbital cycles on coccolithophore evolution, coccolith morphology and carbonate production have not to our knowledge been examined simultaneously. Here we quantify the Pleistocene history of tropical Noelaerhabdaceae evolution at high resolution (around two thousand years, kyr), using coccoliths preserved in nine well-dated sedimentary sections from the Indian and Pacific Oceans cored during International Ocean Discovery Program (IODP) and International Marine Past Global Changes Study (IMAGES) expeditions (Extended Data Table 1 ). We use artificial intelligence microscopy to create a biometric database of over 7 million coccoliths from more than 8,000 samples ( Methods ). The strong similarity of morphometric patterns observed at each site (Extended Data Fig. 1 ) led us to build composite frequency contour plots of coccolith size and mass, representing larger-scale evolutionary change (Fig. 1a , Methods ). Patches denoting high frequency of a particular size correspond in many cases to described acmes of Noelaerhabdaceae species 19 , 20 , 21 or proposed evolutionary events 3 (Fig. 1 ). The most recent evolutive phase, which started around 550 thousand years ago (ka), is attributed to a radiation event and the emergence of new Gephyrocapsa species, on the basis of a genetic study of extant taxa and its temporal correlation to low-resolution coccolith morphometric data 3 . Over the Pleistocene, average coccolith size shows an increase that corresponds to a gradual shift in dominance from smaller to larger coccoliths (Fig. 1b ). On orbital timescales, global ice volume and deep-sea temperature as represented by benthic foraminiferal δ 18 O show a dominance of 41-kyr and later around 100-kyr glacial–interglacial cycles 22 (Fig. 1c ). By contrast, average coccolith length follows a regular cycle that is highly coherent (greater than 99.9%) with the orbital eccentricity periods of 405 kyr (e405) and of 124 and 95 kyr (e100) 23 (Extended Data Fig. 2a ), with larger average size occurring at high eccentricity with a slight time lag (Fig. 1b ). Fig. 1: Noelaerhabdaceae coccolith morphology and accumulation, eccentricity, and climate over the last 2.8 million years. a , Frequency contour plot of multi-site stacked coccolith length ( Methods ). Scanning electron microscope images represent examples of the diversity of Noelaerhabdaceae morphologies over time. 1, Emiliania huxleyi ; 2, Gephyrocapsa ericsonii ; 3, Gephyrocapsa oceanica ; 4, Gephyrocapsa caribbeanica ; 5–6, Gephyrocapsa omega ; 7–8, mid-size Gephyrocapsa ; 9, small Gephyrocapsa ; 10, Pseudemiliania ovata ; 11, Reticulofenestra minuta ; 12, left: P. ovata , right: R. minutula . b , Mean coccolith length in the stack (blue), plotted with Earth’s eccentricity 23 (dotted black line) and low-pass-filtered eccentricity with an angular frequency of 0.021 kyr −1 (red). Described Noelaerhabdaceae acmes 19 , 20 , 21 are shown as black bars (I, E. huxleyi ; II, G. caribbeanica ; III and IV, mid-size Gephyrocapsa ). Coloured stars and diamonds on the eccentricity curve show the timing of actual orbital configurations used in model simulations ( P max , precession with perihelion in December; P min , precession with perihelion in June); smaller grey symbols indicate times throughout the record with similar eccentricity and precession configurations to those modelled ( Methods ). c , LR04 benthic foraminiferal δ 18 O stack 22 . Grey band illustrates the small range of benthic δ 18 O between model simulations. d", "role": "user" }, { "content": "Coccolithophores are microscopic algae that form tiny limestone plates, called coccoliths, around their single cells. The shape and size of coccoliths varies according to the species. After their death, coccolithophores sink to the bottom of the ocean and their coccoliths accumulate in sediments, which faithfully record the detailed evolution of these organisms over geological time. A team of scientists led by CNRS researchers show, in an article published in Nature on December 1, 2021, that certain variations in Earth's orbit have influenced the evolution of coccolithophores. To achieve this, no less that 9 million coccoliths, spanning an interval of 2.8 million years and several locations in the tropical ocean, were measured and classified using automated microscope techniques and artificial intelligence. The researchers observed that coccoliths underwent cycles of higher and lower diversity in size and shape, with rhythms of 100 and 400 thousand years. They also propose a cause: the more or less circular shape of Earth's orbit around the Sun, which varies at the same rhythms. Thus, when Earth's orbit is more circular, as is the case today (this is known as low eccentricity), the equatorial regions show little seasonal variation and species that are not very specialized dominate all the oceans. Conversely, as eccentricity increases and more pronounced seasons appear near the equator, coccolithophores diversify into many specialized species, but collectively produce less limestone. The diversity of coccolithophores and their collective limestome production evolved under the influence of Earth’s orbital eccentricity, which determines the intensity of seasonal variations near the equator. On the other hand, no link to global ice volume or temperature was found. It was therefore not global climate change that dictated micro-algae evolution but perhaps the opposite during certain periods. Credit: Luc BEAUFORT / CNRS / CEREGE Crucially, due to their abundance and global distribution, these organisms are responsible for half of the limestone (calcium carbonate, partly composed of carbon) produced in the oceans and therefore play a major role in the carbon cycle and in determining ocean chemistry. It is therefore likely that the cyclic abundance patterns of these limestone producers played a key role in ancient climates, and may explain hitherto mysterious climate variations in past warm periods. In other words, in the absence of ice, the biological evolution of micro-algae could have set the tempo of climates. This hypothesis remains to be confirmed. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although the role of Earth’s orbital variations in driving global climate cycles has long been recognized, their effect on evolution is hitherto unknown. The fossil remains of coccolithophores, a key calcifying phytoplankton group, enable a detailed assessment of the effect of cyclic orbital-scale climate changes on evolution because of their abundance in marine sediments and the preservation of their morphological adaptation to the changing environment 1 , 2 . Evolutionary genetic analyses have linked broad changes in Pleistocene fossil coccolith morphology to species radiation events 3 . Here, using high-resolution coccolith data, we show that during the last 2.8 million years the morphological evolution of coccolithophores was forced by Earth’s orbital eccentricity with rhythms of around 100,000 years and 405,000 years—a distinct spectral signature to that of coeval global climate cycles 4 . Simulations with an Earth System Model 5 coupled with an ocean biogeochemical model 6 show a strong eccentricity modulation of the seasonal cycle, which we suggest directly affects the diversity of ecological niches that occur over the annual cycle in the tropical ocean. Reduced seasonality in surface ocean conditions favours species with mid-size coccoliths, increasing coccolith carbonate export and burial; whereas enhanced seasonality favours a larger range of coccolith sizes and reduced carbonate export. We posit that eccentricity pacing of phytoplankton evolution contributed to the strong 405,000-year cyclicity that is seen in global carbon cycle records. Main Coccolithophores precipitate half of the biogenic CaCO 3 that is exported from the open ocean 7 and their fossil platelets (coccoliths) first appeared in sediments during the Upper Triassic, around 215 million years ago (Ma). Thereafter, coccolithophores rose to dominance 8 and became a key biological modulator of the global carbon cycle through photosynthesis and calcification 9 . In the dominant Cenozoic Noelaerhabdaceae family (including Emiliania huxleyi and Gephyrocapsa ), species are defined by the morphological characteristics of their coccoliths, with size being a key criterion 10 that is related to cell size 11 . For Gephyrocapsa and Emiliania , phylogenies reconstructed from gene sequences indicate that morphology-based definitions correspond to biological species 3 , 12 . Within a given Noelaerhabdaceae population—which is typically dominated by one species but includes several—interspecific and intraspecific changes in coccolith length and mass occur in response to environmental parameters such as carbonate chemistry 1 and temperature 2 . Studies of coccolithophore evolution have focused on geological-timescale changes in species richness and turnover 13 , coccolith carbonate accumulation 8 , 14 or calcification potentially driven by carbon cycle changes 15 . In addition, climate changes induced by orbital cycles (on timescales of tens to hundreds of thousands of years) strongly influence the composition of nannofossil assemblages 16 , 17 , 18 . However, so far the effects of orbital cycles on coccolithophore evolution, coccolith morphology and carbonate production have not to our knowledge been examined simultaneously. Here we quantify the Pleistocene history of tropical Noelaerhabdaceae evolution at high resolution (around two thousand years, kyr), using coccoliths preserved in nine well-dated sedimentary sections from the Indian and Pacific Oceans cored during International Ocean Discovery Program (IODP) and International Marine Past Global Changes Study (IMAGES) expeditions (Extended Data Table 1 ). We use artificial intelligence microscopy to create a biometric database of over 7 million coccoliths from more than 8,000 samples ( Methods ). The strong similarity of morphometric patterns observed at each site (Extended Data Fig. 1 ) led us to build composite frequency contour plots of coccolith size and mass, representing larger-scale evolutionary change (Fig. 1a , Methods ). Patches denoting high frequency of a particular size correspond in many cases to described acmes of Noelaerhabdaceae species 19 , 20 , 21 or proposed evolutionary events 3 (Fig. 1 ). The most recent evolutive phase, which started around 550 thousand years ago (ka), is attributed to a radiation event and the emergence of new Gephyrocapsa species, on the basis of a genetic study of extant taxa and its temporal correlation to low-resolution coccolith morphometric data 3 . Over the Pleistocene, average coccolith size shows an increase that corresponds to a gradual shift in dominance from smaller to larger coccoliths (Fig. 1b ). On orbital timescales, global ice volume and deep-sea temperature as represented by benthic foraminiferal δ 18 O show a dominance of 41-kyr and later around 100-kyr glacial–interglacial cycles 22 (Fig. 1c ). By contrast, average coccolith length follows a regular cycle that is highly coherent (greater than 99.9%) with the orbital eccentricity periods of 405 kyr (e405) and of 124 and 95 kyr (e100) 23 (Extended Data Fig. 2a ), with larger average size occurring at high eccentricity with a slight time lag (Fig. 1b ). Fig. 1: Noelaerhabdaceae coccolith morphology and accumulation, eccentricity, and climate over the last 2.8 million years. a , Frequency contour plot of multi-site stacked coccolith length ( Methods ). Scanning electron microscope images represent examples of the diversity of Noelaerhabdaceae morphologies over time. 1, Emiliania huxleyi ; 2, Gephyrocapsa ericsonii ; 3, Gephyrocapsa oceanica ; 4, Gephyrocapsa caribbeanica ; 5–6, Gephyrocapsa omega ; 7–8, mid-size Gephyrocapsa ; 9, small Gephyrocapsa ; 10, Pseudemiliania ovata ; 11, Reticulofenestra minuta ; 12, left: P. ovata , right: R. minutula . b , Mean coccolith length in the stack (blue), plotted with Earth’s eccentricity 23 (dotted black line) and low-pass-filtered eccentricity with an angular frequency of 0.021 kyr −1 (red). Described Noelaerhabdaceae acmes 19 , 20 , 21 are shown as black bars (I, E. huxleyi ; II, G. caribbeanica ; III and IV, mid-size Gephyrocapsa ). Coloured stars and diamonds on the eccentricity curve show the timing of actual orbital configurations used in model simulations ( P max , precession with perihelion in December; P min , precession with perihelion in June); smaller grey symbols indicate times throughout the record with similar eccentricity and precession configurations to those modelled ( Methods ). c , LR04 benthic foraminiferal δ 18 O stack 22 . Grey band illustrates the small range of benthic δ 18 O between model simulations. d<|im_end|> <|im_start|>assistant Coccolithophores are microscopic algae that form tiny limestone plates, called coccoliths, around their single cells. The shape and size of coccoliths varies according to the species. After their death, coccolithophores sink to the bottom of the ocean and their coccoliths accumulate in sediments, which faithfully record the detailed evolution of these organisms over geological time. A team of scientists led by CNRS researchers show, in an article published in Nature on December 1, 2021, that certain variations in Earth's orbit have influenced the evolution of coccolithophores. To achieve this, no less that 9 million coccoliths, spanning an interval of 2.8 million years and several locations in the tropical ocean, were measured and classified using automated microscope techniques and artificial intelligence. The researchers observed that coccoliths underwent cycles of higher and lower diversity in size and shape, with rhythms of 100 and 400 thousand years. They also propose a cause: the more or less circular shape of Earth's orbit around the Sun, which varies at the same rhythms. Thus, when Earth's orbit is more circular, as is the case today (this is known as low eccentricity), the equatorial regions show little seasonal variation and species that are not very specialized dominate all the oceans. Conversely, as eccentricity increases and more pronounced seasons appear near the equator, coccolithophores diversify into many specialized species, but collectively produce less limestone. The diversity of coccolithophores and their collective limestome production evolved under the influence of Earth’s orbital eccentricity, which determines the intensity of seasonal variations near the equator. On the other hand, no link to global ice volume or temperature was found. It was therefore not global climate change that dictated micro-algae evolution but perhaps the opposite during certain periods. Credit: Luc BEAUFORT / CNRS / CEREGE Crucially, due to their abundance and global distribution, these organisms are responsible for half of the limestone (calcium carbonate, partly composed of carbon) produced in the oceans and therefore play a major role in the carbon cycle and in determining ocean chemistry. It is therefore likely that the cyclic abundance patterns of these limestone producers played a key role in ancient climates, and may explain hitherto mysterious climate variations in past warm periods. In other words, in the absence of ice, the biological evolution of micro-algae could have set the tempo of climates. This hypothesis remains to be confirmed. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Electronic (e)-cigarette use is rapidly rising, with 20 % of Americans ages 25–44 now using these drug delivery devices. E-cigarette users expose their airways, cells of host defense, and colonizing bacteria to e-cigarette vapor (EV). Here, we report that exposure of human epithelial cells at the air–liquid interface to fresh EV (vaped from an e-cigarette device) resulted in dose-dependent cell death. After exposure to EV, cells of host defense—epithelial cells, alveolar macrophages, and neutrophils—had reduced antimicrobial activity against Staphylococcus aureus ( SA ). Mouse inhalation of EV for 1 h daily for 4 weeks led to alterations in inflammatory markers within the airways and elevation of an acute phase reactant in serum. Upon exposure to e-cigarette vapor extract (EVE), airway colonizer SA had increased biofilm formation, adherence and invasion of epithelial cells, resistance to human antimicrobial peptide LL-37, and up-regulation of virulence genes. EVE-exposed SA were more virulent in a mouse model of pneumonia. These data suggest that e-cigarettes may be toxic to airway cells, suppress host defenses, and promote inflammation over time, while also promoting virulence of colonizing bacteria. Key message Acute exposure to e-cigarette vapor (EV) is cytotoxic to airway cells in vitro. Acute exposure to EV decreases macrophage and neutrophil antimicrobial function. Inhalation of EV alters immunomodulating cytokines in the airways of mice. Inhalation of EV leads to increased markers of inflammation in BAL and serum. Staphylococcus aureus become more virulent when exposed to EV. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Electronic (e)-cigarette “vaping” is the inhalation of an electrically heated and aerosolized liquid containing nicotine. E-cigarettes were invented in 2003 and rapidly gained popularity through adolescent and adult smokers of all ages, sexes, and races [ 1 ]. E-cigarette use is tripling annually, with use increasing in both non-smoking and smoking children and adults [ 2 – 5 ]. Cigarette smokers who also use e-cigarettes do not have higher rates of intention of quit [ 6 – 8 ]. Annual sales of e-cigarettes now total $2 billion, and analysts predict they will outsell traditional cigarettes within 10 years. E-cigarette makers are flavoring and naming their wares to appeal to children and women, who prefer sweet flavors [ 9 ]. One in ten high schoolers have tried e-cigarettes in the past year, double that of the year prior [ 1 ]. Therefore, e-cigarette use is creating a new generation of nicotine addicts. Despite being advertised as a safe alternative to conventional combustible cigarettes, little is known about e-cigarettes’ safety and their potentially deleterious effects on health. E-cigarettes are composed of a cartridge of “e-liquid,” which contains propylene glycol (PG) and/or vegetable glycerin (VG) plus nicotine. Many users mix their own e-liquid so that they can modify the nicotine content [ 10 ]. Nicotine absorption into the bloodstream is similar in the latest generation of e-cigarettes compared to conventional cigarettes [ 11 ]. E-liquid is introduced into a cartridge, which also contains an atomizer and heating vapor coil to produce the vapor. This cartridge is attached to a rechargeable battery. The pathogenic bacteria Staphylococcus aureus (SA) persistently colonizes 20 % of humans and transiently colonizes 60 % [ 12 ]. We recently demonstrated that conventional cigarette smoke promotes SA pathogenicity via a general stress response and leads to increased virulence in vivo [ 13 ]. Suggesting that susceptibility of smokers to bacterial infections may be due in part to pro-virulent effects on colonizing bacteria. Because colonizing SA strains in the nasopharynx are exposed to all inhaled substance, including e-cigarette vapor (EV), we hypothesize that EV may affect SA pathogenicity. The many toxic, inflammatory, and carcinogenic effects of conventional cigarette smoke have been well characterized over the past century [ 14 ]. However, it is unknown whether vaping e-cigarettes will also increase the incidence of inflammatory, infectious, or malignant lung diseases or systemic diseases. To evaluate the potential impact of e-cigarette use on susceptibility to bacterial infections and development of inflammatory responses, we undertook these studies of e-cigarette effects on both host and pathogen functions. Methods E-cigarettes E-cigarettes were purchased from San Diego County gas stations and vaporiums, as well online from Xtreme Vaping. Flavored and unflavored e-liquids were selected, as well as with and without nicotine (Table 1 ). E-liquid was never added directly to media or cells; all exposures were done by creating aerosol (“vapor”) with e-cigarette devices, via application of voltage to the heating coil within the e-liquid, and aerosolization. Unless otherwise noted, the e-cigarette liquid was mixed in the lab, using 50 % PG, 50 % VG, and 24 mg/mL (148 mM) nicotine (PG + VG + N; a common blend of e-liquid, based on content labels on multiple brands of e-cigarettes and by blogs of e-cigarette users who make their own e-liquid). Cartridges and batteries were bought from Xtreme Vaping, with each e-liquid brand having a dedicated cartridge, except the brands that came pre-loaded (NJoy and Green Smart Living (GSL)) (Table 1 ). Table 1 E-cigarette brands and composition Full size table E-cigarette vapor extract See Supplementary material . Cells and culture methods Two types of human epithelial cells were used for these studies—human keratinocytes (HaCaTs; CLS) and human lung alveolar type II epithelial cells (A549 cells; ATCC CCL-185) [ 15 ]. Both cell types express nicotinic receptors, which are believed to play a role in lung cancer pathogenesis [ 16 , 17 ]. HaCaTs express nicotinic acid receptors GPR109A and B [ 18 ], while A549 cells express α5-nicotinic acetylcholine receptors (nAChRs) [ 19 , 20 ]. HaCaTs and A549s were cultured in RPMI + 10 % fetal bovine serum (FBS). MH-S cells (ATCC CRL-2019) were cultured in RPMI + 10 % FBS + 0.05 mM beta-mercaptoethanol. MRSA USA300 was used for all mammalian cell infections and bacterial studies. Cultures of MRSA were started the day prior to assays and grown overnight in Todd Hewitt Broth (THB) at 37 °C with shaking. Control media and e-cigarette vapor extract (EVE) for mammalian cell", "role": "user" }, { "content": "Researchers at the University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System report data suggesting that e-cigarettes are toxic to human airway cells, suppress immune defenses and alter inflammation, while at the same time boosting bacterial virulence. The mouse study is published January 25 by the Journal of Molecular Medicine. \"This study shows that e-cigarette vapor is not benign—at high doses it can directly kill lung cells, which is frightening,\" said senior author Laura E. Crotty Alexander, MD, staff physician at the Veterans Affairs San Diego Healthcare System and assistant clinical professor at UC San Diego School of Medicine. \"We already knew that inhaling heated chemicals, including the e-liquid ingredients nicotine and propylene glycol, couldn't possibly be good for you. This work confirms that inhalation of e-cigarette vapor daily leads to changes in the inflammatory milieu inside the airways.\" Crotty Alexander reported the preliminary results of this work at the American Thoracic Society annual meetings in 2014 and 2015. But now her team has also seen their findings hold up in mice. Inflammatory markers—signs of full-body inflammation—in the airways and blood of mice that inhaled e-cigarette vapors for one hour a day, five days a week, for four weeks were elevated by 10 percent compared to unexposed mice. \"We don't know specifically which lung and systemic diseases will be caused by the inflammatory changes induced by e-cigarette vapor inhalation, but based on clinical reports of acute toxicities and what we have found in the lab, we believe that they will cause disease in the end,\" Crotty Alexander said. \"Some of the changes we have found in mice are also found in the airways and blood of conventional cigarette smokers, while others are found in humans with cancer or inflammatory lung diseases.\" Conversely, bacterial pathogens exposed to e-cigarette vapor benefited. Specifically, Staphylococcus aureus bacteria were better able to form biofilms, adhere to and invade airway cells and resist human antimicrobial peptides after exposure to e-cigarette vapor. E-cigarette vapor extract-exposed bacteria were also more virulent in a mouse model of pneumonia. All mice infected with normal methicillin-resistant S. aureus (MRSA), an antibiotic-resistant \"superbug,\" survived. Meanwhile, 25 percent of mice infected with MRSA pre-exposed to e-cigarette vapor died. The results were consistent with e-liquids from seven different manufacturers, demonstrating that the findings are not limited to one formula or brand. Crotty Alexander and team also recently reported that MRSA bacteria exposed to conventional cigarette smoke are more resistant to killing by the immune system than unexposed bacteria. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Electronic (e)-cigarette use is rapidly rising, with 20 % of Americans ages 25–44 now using these drug delivery devices. E-cigarette users expose their airways, cells of host defense, and colonizing bacteria to e-cigarette vapor (EV). Here, we report that exposure of human epithelial cells at the air–liquid interface to fresh EV (vaped from an e-cigarette device) resulted in dose-dependent cell death. After exposure to EV, cells of host defense—epithelial cells, alveolar macrophages, and neutrophils—had reduced antimicrobial activity against Staphylococcus aureus ( SA ). Mouse inhalation of EV for 1 h daily for 4 weeks led to alterations in inflammatory markers within the airways and elevation of an acute phase reactant in serum. Upon exposure to e-cigarette vapor extract (EVE), airway colonizer SA had increased biofilm formation, adherence and invasion of epithelial cells, resistance to human antimicrobial peptide LL-37, and up-regulation of virulence genes. EVE-exposed SA were more virulent in a mouse model of pneumonia. These data suggest that e-cigarettes may be toxic to airway cells, suppress host defenses, and promote inflammation over time, while also promoting virulence of colonizing bacteria. Key message Acute exposure to e-cigarette vapor (EV) is cytotoxic to airway cells in vitro. Acute exposure to EV decreases macrophage and neutrophil antimicrobial function. Inhalation of EV alters immunomodulating cytokines in the airways of mice. Inhalation of EV leads to increased markers of inflammation in BAL and serum. Staphylococcus aureus become more virulent when exposed to EV. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Electronic (e)-cigarette “vaping” is the inhalation of an electrically heated and aerosolized liquid containing nicotine. E-cigarettes were invented in 2003 and rapidly gained popularity through adolescent and adult smokers of all ages, sexes, and races [ 1 ]. E-cigarette use is tripling annually, with use increasing in both non-smoking and smoking children and adults [ 2 – 5 ]. Cigarette smokers who also use e-cigarettes do not have higher rates of intention of quit [ 6 – 8 ]. Annual sales of e-cigarettes now total $2 billion, and analysts predict they will outsell traditional cigarettes within 10 years. E-cigarette makers are flavoring and naming their wares to appeal to children and women, who prefer sweet flavors [ 9 ]. One in ten high schoolers have tried e-cigarettes in the past year, double that of the year prior [ 1 ]. Therefore, e-cigarette use is creating a new generation of nicotine addicts. Despite being advertised as a safe alternative to conventional combustible cigarettes, little is known about e-cigarettes’ safety and their potentially deleterious effects on health. E-cigarettes are composed of a cartridge of “e-liquid,” which contains propylene glycol (PG) and/or vegetable glycerin (VG) plus nicotine. Many users mix their own e-liquid so that they can modify the nicotine content [ 10 ]. Nicotine absorption into the bloodstream is similar in the latest generation of e-cigarettes compared to conventional cigarettes [ 11 ]. E-liquid is introduced into a cartridge, which also contains an atomizer and heating vapor coil to produce the vapor. This cartridge is attached to a rechargeable battery. The pathogenic bacteria Staphylococcus aureus (SA) persistently colonizes 20 % of humans and transiently colonizes 60 % [ 12 ]. We recently demonstrated that conventional cigarette smoke promotes SA pathogenicity via a general stress response and leads to increased virulence in vivo [ 13 ]. Suggesting that susceptibility of smokers to bacterial infections may be due in part to pro-virulent effects on colonizing bacteria. Because colonizing SA strains in the nasopharynx are exposed to all inhaled substance, including e-cigarette vapor (EV), we hypothesize that EV may affect SA pathogenicity. The many toxic, inflammatory, and carcinogenic effects of conventional cigarette smoke have been well characterized over the past century [ 14 ]. However, it is unknown whether vaping e-cigarettes will also increase the incidence of inflammatory, infectious, or malignant lung diseases or systemic diseases. To evaluate the potential impact of e-cigarette use on susceptibility to bacterial infections and development of inflammatory responses, we undertook these studies of e-cigarette effects on both host and pathogen functions. Methods E-cigarettes E-cigarettes were purchased from San Diego County gas stations and vaporiums, as well online from Xtreme Vaping. Flavored and unflavored e-liquids were selected, as well as with and without nicotine (Table 1 ). E-liquid was never added directly to media or cells; all exposures were done by creating aerosol (“vapor”) with e-cigarette devices, via application of voltage to the heating coil within the e-liquid, and aerosolization. Unless otherwise noted, the e-cigarette liquid was mixed in the lab, using 50 % PG, 50 % VG, and 24 mg/mL (148 mM) nicotine (PG + VG + N; a common blend of e-liquid, based on content labels on multiple brands of e-cigarettes and by blogs of e-cigarette users who make their own e-liquid). Cartridges and batteries were bought from Xtreme Vaping, with each e-liquid brand having a dedicated cartridge, except the brands that came pre-loaded (NJoy and Green Smart Living (GSL)) (Table 1 ). Table 1 E-cigarette brands and composition Full size table E-cigarette vapor extract See Supplementary material . Cells and culture methods Two types of human epithelial cells were used for these studies—human keratinocytes (HaCaTs; CLS) and human lung alveolar type II epithelial cells (A549 cells; ATCC CCL-185) [ 15 ]. Both cell types express nicotinic receptors, which are believed to play a role in lung cancer pathogenesis [ 16 , 17 ]. HaCaTs express nicotinic acid receptors GPR109A and B [ 18 ], while A549 cells express α5-nicotinic acetylcholine receptors (nAChRs) [ 19 , 20 ]. HaCaTs and A549s were cultured in RPMI + 10 % fetal bovine serum (FBS). MH-S cells (ATCC CRL-2019) were cultured in RPMI + 10 % FBS + 0.05 mM beta-mercaptoethanol. MRSA USA300 was used for all mammalian cell infections and bacterial studies. Cultures of MRSA were started the day prior to assays and grown overnight in Todd Hewitt Broth (THB) at 37 °C with shaking. Control media and e-cigarette vapor extract (EVE) for mammalian cell<|im_end|> <|im_start|>assistant Researchers at the University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System report data suggesting that e-cigarettes are toxic to human airway cells, suppress immune defenses and alter inflammation, while at the same time boosting bacterial virulence. The mouse study is published January 25 by the Journal of Molecular Medicine. "This study shows that e-cigarette vapor is not benign—at high doses it can directly kill lung cells, which is frightening," said senior author Laura E. Crotty Alexander, MD, staff physician at the Veterans Affairs San Diego Healthcare System and assistant clinical professor at UC San Diego School of Medicine. "We already knew that inhaling heated chemicals, including the e-liquid ingredients nicotine and propylene glycol, couldn't possibly be good for you. This work confirms that inhalation of e-cigarette vapor daily leads to changes in the inflammatory milieu inside the airways." Crotty Alexander reported the preliminary results of this work at the American Thoracic Society annual meetings in 2014 and 2015. But now her team has also seen their findings hold up in mice. Inflammatory markers—signs of full-body inflammation—in the airways and blood of mice that inhaled e-cigarette vapors for one hour a day, five days a week, for four weeks were elevated by 10 percent compared to unexposed mice. "We don't know specifically which lung and systemic diseases will be caused by the inflammatory changes induced by e-cigarette vapor inhalation, but based on clinical reports of acute toxicities and what we have found in the lab, we believe that they will cause disease in the end," Crotty Alexander said. "Some of the changes we have found in mice are also found in the airways and blood of conventional cigarette smokers, while others are found in humans with cancer or inflammatory lung diseases." Conversely, bacterial pathogens exposed to e-cigarette vapor benefited. Specifically, Staphylococcus aureus bacteria were better able to form biofilms, adhere to and invade airway cells and resist human antimicrobial peptides after exposure to e-cigarette vapor. E-cigarette vapor extract-exposed bacteria were also more virulent in a mouse model of pneumonia. All mice infected with normal methicillin-resistant S. aureus (MRSA), an antibiotic-resistant "superbug," survived. Meanwhile, 25 percent of mice infected with MRSA pre-exposed to e-cigarette vapor died. The results were consistent with e-liquids from seven different manufacturers, demonstrating that the findings are not limited to one formula or brand. Crotty Alexander and team also recently reported that MRSA bacteria exposed to conventional cigarette smoke are more resistant to killing by the immune system than unexposed bacteria. <|im_end|>

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2,042

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Kerr-type nonlinearities form the basis for our physical understanding of nonlinear optical phenomena in condensed matter, such as self-focusing, solitary waves and wave mixing 1 , 2 , 3 . In strong fields, they are complemented by higher-order nonlinearities that enable high-harmonic generation, which is currently understood as the interplay of light-driven intraband charge dynamics and interband recombination 4 , 5 , 6 . Remarkably, the nonlinear response emerging from the subcycle injection dynamics of electrons into the conduction band, that is from ionization, has been almost completely overlooked in solids and only partially considered in the gas phase 7 , 8 , 9 , 10 . Here, we reveal this strong-field-induced nonlinearity in a-SiO 2 as a typical wide-bandgap dielectric by means of time-resolved, low-order wave-mixing experiments, and show that, close to the material damage threshold, the so far unexplored injection current provides the leading contribution. The sensitivity of the harmonic emission to the subcycle ionization dynamics offers an original approach to characterize the evolution of laser-induced plasma formation in optical microprocessing. Main When solid dielectrics are exposed to an intense infrared laser field, the quasi-instantaneous Kerr-type interband polarization 1 that is associated with a virtual conduction-band population 11 is accompanied by interband excitation, that is the persistent transfer of charge carriers from the valence to the conduction band near the peaks of the oscillating laser field via strong-field ionization 12 (step 1 in Fig. 1 ). After subsequent laser-driven acceleration of the electron in the conduction band (step 2), interband recombination with the hole that is left behind (step 3) can lead to the emission of high harmonics of the driving field 13 , 14 , in analogy to high-harmonic generation (HHG) in the gas phase 15 , 16 . The non-parabolic landscape of the valence and conduction bands along which electrons and holes are driven by the laser field in step 2 can give rise to an additional intraband contribution to the nonlinear response that has no direct equivalent in atomic HHG 5 , 6 , 17 . The sensitivity of these inter- and intraband mechanisms to the band structure and crystal orientation with respect to the laser polarization has turned high-harmonic spectroscopy into an important new tool for optical characterization of the electronic structure and dynamics of solids 4 , 17 , 18 , 19 , 20 . Fig. 1: Schematic description of harmonic generation in solids. The strong-field-induced electron dynamics can be divided into three major phases. It begins with interband excitation of electrons from the valence to the conduction band via strong-field ionization (step 1) followed by laser-field-driven intraband motion of the excited electron in the conduction band and the remaining hole in the valence band (step 2), and can finally lead to interband recombination of the electron with the hole (step 3). Each of these steps is associated with distinct nonlinearities that contribute to the harmonic emission and compete with the low-order perturbative Kerr-type contributions associated with virtual level population (as indicated). Our work demonstrates the dominant contribution of the injection step for the emission of low-order harmonics from amorphous wide-bandgap dielectrics for laser intensities close to the damage threshold. Full size image In addition to contributions from intraband currents due to band anharmonicity and interband recombination that dominate HHG in dielectric solids, the subcycle dynamics of the promotion of valence electrons into the conduction band in step 1 can lead to harmonics as well, as suggested by Brunel 8 in the context of HHG in the gas phase. Brunel assumed a stepwise injection of electrons into the continuum via tunnel ionization, with one step at the peak of each laser half cycle, and studied the harmonic emission associated with the acceleration of this temporally modulated electron population in the continuum by the laser field, while the current associated with the injection itself was not considered. Such Brunel-type harmonics show a rapid roll-off with increasing order and do not produce a plateau. In a solid, the two underlying elementary steps of injection and laser-driven motion could be associated with interband and intraband processes, respectively, impeding a clear classification based on this terminology. In fact, two-band calculations support the view that both inter- and intraband currents contribute to low-order harmonic emission 21 . Apart from dressed-state effects (time-resolved Franz–Keldysh effect), a substantial impact of persistent electronic excitation, in particular of the subcycle carrier injection dynamics, on the optical response of dielectrics has been predicted at high laser intensities 22 . Despite the well known impact of subcycle ionization dynamics on the absorption of intense laser pulses in gases 23 and solids 11 , 24 , the role of injection-induced nonlinearities in the wave mixing inside solids remains essentially unresolved, though a pioneering experiment provided indications of their importance 7 . Of particular interest is the relative impact of such ionization-induced nonlinearities compared with all other contributions, including the Kerr response. Here we present time-resolved, two-colour wave-mixing experiments that provide evidence for the dominance of ionization-induced low-order harmonic emission at intensities near the material damage threshold. Most importantly, our results expose the underlying mechanism and show that the corresponding nonlinear response does not reflect the conventional Brunel contribution (that is stepwise increase in the density of accelerated electrons) but stems from the so far overlooked contribution of the injection current itself. The resulting nonlinear polarization is associated with the charge displacement resulting from the strong-field-induced interband excitation process, in analogy to the current resulting from tunnelling in a low-frequency laser field 23 . In the experiment, an intense mid-infrared (mid-IR) pump laser pulse (central wavelength at λ pump = 2.1 μm) and a weak, time-delayed near-infrared (NIR) probe laser pulse (central wavelength at λ probe = 800 nm) were focused into a thin amorphous quartz (a-SiO 2 ) plate (0.5-mm thickness, 7.7-eV bandgap) using a close-to-collinear pump–probe geometry (Fig. 2a ). The angles of the pump and probe beams have been arranged such that only mixing orders including one probe photon are recorded (see", "role": "user" }, { "content": "Steering and monitoring the light-driven motion of electrons inside matter on the time-scale of a single optical cycle is a key challenge in ultrafast light wave electronics and laser-based material processing. Physicists from the Max Born Institute in Berlin and the University of Rostock have now revealed a so-far overlooked nonlinear optical mechanism that emerges from the light-induced tunneling of electrons inside dielectrics. For intensities near the material damage threshold, the nonlinear current arising during tunneling becomes the dominant source of bright bursts of light, which are low-order harmonics of the incident radiation. These findings, which have just been published in Nature Physics, significantly expand both the fundamental understanding of optical non-linearity in dielectric materials and its potential for applications in information processing and light-based material processing. Our current understanding of non-linear optics at moderate light intensities is based on the so-called Kerr non-linearity, which describes the non-linear displacement of tightly bound electrons under the influence of an incident optical light field. This picture changes dramatically when the intensity of this light field is sufficiently high to eject bound electrons from their ground state. At long wavelengths of the incident light field, this scenario is associated with the phenomenon of tunneling, a quantum process where an electron performs a classically forbidden transit through a barrier formed by the combined action of the light force and the atomic potential. Since the 1990's and pioneered by studies from the Canadian scientist François Brunel, the motion of electrons that have emerged at the \"end of the tunnel,\" which happens with maximal probability at the crest of the light wave, has been considered as an important source for optical non-linearity. This picture has now changed fundamentally. \"In the new experiment on glass, we could show that the current associated with the quantum mechanical tunneling process itself creates an optical non-linearity that surpasses the traditional Brunel mechanism,\" explains Dr. Alexandre Mermillod-Blondin from the Max Born Institute for Nonlinear Optics and Short Pulse Spectroscopy, who supervised the experiment. In the experiment, two ultrashort light pulses with different wavelengths and slightly different propagation directions were focused onto a thin slab of glass, and a time- and frequency-resolved analysis of the emerging light emission was performed. Identification of the mechanism responsible for this emission was made possible by a theoretical analysis of the measurements that was performed by the group of Prof. Thomas Fennel, who works at the University of Rostock and at the Max Born Institute in the framework of a DFG Heisenberg Professorship. \"The analysis of the measured signals in terms of a quantity that we termed the effective non-linearity was key to distinguish the new ionization current mechanism from other possible mechanisms and to demonstrate its dominance,\" explains Fennel. Future studies using this knowledge and the novel metrology method that was developed in the course of this work may enable researchers to temporally resolve and steer strong-field ionization and avalanching in dielectric materials with unprecedented resolution, ultimately possibly on the time-scale of a single cycle of light. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Kerr-type nonlinearities form the basis for our physical understanding of nonlinear optical phenomena in condensed matter, such as self-focusing, solitary waves and wave mixing 1 , 2 , 3 . In strong fields, they are complemented by higher-order nonlinearities that enable high-harmonic generation, which is currently understood as the interplay of light-driven intraband charge dynamics and interband recombination 4 , 5 , 6 . Remarkably, the nonlinear response emerging from the subcycle injection dynamics of electrons into the conduction band, that is from ionization, has been almost completely overlooked in solids and only partially considered in the gas phase 7 , 8 , 9 , 10 . Here, we reveal this strong-field-induced nonlinearity in a-SiO 2 as a typical wide-bandgap dielectric by means of time-resolved, low-order wave-mixing experiments, and show that, close to the material damage threshold, the so far unexplored injection current provides the leading contribution. The sensitivity of the harmonic emission to the subcycle ionization dynamics offers an original approach to characterize the evolution of laser-induced plasma formation in optical microprocessing. Main When solid dielectrics are exposed to an intense infrared laser field, the quasi-instantaneous Kerr-type interband polarization 1 that is associated with a virtual conduction-band population 11 is accompanied by interband excitation, that is the persistent transfer of charge carriers from the valence to the conduction band near the peaks of the oscillating laser field via strong-field ionization 12 (step 1 in Fig. 1 ). After subsequent laser-driven acceleration of the electron in the conduction band (step 2), interband recombination with the hole that is left behind (step 3) can lead to the emission of high harmonics of the driving field 13 , 14 , in analogy to high-harmonic generation (HHG) in the gas phase 15 , 16 . The non-parabolic landscape of the valence and conduction bands along which electrons and holes are driven by the laser field in step 2 can give rise to an additional intraband contribution to the nonlinear response that has no direct equivalent in atomic HHG 5 , 6 , 17 . The sensitivity of these inter- and intraband mechanisms to the band structure and crystal orientation with respect to the laser polarization has turned high-harmonic spectroscopy into an important new tool for optical characterization of the electronic structure and dynamics of solids 4 , 17 , 18 , 19 , 20 . Fig. 1: Schematic description of harmonic generation in solids. The strong-field-induced electron dynamics can be divided into three major phases. It begins with interband excitation of electrons from the valence to the conduction band via strong-field ionization (step 1) followed by laser-field-driven intraband motion of the excited electron in the conduction band and the remaining hole in the valence band (step 2), and can finally lead to interband recombination of the electron with the hole (step 3). Each of these steps is associated with distinct nonlinearities that contribute to the harmonic emission and compete with the low-order perturbative Kerr-type contributions associated with virtual level population (as indicated). Our work demonstrates the dominant contribution of the injection step for the emission of low-order harmonics from amorphous wide-bandgap dielectrics for laser intensities close to the damage threshold. Full size image In addition to contributions from intraband currents due to band anharmonicity and interband recombination that dominate HHG in dielectric solids, the subcycle dynamics of the promotion of valence electrons into the conduction band in step 1 can lead to harmonics as well, as suggested by Brunel 8 in the context of HHG in the gas phase. Brunel assumed a stepwise injection of electrons into the continuum via tunnel ionization, with one step at the peak of each laser half cycle, and studied the harmonic emission associated with the acceleration of this temporally modulated electron population in the continuum by the laser field, while the current associated with the injection itself was not considered. Such Brunel-type harmonics show a rapid roll-off with increasing order and do not produce a plateau. In a solid, the two underlying elementary steps of injection and laser-driven motion could be associated with interband and intraband processes, respectively, impeding a clear classification based on this terminology. In fact, two-band calculations support the view that both inter- and intraband currents contribute to low-order harmonic emission 21 . Apart from dressed-state effects (time-resolved Franz–Keldysh effect), a substantial impact of persistent electronic excitation, in particular of the subcycle carrier injection dynamics, on the optical response of dielectrics has been predicted at high laser intensities 22 . Despite the well known impact of subcycle ionization dynamics on the absorption of intense laser pulses in gases 23 and solids 11 , 24 , the role of injection-induced nonlinearities in the wave mixing inside solids remains essentially unresolved, though a pioneering experiment provided indications of their importance 7 . Of particular interest is the relative impact of such ionization-induced nonlinearities compared with all other contributions, including the Kerr response. Here we present time-resolved, two-colour wave-mixing experiments that provide evidence for the dominance of ionization-induced low-order harmonic emission at intensities near the material damage threshold. Most importantly, our results expose the underlying mechanism and show that the corresponding nonlinear response does not reflect the conventional Brunel contribution (that is stepwise increase in the density of accelerated electrons) but stems from the so far overlooked contribution of the injection current itself. The resulting nonlinear polarization is associated with the charge displacement resulting from the strong-field-induced interband excitation process, in analogy to the current resulting from tunnelling in a low-frequency laser field 23 . In the experiment, an intense mid-infrared (mid-IR) pump laser pulse (central wavelength at λ pump = 2.1 μm) and a weak, time-delayed near-infrared (NIR) probe laser pulse (central wavelength at λ probe = 800 nm) were focused into a thin amorphous quartz (a-SiO 2 ) plate (0.5-mm thickness, 7.7-eV bandgap) using a close-to-collinear pump–probe geometry (Fig. 2a ). The angles of the pump and probe beams have been arranged such that only mixing orders including one probe photon are recorded (see<|im_end|> <|im_start|>assistant Steering and monitoring the light-driven motion of electrons inside matter on the time-scale of a single optical cycle is a key challenge in ultrafast light wave electronics and laser-based material processing. Physicists from the Max Born Institute in Berlin and the University of Rostock have now revealed a so-far overlooked nonlinear optical mechanism that emerges from the light-induced tunneling of electrons inside dielectrics. For intensities near the material damage threshold, the nonlinear current arising during tunneling becomes the dominant source of bright bursts of light, which are low-order harmonics of the incident radiation. These findings, which have just been published in Nature Physics, significantly expand both the fundamental understanding of optical non-linearity in dielectric materials and its potential for applications in information processing and light-based material processing. Our current understanding of non-linear optics at moderate light intensities is based on the so-called Kerr non-linearity, which describes the non-linear displacement of tightly bound electrons under the influence of an incident optical light field. This picture changes dramatically when the intensity of this light field is sufficiently high to eject bound electrons from their ground state. At long wavelengths of the incident light field, this scenario is associated with the phenomenon of tunneling, a quantum process where an electron performs a classically forbidden transit through a barrier formed by the combined action of the light force and the atomic potential. Since the 1990's and pioneered by studies from the Canadian scientist François Brunel, the motion of electrons that have emerged at the "end of the tunnel," which happens with maximal probability at the crest of the light wave, has been considered as an important source for optical non-linearity. This picture has now changed fundamentally. "In the new experiment on glass, we could show that the current associated with the quantum mechanical tunneling process itself creates an optical non-linearity that surpasses the traditional Brunel mechanism," explains Dr. Alexandre Mermillod-Blondin from the Max Born Institute for Nonlinear Optics and Short Pulse Spectroscopy, who supervised the experiment. In the experiment, two ultrashort light pulses with different wavelengths and slightly different propagation directions were focused onto a thin slab of glass, and a time- and frequency-resolved analysis of the emerging light emission was performed. Identification of the mechanism responsible for this emission was made possible by a theoretical analysis of the measurements that was performed by the group of Prof. Thomas Fennel, who works at the University of Rostock and at the Max Born Institute in the framework of a DFG Heisenberg Professorship. "The analysis of the measured signals in terms of a quantity that we termed the effective non-linearity was key to distinguish the new ionization current mechanism from other possible mechanisms and to demonstrate its dominance," explains Fennel. Future studies using this knowledge and the novel metrology method that was developed in the course of this work may enable researchers to temporally resolve and steer strong-field ionization and avalanching in dielectric materials with unprecedented resolution, ultimately possibly on the time-scale of a single cycle of light. <|im_end|>

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2,007

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective To determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury. Design Double blinded, multicenter, parallel, randomized controlled trial. Setting Six hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers. Participants 6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. Interventions An electronic health record based “pop-up” alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient’s medical record. Main outcome measures A composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury. Results 6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group v 8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes. Conclusions Alerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury. Trial registration ClinicalTrials.gov NCT02753751 . Introduction Acute kidney injury—an abrupt decline in the kidney’s filtration function—is a common occurrence in patients in hospital and is associated with nearly a 10-fold increase in inpatient mortality. 1 2 3 In survivors, acute kidney injury is associated with increased risks of chronic kidney disease, end stage kidney disease, and mortality. 4 5 Despite the strong association with important outcomes, the syndrome (which is asymptomatic) is often missed in the course of clinical care; it occurs in roughly 15% of patients in hospital and yet is recorded in the electronic health record in fewer than half of patients with acute kidney injury. 6 7 8 9 10 Best practices for acute kidney injury, such as routine urinalysis and measurement of urine output, occur infrequently, and even repeat measurement of creatinine is not universal. These deficiencies provide a reason for alerting providers about the presence of acute kidney injury. 11 With the assumption that increased recognition of acute kidney injury will improve care of these patients and thus improve clinical outcomes, many health systems in the United States, and the National Health Service in the United Kingdom, have introduced an electronic alert for acute kidney injury as part of routine clinical care. 12 13 14 Data on the efficacy of these alerts are limited, however, and definitive evidence of their benefit for patient outcomes remains absent. Additionally, as acute kidney injury is a heterogeneous condition, lacking proven strategies for its mitigation, an alert might prompt actions that are unnecessary or even harmful. The effectiveness of alerting probably depends on a combination of patient, provider, and disease factors, and might differ in different care environments, thus requiring rigorous evaluation. We conducted a multicenter randomized clinical trial of usual care versus usual care plus pop-up acute kidney injury alerts delivered through an electronic health record. The alert was designed to reach multiple providers and was implemented using an identical protocol across a diverse set of hospitals. We hypothesized that alerts would influence provider behavior and improve clinical outcomes. Methods Extended details of the methods are shown in a supplementary web appendix. Trial design and oversight A detailed description of the trial design and rationale has been previously published. 15 Briefly, we conducted a patient level, parallel group, randomized controlled trial of health record electronic alerts versus usual care in adults with acute kidney injury at six hospitals in the Yale New Haven Health System in Connecticut and Rhode Island, US. The trial was conducted in accordance with the principles of the Declaration of Helsinki, and two institutional review boards associated with the six study hospitals approved the study, which was deemed minimal risk. Patients were enrolled, and a requirement for informed consent was waived, as the alert was deemed unlikely to affect patient welfare and informing patients of their diagnosis of acute kidney injury would contaminate the usual care group. An external data and safety monitoring board performed four independent assessments during the trial, including one formal interim analysis at 50% recruitment. These analyses were not stratified by hospital. Hospitals were given guidelines to terminate the study if the P value associated with interim analysis was less than or equal to 0.001 for efficacy or less than or equal to 0.005 for harm. The hospitals also had the authority to terminate the study of their own accord regardless of those recommendations. This trial was registered with clinicaltrials.gov under registration number NCT02753751 on 25 April 2016, before study initiation and patient enrolment. Patients Inpatient adults aged 18 or older with acute kidney injury, defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria as an increase in creatinine 0.3 mg/dL (26.5 μmol/L) within 48 hours or 1.5 times the lowest measured creatinine within the previous seven days of admission to hospital, were eligible. 16 Owing to missing and inaccurate urine output data, urine output was not used to classify acute kidney injury. Patients with a history of end stage kidney disease (based on International Classification of Disease, ninth and 10th revision (ICD-9 and ICD-10) codes, a dialysis order in the past year, or an initial hospital creatinine greater than 354 μmol/L", "role": "user" }, { "content": "Electronic alert systems created to provide an early warning of acute kidney injury (AKI) in hospitalized patients have no effect on a patient's risk of death and may even lead to worse patient outcomes, according to a new study by Yale researchers. The study, led by Dr. F. Perry Wilson, appears in the Jan. 16 edition of the British Medical Journal. \"The prevailing wisdom was that these alerts could only benefit patients,\" said Wilson. \"But after our study, the safest conclusion is that we can't provide any evidence that these alerts are beneficial.\" Acute kidney injury is an abrupt decline in the kidney's filtration function that is found in 15% of hospitalized patients and increases a patient's likelihood of death ten-fold. Despite this, AKI is not well tracked or consistently treated, researchers say. Many health systems have adopted a system that delivers an automated alert in the patient's electronic health record when laboratory results indicate AKI—specifically, a rapid rise in creatinine, a chemical waste product produced by the muscles, in the blood. The problem, said Wilson, associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator, is that there is limited data on whether the alerts improve patient outcomes. Wilson and others examined patients across six Yale-affiliated hospitals—four teaching and two non-teaching—located in both rural and urban settings. They looked at 6,030 adult inpatients with AKI, measuring AKI progression and whether patients required dialysis or died within 14 days. While all had AKI, for the study only half of these patients' providers received a pop-up alert; for the other half the alert function was switched off. The researchers found that the alert, when present, led to modest changes in provider behavior—including additional urinalysis tests, more creatinine measurement, and increased documentation of the patients' AKI—but did not make a difference in clinical outcomes. These patients were just as likely to have worsening AKI-related conditions, require dialysis, or die. Even more alarming, the researchers found that for the two non-teaching hospitals, health outcomes for patients whose records included an AKI alert were actually worse than for those who didn't, with significantly higher death rates among the patients receiving the alert (15.6% in the alert group compared with 8.6% in the usual care group), suggesting evidence of harm. \"What our study says is that we need to go back to the drawing board to find out what's not working,\" said Wilson. \"We need to look more closely at provider behaviors. Are they giving too much IV fluid? Are they getting distracted? We don't have one clear culprit to explain the bad outcomes.\" This study, said Wilson, points to the importance of evaluating standard clinical practice, and using data to drive processes. \"It was Yale's commitment to robust research methods that led us to discover this potential issue which has wide-ranging consequences,\" he said. \"Most health systems wouldn't systematically test these things.\" He added that additional studies will look at AKI alerts with greater detail, and whether alerts related to the toxicity of prescribed medicines for patients with AKI affect health outcomes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective To determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury. Design Double blinded, multicenter, parallel, randomized controlled trial. Setting Six hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers. Participants 6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. Interventions An electronic health record based “pop-up” alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient’s medical record. Main outcome measures A composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury. Results 6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group v 8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes. Conclusions Alerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury. Trial registration ClinicalTrials.gov NCT02753751 . Introduction Acute kidney injury—an abrupt decline in the kidney’s filtration function—is a common occurrence in patients in hospital and is associated with nearly a 10-fold increase in inpatient mortality. 1 2 3 In survivors, acute kidney injury is associated with increased risks of chronic kidney disease, end stage kidney disease, and mortality. 4 5 Despite the strong association with important outcomes, the syndrome (which is asymptomatic) is often missed in the course of clinical care; it occurs in roughly 15% of patients in hospital and yet is recorded in the electronic health record in fewer than half of patients with acute kidney injury. 6 7 8 9 10 Best practices for acute kidney injury, such as routine urinalysis and measurement of urine output, occur infrequently, and even repeat measurement of creatinine is not universal. These deficiencies provide a reason for alerting providers about the presence of acute kidney injury. 11 With the assumption that increased recognition of acute kidney injury will improve care of these patients and thus improve clinical outcomes, many health systems in the United States, and the National Health Service in the United Kingdom, have introduced an electronic alert for acute kidney injury as part of routine clinical care. 12 13 14 Data on the efficacy of these alerts are limited, however, and definitive evidence of their benefit for patient outcomes remains absent. Additionally, as acute kidney injury is a heterogeneous condition, lacking proven strategies for its mitigation, an alert might prompt actions that are unnecessary or even harmful. The effectiveness of alerting probably depends on a combination of patient, provider, and disease factors, and might differ in different care environments, thus requiring rigorous evaluation. We conducted a multicenter randomized clinical trial of usual care versus usual care plus pop-up acute kidney injury alerts delivered through an electronic health record. The alert was designed to reach multiple providers and was implemented using an identical protocol across a diverse set of hospitals. We hypothesized that alerts would influence provider behavior and improve clinical outcomes. Methods Extended details of the methods are shown in a supplementary web appendix. Trial design and oversight A detailed description of the trial design and rationale has been previously published. 15 Briefly, we conducted a patient level, parallel group, randomized controlled trial of health record electronic alerts versus usual care in adults with acute kidney injury at six hospitals in the Yale New Haven Health System in Connecticut and Rhode Island, US. The trial was conducted in accordance with the principles of the Declaration of Helsinki, and two institutional review boards associated with the six study hospitals approved the study, which was deemed minimal risk. Patients were enrolled, and a requirement for informed consent was waived, as the alert was deemed unlikely to affect patient welfare and informing patients of their diagnosis of acute kidney injury would contaminate the usual care group. An external data and safety monitoring board performed four independent assessments during the trial, including one formal interim analysis at 50% recruitment. These analyses were not stratified by hospital. Hospitals were given guidelines to terminate the study if the P value associated with interim analysis was less than or equal to 0.001 for efficacy or less than or equal to 0.005 for harm. The hospitals also had the authority to terminate the study of their own accord regardless of those recommendations. This trial was registered with clinicaltrials.gov under registration number NCT02753751 on 25 April 2016, before study initiation and patient enrolment. Patients Inpatient adults aged 18 or older with acute kidney injury, defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria as an increase in creatinine 0.3 mg/dL (26.5 μmol/L) within 48 hours or 1.5 times the lowest measured creatinine within the previous seven days of admission to hospital, were eligible. 16 Owing to missing and inaccurate urine output data, urine output was not used to classify acute kidney injury. Patients with a history of end stage kidney disease (based on International Classification of Disease, ninth and 10th revision (ICD-9 and ICD-10) codes, a dialysis order in the past year, or an initial hospital creatinine greater than 354 μmol/L<|im_end|> <|im_start|>assistant Electronic alert systems created to provide an early warning of acute kidney injury (AKI) in hospitalized patients have no effect on a patient's risk of death and may even lead to worse patient outcomes, according to a new study by Yale researchers. The study, led by Dr. F. Perry Wilson, appears in the Jan. 16 edition of the British Medical Journal. "The prevailing wisdom was that these alerts could only benefit patients," said Wilson. "But after our study, the safest conclusion is that we can't provide any evidence that these alerts are beneficial." Acute kidney injury is an abrupt decline in the kidney's filtration function that is found in 15% of hospitalized patients and increases a patient's likelihood of death ten-fold. Despite this, AKI is not well tracked or consistently treated, researchers say. Many health systems have adopted a system that delivers an automated alert in the patient's electronic health record when laboratory results indicate AKI—specifically, a rapid rise in creatinine, a chemical waste product produced by the muscles, in the blood. The problem, said Wilson, associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator, is that there is limited data on whether the alerts improve patient outcomes. Wilson and others examined patients across six Yale-affiliated hospitals—four teaching and two non-teaching—located in both rural and urban settings. They looked at 6,030 adult inpatients with AKI, measuring AKI progression and whether patients required dialysis or died within 14 days. While all had AKI, for the study only half of these patients' providers received a pop-up alert; for the other half the alert function was switched off. The researchers found that the alert, when present, led to modest changes in provider behavior—including additional urinalysis tests, more creatinine measurement, and increased documentation of the patients' AKI—but did not make a difference in clinical outcomes. These patients were just as likely to have worsening AKI-related conditions, require dialysis, or die. Even more alarming, the researchers found that for the two non-teaching hospitals, health outcomes for patients whose records included an AKI alert were actually worse than for those who didn't, with significantly higher death rates among the patients receiving the alert (15.6% in the alert group compared with 8.6% in the usual care group), suggesting evidence of harm. "What our study says is that we need to go back to the drawing board to find out what's not working," said Wilson. "We need to look more closely at provider behaviors. Are they giving too much IV fluid? Are they getting distracted? We don't have one clear culprit to explain the bad outcomes." This study, said Wilson, points to the importance of evaluating standard clinical practice, and using data to drive processes. "It was Yale's commitment to robust research methods that led us to discover this potential issue which has wide-ranging consequences," he said. "Most health systems wouldn't systematically test these things." He added that additional studies will look at AKI alerts with greater detail, and whether alerts related to the toxicity of prescribed medicines for patients with AKI affect health outcomes. <|im_end|>

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1,988