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science.chia_ner | science.chia_ner.892 | [
{
"content": "Analyze the provided clinical trial criteria. Identify and extract distinct entities from the text.\n\nReturn the results as a JSON structure. Ensure the output is strictly in JSON format without any additional commentary.\n\nCriteria Text:\n\nInability to perform exercise tests\nDiagnosed psychiatric or cognitive disorders\nProgressive neurological or neuromuscular disorders having a major impact on exercise capacity",
"role": "user"
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"content": "{\"Condition\": [\"impact on exercise capacity\", \"Inability to perform\", \"uromuscular disorders h ogressive n\", \"cognitive disorders\", \"sorders h ogressive neurological o\", \"sychiatric isorders\"], \"Device\": [], \"Drug\": [], \"Measurement\": [], \"Mood\": [], \"Multiplier\": [], \"Negation\": [], \"Observation\": [], \"Person\": [], \"Procedure\": [\"exercise tests\"], \"Qualifier\": [], \"ReferencePoint\": [], \"Scope\": [\"Progressive neurological or neuromuscular disorders\"], \"Temporal\": [], \"Value\": [], \"Visit\": []}",
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science.qasper_extractive_qa | science.qasper_extractive_qa.161.2 | [
{
"content": "Analyze the given research paper excerpts and address the question provided. Extract the necessary information directly from the text. Your answer should be formatted as a JSON object with the following structure:\n\n\"answer\": A list of text segments from the paper that directly respond to the question.\n\"evidence\": A list of text segments from the paper where the answer can be found.\n\nIf the question cannot be answered with the given text, return \"null\".\n\nDocument: What Gets Echoed? Understanding the\"Pointers\"in Explanations of Persuasive Arguments\n\nExplanations are central to everyday life, and are a topic of growing interest in the AI community. To investigate the process of providing natural language explanations, we leverage the dynamics of the /r/ChangeMyView subreddit to build a dataset with 36K naturally occurring explanations of why an argument is persuasive. We propose a novel word-level prediction task to investigate how explanations selectively reuse, or echo, information from what is being explained (henceforth, explanandum). We develop features to capture the properties of a word in the explanandum, and show that our proposed features not only have relatively strong predictive power on the echoing of a word in an explanation, but also enhance neural methods of generating explanations. In particular, while the non-contextual properties of a word itself are more valuable for stopwords, the interaction between the constituent parts of an explanandum is crucial in predicting the echoing of content words. We also find intriguing patterns of a word being echoed. For example, although nouns are generally less likely to be echoed, subjects and objects can, depending on their source, be more likely to be echoed in the explanations.\n\nIntroduction\nExplanations are essential for understanding and learning BIBREF0. They can take many forms, ranging from everyday explanations for questions such as why one likes Star Wars, to sophisticated formalization in the philosophy of science BIBREF1, to simply highlighting features in recent work on interpretable machine learning BIBREF2.\nAlthough everyday explanations are mostly encoded in natural language, natural language explanations remain understudied in NLP, partly due to a lack of appropriate datasets and problem formulations. To address these challenges, we leverage /r/ChangeMyView, a community dedicated to sharing counterarguments to controversial views on Reddit, to build a sizable dataset of naturally-occurring explanations. Specifically, in /r/ChangeMyView, an original poster (OP) first delineates the rationales for a (controversial) opinion (e.g., in Table TABREF1, “most hit music artists today are bad musicians”). Members of /r/ChangeMyView are invited to provide counterarguments. If a counterargument changes the OP's view, the OP awards a $\\Delta $ to indicate the change and is required to explain why the counterargument is persuasive. In this work, we refer to what is being explained, including both the original post and the persuasive comment, as the explanandum.\nAn important advantage of explanations in /r/ChangeMyView is that the explanandum contains most of the required information to provide its explanation. These explanations often select key counterarguments in the persuasive comment and connect them with the original post. As shown in Table TABREF1, the explanation naturally points to, or echoes, part of the explanandum (including both the persuasive comment and the original post) and in this case highlights the argument of “music serving different purposes.”\nThese naturally-occurring explanations thus enable us to computationally investigate the selective nature of explanations: “people rarely, if ever, expect an explanation that consists of an actual and complete cause of an event. Humans are adept at selecting one or two causes from a sometimes infinite number of causes to be the explanation” BIBREF3. To understand the selective process of providing explanations, we formulate a word-level task to predict whether a word in an explanandum will be echoed in its explanation.\nInspired by the observation that words that are likely to be echoed are either frequent or rare, we propose a variety of features to capture how a word is used in the explanandum as well as its non-contextual properties in Section SECREF4. We find that a word's usage in the original post and in the persuasive argument are similarly related to being echoed, except in part-of-speech tags and grammatical relations. For instance, verbs in the original post are less likely to be echoed, while the relationship is reversed in the persuasive argument.\nWe further demonstrate that these features can significantly outperform a random baseline and even a neural model with significantly more knowledge of a word's context. The difficulty of predicting whether content words (i.e., non-stopwords) are echoed is much greater than that of stopwords, among which adjectives are the most difficult and nouns are relatively the easiest. This observation highlights the important role of nouns in explanations. We also find that the relationship between a word's usage in the original post and in the persuasive comment is crucial for predicting the echoing of content words. Our proposed features can also improve the performance of pointer generator networks with coverage in generating explanations BIBREF4.\nTo summarize, our main contributions are:\n[itemsep=0pt,leftmargin=*,topsep=0pt]\nWe highlight the importance of computationally characterizing human explanations and formulate a concrete problem of predicting how information is selected from explananda to form explanations, including building a novel dataset of naturally-occurring explanations.\nWe provide a computational characterization of natural language explanations and demonstrate the U-shape in which words get echoed.\nWe identify interesting patterns in what gets echoed through a novel word-level classification task, including the importance of nouns in shaping explanations and the importance of contextual properties of both the original post and persuasive comment in predicting the echoing of content words.\nWe show that vanilla LSTMs fail to learn some of the features we develop and that the proposed features can even improve performance in generating explanations with pointer networks.\nOur code and dataset is available at https://chenhaot.com/papers/explanation-pointers.html.\n\nUnderstanding the Pointers in Explanations\nTo further investigate how explanations select words from the explanandum, we formulate a word-level prediction task to predict whether words in an OP or PC are echoed in its explanation. Formally, given a tuple of (OP, PC, explanation), we extract the unique stemmed words as $\\mathcal {V}_{\\text{OP}}, \\mathcal {V}_{\\text{PC}}, \\mathcal {V}_{\\text{EXP}}$. We then define the label for each word in the OP or PC, $w \\in \\mathcal {V}_{\\text{OP}} \\cup \\mathcal {V}_{\\text{PC}}$, based on the explanation as follows:\nOur prediction task is thus a straightforward binary classification task at the word level. We develop the following five groups of features to capture properties of how a word is used in the explanandum (see Table TABREF18 for the full list):\n[itemsep=0pt,leftmargin=*,topsep=0pt]\nNon-contextual properties of a word. These features are derived directly from the word and capture the general tendency of a word being echoed in explanations.\nWord usage in an OP or PC (two groups). These features capture how a word is used in an OP or PC. As a result, for each feature, we have two values for the OP and PC respectively.\nHow a word connects an OP and PC. These features look at the difference between word usage in the OP and PC. We expect this group to be the most important in our task.\nGeneral OP/PC properties. These features capture the general properties of a conversation. They can be used to characterize the background distribution of echoing.\nTable TABREF18 further shows the intuition for including each feature, and condensed $t$-test results after Bonferroni correction. Specifically, we test whether the words that were echoed in explanations have different feature values from those that were not echoed. In addition to considering all words, we also separately consider stopwords and content words in light of Figure FIGREF8. Here, we highlight a few observations:\n[itemsep=0pt,leftmargin=*,topsep=0pt]\nAlthough we expect more complicated words (#characters) to be echoed more often, this is not the case on average. We also observe an interesting example of Simpson's paradox in the results for Wordnet depth BIBREF38: shallower words are more likely to be echoed across all words, but deeper words are more likely to be echoed in content words and stopwords.\nOPs and PCs generally exhibit similar behavior for most features, except for part-of-speech and grammatical relation (subject, object, and other.) For instance, verbs in an OP are less likely to be echoed, while verbs in a PC are more likely to be echoed.\nAlthough nouns from both OPs and PCs are less likely to be echoed, within content words, subjects and objects from an OP are more likely to be echoed. Surprisingly, subjects and objects in a PC are less likely to be echoed, which suggests that the original poster tends to refer back to their own subjects and objects, or introduce new ones, when providing explanations.\nLater words in OPs and PCs are more likely to be echoed, especially in OPs. This could relate to OPs summarizing their rationales at the end of their post and PCs putting their strongest points last.\nAlthough the number of surface forms in an OP or PC is positively correlated with being echoed, the differences in surface forms show reverse trends: the more surface forms of a word that show up only in the PC (i.e., not in the OP), the more likely a word is to be echoed. However, the reverse is true for the number of surface forms in only the OP. Such contrast echoes BIBREF31, in which dissimilarity in word usage between the OP and PC was a predictive feature of successful persuasion.\n\nPredicting Pointers\nWe further examine the effectiveness of our proposed features in a predictive setting. These features achieve strong performance in the word-level classification task, and can enhance neural models in both the word-level task and generating explanations. However, the word-level task remains challenging, especially for content words.\n\nPredicting Pointers ::: The Effect on Generating Explanations\nOne way to measure the ultimate success of understanding pointers in explanations is to be able to generate explanations. We use the pointer generator network with coverage as our starting point BIBREF4, BIBREF46 (see the supplementary material for details). We investigate whether concatenating our proposed features with word embeddings can improve generation performance, as measured by ROUGE scores.\nConsistent with results in sequence tagging for word-level echoing prediction, our proposed features can enhance a neural model with copying mechanisms (see Table TABREF37). Specifically, their use leads to statistically significant improvement in ROUGE-1 and ROUGE-L, while slightly hurting the performance in ROUGE-2 (the difference is not statistically significant). We also find that our features can increase the likelihood of copying: an average of 17.59 unique words get copied to the generated explanation with our features, compared to 14.17 unique words without our features. For comparison, target explanations have an average of 34.81 unique words. We emphasize that generating explanations is a very challenging task (evidenced by the low ROUGE scores and examples in the supplementary material), and that fully solving the generation task requires more work.\n\nTable 3: Feature importance for the full XGBoost model, as measured by total gain.\n\nTable 4: Parameters tuned on validation dataset containing 5k instances.\n\nInquiry: What are their proposed features?",
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"content": "{\"answer\": [\"Non-contextual properties of a word\", \"Word usage in an OP or PC (two groups)\", \"How a word connects an OP and PC.\", \"General OP/PC properties\"], \"evidence\": [\"Our prediction task is thus a straightforward binary classification task at the word level. We develop the following five groups of features to capture properties of how a word is used in the explanandum (see Table TABREF18 for the full list):\", \"[itemsep=0pt,leftmargin=*,topsep=0pt]\", \"Non-contextual properties of a word. These features are derived directly from the word and capture the general tendency of a word being echoed in explanations.\", \"Word usage in an OP or PC (two groups). These features capture how a word is used in an OP or PC. As a result, for each feature, we have two values for the OP and PC respectively.\", \"How a word connects an OP and PC. These features look at the difference between word usage in the OP and PC. We expect this group to be the most important in our task.\", \"General OP/PC properties. These features capture the general properties of a conversation. They can be used to characterize the background distribution of echoing.\", \"Table TABREF18 further shows the intuition for including each feature, and condensed $t$-test results after Bonferroni correction. Specifically, we test whether the words that were echoed in explanations have different feature values from those that were not echoed. In addition to considering all words, we also separately consider stopwords and content words in light of Figure FIGREF8. Here, we highlight a few observations:\"]}",
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science.anat_em_ner | science.anat_em_ner.194 | [
{
"content": "Analyze the provided text from a biomedical study. Your task is to detect and list entities based on predefined categories.\n\nPresent your results in a JSON format: {\"AnatomicalEntity\": [\"entity1\", \"entity2\", ...]}. Each category should have a corresponding list of identified entities. \n\nText:\n\nAcute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells.\nPhysiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1alpha protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.",
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"content": "{\"AnatomicalEntity\": [\"capillary network\", \"cord\", \"nuclear\", \"cell\", \"endothelial\", \"endothelial cell cord\", \"endothelial cells\", \"blood\", \"wound\", \"wounds\", \"endothelial cell\"]}",
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science.pico_ner | science.pico_ner.390 | [
{
"content": "Examine the following abstract and identify distinct entities. Focus on extracting entities related to participants, interventions, and outcomes.\n\nPresent your findings in a JSON format like: {\"Participant\": [\"example entity\", ...], \"Intervention\": [\"example entity\", ...], \"Outcome\": [\"example entity\", ...]}. If no entities are found for a category, use an empty list.\n\nAbstract Content:\n\nComparison of comfort and local complications after cardiac catheterization . The purpose of this study was to compare the effects of 4 hours of bed rest versus 6 hours of bed rest on patients ' safety , comfort , and satisfaction levels . Using a quasi-experimental design , the authors studied 118 left-heart catheterization patients who were randomly assigned to 4 hours or 6 hours of bed rest . Among the study participants , only 1 in the 6-hour group had significant bleeding . There were no complications in the 4-hour group . There were no statistically significant differences between the two groups on any of the other study variables . Given the lack of significant complications for the 4-hour group and similar comfort levels for both study groups , these findings suggest the feasibility of reducing the standard period of postcatheterization bed rest from 6 hours to 4 hours , thereby possibly lowering the cost of the outpatient procedure .",
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"content": "{\"Intervention\": [\"left-heart catheterization\", \"cardiac catheterization\", \"bed rest\"], \"Outcome\": [\"local complications\", \"satisfaction levels\", \"safety\", \"comfort levels\", \"cost of the outpatient procedure\", \"comfort\", \"significant bleeding\", \"complications\"], \"Participant\": [\"118\", \"cardiac catheterization\", \"left-heart catheterization patients\"]}",
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science.chia_ner | science.chia_ner.179 | [
{
"content": "Analyze the provided clinical trial criteria. Identify and extract distinct entities from the text.\n\nReturn the results as a JSON structure. Ensure the output is strictly in JSON format without any additional commentary.\n\nCriteria Text:\n\nScheduled to undergo revision total knee arthroplasty",
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"content": "{\"Condition\": [], \"Device\": [], \"Drug\": [], \"Measurement\": [], \"Mood\": [], \"Multiplier\": [], \"Negation\": [], \"Observation\": [], \"Person\": [], \"Procedure\": [\"revision total knee arthroplasty\"], \"Qualifier\": [], \"ReferencePoint\": [], \"Scope\": [], \"Temporal\": [], \"Value\": [], \"Visit\": []}",
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science.healthver_entailment | science.healthver_entailment.2639 | [
{
"content": "Evaluate the given public health statement using the provided research abstract. Your goal is to determine the relationship between the claim and the abstract content.\n\n- \"decision\": Indicate whether the abstract \"SUPPORTS\", \"CONTRADICTS\", or provides \"INSUFFICIENT\" information regarding the claim.\n- \"justification\": List sentences from the abstract that back your decision. If the decision is \"INSUFFICIENT\", leave this list empty.\n\nStatement: Should all diabetics be labeled 'high risk' for COVID-19? Maybe not\n\nResearch Abstract:\nSome comorbidities are associated with severe coronavirus disease (Covid-19) but it is unclear whether some increase susceptibility to Covid-19.\nIn this case-control Mexican study we found that obesity represents the strongest predictor for Covid-19 followed by diabetes and hypertension in both sexes and chronic renal failure in females only.\nActive smoking was associated with decreased odds of Covid-19.\nThese findings indicate that these comorbidities are not only associated with severity of disease but also predispose for getting Covid-19.\nFuture research is needed to establish the mechanisms involved in each comorbidity and the apparent \"protective\" effect of cigarette smoking.",
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{
"content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"In this case-control Mexican study we found that obesity represents the strongest predictor for Covid-19 followed by diabetes and hypertension in both sexes and chronic renal failure in females only.\"]}",
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science.craftchem_ner | science.craftchem_ner.3932 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nTheresultsoftheESTdidnotdistinguishbetweenaprimarycardiacabnormalityversuseffectssecondarytotheexhaustioncausedbyreducedexercisetolerancerelatedtoskeletalmuscledysfunction.",
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{
"content": "[]",
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science.pubmedqa_qa | science.pubmedqa_qa.165 | [
{
"content": "Analyze the given text and respond to the inquiry. Choose from: \"YES\", \"NO\", or \"MAYBE\".\n\nText:\n(OBJECTIVE) To discuss and compare the results of suturing the nasal septum after septoplasty with the results of nasal packing.\n(METHODS) A prospective study, which was performed at Prince Hashem Military Hospital in Zarqa, Jordan and Prince Rashed Military Hospital in Irbid, Jordan between September 2005 and August 2006 included 169 consecutive patients that underwent septoplasty. The patients were randomly divided into 2 groups. After completion of surgery, the nasal septum was sutured in the first group while nasal packing was performed in the second group.\n(RESULTS) Thirteen patients (15.3%) in the first group and 11 patients (13%) in the second group had minor oozing in the first 24 hours, 4 patients (4.8%) had bleeding after removal of the pack in the second group. Four patients (4.8%) developed septal hematoma in the second group. Two patients (2.4%) had septal perforation in the second group. One patient (1.1%) in the first group, and 5 patients (5.9%) in the second group had postoperative adhesions. Five patients (5.9%) were found to have remnant deviated nasal septum in each group. The operating time was 4 minutes longer in the first group.\n\nInquiry:\nSuturing of the nasal septum after septoplasty, is it an effective alternative to nasal packing?\n\nResponse:",
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{
"content": "YES",
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science.data_reco_mcq_sc | science.data_reco_mcq_sc.4435 | [
{
"content": "Explore the following research question and associated terms. Identify the most suitable dataset from the list provided. Use the dataset descriptions to guide your choice.\n\nInquiry: We present an approach for maven search that incorporates semantic and temporal information to discover latent topics between authors\n\nKeywords: maven search text\n\nDataset Information:\n2D-3D-S: The 2D-3D-S dataset provides a variety of mutually registered modalities from 2D, 2.5D and 3D domains, with instance-level semantic and geometric annotations. It covers over 6,000 m2 collected in 6 large-scale indoor areas that originate from 3 different buildings.\nFineGym: FineGym is an action recognition dataset build on top of gymnasium videos. Compared to existing action recognition datasets, FineGym is distinguished in richness, quality, and diversity.\nROCStories: ROCStories is a collection of commonsense short stories. The corpus consists of 100,000 five-sentence stories.\nDBLP: The DBLP is a citation network dataset. The citation data is extracted from DBLP, ACM, MAG (Microsoft Academic Graph), and other sources.\n\nAvailable Datasets: A: 2D-3D-S B: FineGym C: ROCStories D: DBLP",
"role": "user"
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"content": "DBLP",
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science.scientific_papers_summarization_single_doc_arxiv | science.scientific_papers_summarization_single_doc_arxiv.113139 | [
{
"content": "Write an abstract for the research paper below. Your response should only include the abstract and no additional text.\n\nArticle text:\nthe 3rd ipn began with the launch of ulysses in november 1990 .\nulysses is in a heliocentric orbit roughly perpendicular to the ecliptic , with perihelion of about 1.5 au and an aphelion of about 5 au . until 1992 ,\nthe network had ulysses and pioneer venus orbiter ( pvo ) as its distant points , and utilized many near - earth spacecraft such as the compton gamma - ray observatory ( cgro ) as its third point .\npvo entered the atmosphere of venus in 1992 , and it was to be replaced in the ipn by nasa s mars observer , which was lost during insertion into martian orbit .\nfinally , in 1999 , the network was completed by the x- and gamma - ray spectrometer experiment aboard the near earth asteroid rendezvous ( near ) spacecraft . in this configuration ,\nthe ipn operated quite successfully until near landed on the asteroid eros in february 2001 .\nfigure 1 summarizes some of the results .\nthe mars odyssey mission , launched in april of that year , contains two experiments which have been modified for gamma - ray burst detection , the gamma - ray spectrometer ( grs ) and the high energy neutron detector ( hend ) . as the grs will not be turned on permanently until the spacecraft completes its aerobraking maneuver\n, we will discuss the results obtained with hend .\nhend has an effective area of about 40 @xmath0 of csi and operates in the energy range above 40 kev .\nit transmits data continuously with a time resolution of 0.25 s , so that `` triggering '' is done with ground software .\nin addition , whenever a burst is recorded by konus , the bepposax grbm , ulysses , or hete - ii , hend data are extracted for the appropriate crossing window and transmitted to goddard and berkeley for analysis .\nhend was been on for a large fraction of the cruise phase , and has detected many cosmic , solar , and soft gamma repeater ( sgr ) events , some of which are listed in table 1 .\n.a partial list of hend solar , cosmic , and sgr bursts . [ cols=\"^,^,^,^,^,^,^,^\",options=\"header \" , ] this table is neither exhaustive , since we have not been able to analyze all the data yet , nor representative , since there were numerous solar flare particle events which raised the backgrounds and reduced the sensitivities of some ipn experiments .\n( solar activity will be decreasing in the years to come . )\nthus in about 4.5 months , hend detected 21 confirmed cosmic or sgr events .\nhend is now on almost continuously , but in an eccentric orbit which leads to a variable background rate .\nthe orbit is gradually being circularized by aerobraking . in figure 1\nwe show an example of a hend burst .\nalthough the grs has been on only sporadically during cruise , it too has detected several bursts .\nthe mars odyssey mission will collect data for at least one martian year .\nthe nominal end of mission will be around early 2004 .\nulysses is currently funded through at least the start of 2004 , with a slight extension possible .\nhowever , the decay of the radioactive power system probably precludes operation past the end of 2004 .\nthe wind mission is funded through 2002 at least .\nthe bepposax is presently funded until april 2002 , but it may be extended until it re - enters .\nhete - ii is funded through 2002 at least , and possibly for two years beyond .\nthe integral mission is due to be launched into a highly elliptical orbit in october 2002 . it will therefore either replace or complement the near - earth spacecraft , depending on whether they remain operational or\nhave been terminated by that time .\nfinally , swift should be launched in late 2003 .\nthus , we expect to maintain a viable three - spacecraft ipn for a minimum of about 2.5 years .\nthis new ipn is similar in many respects to one which was in operation when near was in the network . between december 1999 and january 2001 , that ipn localized 57 grbs and circulated their positions to the wide astronomical community via the grb coordinates network ( gcn ) .\nof the 25 bursts which were followed up with long - wavelength observations , counterparts were found for 9 .\nthe success rate , 9/25 or 36% , is consistent with the overall success rate for bursts , which is about 40% .\nthere are factors which will both increase and decrease the performance of the new ipn compared to the old one .\nwe first list the `` increase '' factors . \\1 . in the old network ,\nthe earth - ulysses distance varied between 2.3 and 4.4 au , while the earth - near distance varied between 0.8 and 2.1 . in the new network\n, the earth - ulysses distance will vary between 2 and 6 au , while the earth - mars distance will vary between 0.45 and 1.8 au .\nthus the average baselines , and hence the annulus widths , will be slightly better . \\2 . in the old network ,\nthe near xgrs experiment had a time resolution of 1 second . in the new network\n, the time resolution will be between 0.031 s ( for grs ) and 0.250 s ( for hend ) , resulting in a gain in accuracy of the cross - correlations and thus narrower annuli .\n\\3 . in the old network ,\nthe xgrs detector had a lower energy threshold of 150 kev .\nthe other experiments in the network have energy ranges of 25 - 150 kev .\nsince grb time histories are energy - dependent , this led to increased uncertainty in the cross - correlations and thus wider annuli .\nhend operates in an energy range which is better matched to those of the other ipn instruments .\n\\4 . based on the number of bursts observed with hend during the cruise phase ( 21 in 4.5 mo ) , and taking into account the facts that hend was not on continuously , and that all the data have not been examined , the burst detection rate , 4.7/month , was greater than that of the old network .\nthe following are `` decrease '' effects : \\1 .\nonce mo is in a circular orbit , hend will have an unobstructed field of view of about 2 pi sr , or a factor of about 2 less than in the cruise phase .\nthis decrease should be offset by two other factors , however .\nfirst , bursts arriving from the anti - planet hemisphere should still be detectable in some cases , since they will either penetrate the material behind the detectors , and/or backscatter off the martian atmosphere .\nsecond , grs will be on continuously , and due to its different detection efficiency , energy range , and field of view , it will detect some bursts that hend does not .\nthe future tracking efficiencies ( that is , the length of time between telemetry passes ) of some spacecraft in the network are unknown .\nthis applies particularly to konus - wind and to mars odyssey .\nlonger periods between downlinks translate to later error boxes , which must be searched more deeply for counterparts .\nall these effects are difficult to quantify , but our expectation is nevertheless that the performance of this network will closely resemble that of its predecessor .\nin the 2.5 year mo mission , we expect to detect and localize over 100 grbs and circulate their positions rapidly to astronomers around the world for multiwavelength counterpart studies .\nthis should lead to the observation of numerous afterglows and the determination of many grb redshifts .",
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"content": "the 3rd interplanetary network ( ipn ) has been operating since april 2001 with two distant spacecraft , ulysses and mars odyssey , and numerous near - earth spacecraft , such as bepposax , wind , and hete - ii . mars odyssey is presently in orbit about mars , and the network has detected approximately 30 cosmic , sgr , and solar bursts . we discuss the results obtained to date and use them to predict the future performance of the network .",
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science.chemsum_single_document_summarization | science.chemsum_single_document_summarization.42136 | [
{
"content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nSynthesis and SAR of selective small molecule Neuropeptide Y Y2 receptor antagonists\n\nContent Extracts:\n\n<p>Neuropeptide Y (NPY) is a highly conserved 36-amino acid peptide neurotransmitter, structurally and functionally related to the 36-amino acid pancreatic peptide (PYY) and pancreatic polypeptide (PP) and one of the most abundant neuropeptides in the mammalian brain.1,2 NPY is involved in a variety of physiological processes such as regulation of energy balance, anxiety, food intake, water consumption, circadian rhythms, learning, memory, anxiety, cell proliferation, and angiogenesis.3–6 Four different receptor subtypes7,8 (Y1, Y2, Y4, Y5) have been identified as endogenous receptors in humans that bind to NPY and are expressed in both the central and peripheral nervous systems. All NPY receptor subtypes belong to the family of G protein coupled receptors (GPCR) and mediate their biological responses via Gαi signaling pathways.</p><p>The NPY Y2 receptor has attracted considerable interest since it has been associated with various physiological and pathological processes such as affective disorders, infertility, bone mass formation, responses to ethanol and drugs of abuse, angiogenesis, and food intake.9 Doods et al10 reported a highly potent (IC50 = 3.3 nM) peptide-like NPY Y2 antagonist BIIE0246, which decreased ethanol consumption in rats and induced antidepressant-like effects in mice11 following intracerebroventricular (icv) administration. However, the potential therapeutic application of this compound is limited due to its peptide-like structure, high molecular weight, poor brain penetration and off-target selectivity.12,13 While most of the efforts in the literature have been focused on the discovery and development of NPY Y1 and Y5 receptor antagonists as potential therapeutic agents for obesity and feeding disorders, there are only few reports on the identification of selective NPY Y2 receptor antagonists.14–18 Therefore, selective NPY Y2 antagonists with good physicochemical properties, suitable for in vivo studies are desired.</p><p>With an aim to identify selective, brain-penetrant, non-peptidic NPY Y2 antagonists that are suitable for in vivo studies, we performed whole-cell based high throughput screening of a library of small molecules available through the auspices of the National Institutes of Health. From the screening, we identified four distinct chemotypes (SF-11, SF-21, SF-31 and SF-41) that are novel, brain-penetrant, and selective against the NPY Y1 and 38 off-target receptors, including GPCRs, transporters and ion-channels.19 The four chemotypes (Figure 1) exhibited antagonism at the NPY Y2 receptor with IC50 values ranging from 0.19 to 4.4 μM. The hits are being followed up to further improve the potency, brain-penetration and drug-likeness. Here, we report the synthesis and SAR investigations of one of the hit molecules SF-11.</p><p>The hit molecule SF-11 was divided into three parts A (phenyl ring), B (diphenylcarbinol) and C (linker) to explore the SAR systematically (Figure 1). The preliminary SAR, observed from a tiny set of SF-11 analogues from the HTS campaign, indicated that the NPY Y2 antagonist activity may depend on both the position and type of the substituent present on the phenyl ring (A).19 Therefore, we have primarily explored the substitution on the aryl ring (A). The desired analogues (1–30, Table 1) were prepared by the coupling of commercially available α,α-diphenylpiperidino-4-methanol with a variety of aryl isothiocyanates (Scheme 1). The non-commercially available aryl isothiocyanates were prepared from appropriate anilines and thionating reagent di-2-pyridyl thionocarbonate.20 All compounds were determined to be >95% pure by 1H NMR and LC-MS.21 The compounds were tested against NPY Y2 and Y1 receptors using the cAMP biosensor assay as previously described.19 The activity data is presented in Table 1.</p><p>To determine the minimal structural requirements for the antagonist activity, the ethoxy group of the hit molecule SF-11 was removed as exemplified by 1, which resulted in complete loss of activity, suggesting a substitution on the aryl ring is essential. The replacement of the ethoxy group with a methoxy (2), isopropoxy (3) or trifluoromethoxy (4) resulted in decreased potency, which indicates the presence of a hydrophobic pocket with steric-constraints at the binding site. Interestingly, the n-propyl analogue 5 was less potent than the ethoxy analogue SF-11, suggesting the presence of both a hydrogen-bond acceptor and optimal hydrophobic group at this position would improve the antagonist activity. We have consequently investigated a variety of hydrogen-bond acceptor containing groups such as dialkylamines, esters, carboxamides, and sulfonamides. The diethylamine analogue 8 showed nearly 3-fold increase in the potency compared to SF-11. The dimethyl amine analogue 7, as well as cyclic amines 9 and 10 were less potent than the diethyl amine analogue 8 and SF-11, corroborating the SAR. The ethyl ester analogue 11 and ethyl amide analogue 13 exhibited similar potency to SF-11. The N,N-dialkylamide analogues 14 and 15 were more potent than the monoalkylamides 12 and 13, of which N,N-diethylamide analogue 15 was 4-fold more potent than N,N-dimethylamide analogue 14. In contrast to N,N-dialkylamide analogues 14 and 15, N,N-dimethyl sulfonamide analogue 16 (CYM 9484) displayed higher potency (IC50 = 19 nM) than N,N-diethyl sulfonamide analogue 17 and was 10-fold more potent than the hit molecule SF-11.</p><p>The importance of the position of the substituent on the phenyl ring (A) was studied subsequently. The 3-substituted analogues 20 and 21 were less potent than the corresponding 4-substituted analogues 2 and 6, except compound 22 which displayed similar potency to 11, but exhibited partial antagonism. To understand the effect of an additional substituent on the antagonist activity, we also explored 3, 4- and 2, 4-disubstitutions on the phenyl ring (A) as exemplified by 23–30. The chloro (24) and cyano (25 and 26) groups were tolerated at the 3-position, but did not improve the potency significantly compared to the corresponding 4-substittuted analogues 8, SF-11 and 3. The incorporation of methyl (27), trifluoromethyl (28) and chloro (29) groups at the 2-position resulted in complete loss of activity, whereas the fluoro (30) group was tolerable, but nearly 7-fold less potent than the corresponding analogue SF-11. The SAR exploration of groups on phenyl ring (A) suggests that a substitution at the 4-position of phenyl ring is important for antagonist activity, of which the N,N-dimethyl sulfonamide group is optimal.</p><p>We then performed SAR studies on the diphenylcarbinol (B) of the hit molecule (Table 2). The removal of either one of the phenyl rings (31) or hydroxyl group of the diphenylcarbinol (34–36) was detrimental to the activity. The hydroxyl group was methylated to identify the necessity of a hydrogen-bond donor for the antagonist activity. The methylated analogue 35 displayed no activity, signifying the essentiality of a hydrogen-bond donor. Interestingly, the piperazine analogue 36 retained the activity in contrast to the piperidine analogue 32, supporting the requirement of a hydrogen-bond donor. Subsequently, we focused our efforts on modification of one of the phenyl rings of the diphenylcarbinol. The replacement of one of the phenyl rings with a cyclohexyl group (38) resulted in complete loss of activity. The heteroaryl analogues such as pyridin-2-yl 40 and thiophen-3-yl 41 were tolerable, whereas the furan-3-yl 42, 3-pyridin-3-yl 39 and 3,5-dimethylisoxazol-4-yl 43 analogues significantly lost the activity. The substitution of a fluorine at the 4-position (44) of one of the phenyl rings of diphenylcarbinol was tolerable, but not beneficial. We also explored the conformationally-constrained tricyclic moieties as exemplified by 45 and 46 to investigate the conformational requisite of the phenyl rings of diphenylcarbinol. Notably, the dibenzoazepinone analogue 46 displayed higher potency than the corresponding analogue 37, whereas the less-constrained tricyclic analogue 45 was inactive. The SAR studies of part B of the hit molecule suggest that a hydrogen-bond donor and the conformation of phenyl rings of diphenylcarbinol are important for the antagonist activity.</p><p>The synthesis of analogues 32–34 was carried out as shown in scheme 2. Dehydration of commercially available α,α-diphenylpiperidino-4-methanol using TFA gave the 4-(diphenylmethylene)piperidine, which was then reduced with trimethyl silane to yield the 4-benzhydrylpiperidine. Both, 4-(diphenylmethylene)piperidine and 4-benzhydrylpiperidine were coupled with aryl isothiocyanates to yield the target compounds 32–34.</p><p>The synthesis of analogues 38–44 is outlined in scheme 3. The addition of cyclohexyl or various heteroaryl groups to the benzyl or ethyl-4-benzoylpiperidine-1-carboxylate was achieved by reacting with cyclohexylmagnesium bromide or heteroaryl lithiums that were generated in situ by treating the appropriate heteroaryl bromides with n-BuLi. The resulting benzyloxycarbonyl- or ethoxycarbonyl- protected 4-bis-arylcarbinolpiperidines, after deprotection by hydrogenation using Pd/C or basic conditions using K2CO3, were reacted with appropriate aryl isothiocyanates to afford the target compounds.</p><p>Compound 46 was prepared according to the scheme 4. The anthraquinone was transformed into 5H-dibenzo[b,e]azepine-6,11-dione22 (47), by treating with conc. H2SO4 and NaN3, which was then reduced to the alcohol 48 with sodium borohydride in MeOH. The resulting alcohol 48 was converted into the chloro derivative, 11-chloro-5H-dibenzo[b,e]azepin-6(11H)-one (49) by refluxing in thionyl chloride. The chloro group of the corresponding compound was displaced with piperazine using microwave irradiation to obtain 11-piperazin-1-yl-5,11-dihydrodibenzo[b,e]azepine-6-one (50), which was subsequently reacted with 4-isothiocyanato-N,N-dimethylbenzenesulfonamide to afford the desired compound 46. Compound 45 was prepared similarly to compound 46, starting from commercially available 5-chloro-10,11-dihydro-5H-dibenzo[a,d][7]annulene.</p><p>We subsequently modified the thiourea linker (C) of the hit molecule by replacing it with urea and carbamate functionalities. A variety of urea derivatives (not shown) that had different groups at 4-position of phenyl ring (A) were prepared and found to be inactive at 10 μM. Notably, the carbamate linker was very well tolerated (Table 3). In the carbamate series, we explored the groups that were good in the thiourea series at the 4-position of phenyl ring (A). In contrast to the thiourea series, the N,N-diethylsulfonamide analogue 54 (CYM 9552) was more potent (IC50 = 12 nM) than its corresponding N,N-dimethylsulfonamide analogue 53. The N,N-diethylamide analogue 60 was 18-fold less potent than the N,N-diethyl sulfonamide analogue 54. We also explored sulfones 56–59 at the 4-position, which displayed similar potency to the corresponding sulfonamide analogues 53 and 54. While the reverse sulfonamide analogue 63 retained the antagonist activity, the reverse carboxamide analogues 61 and 62 completely lost the activity. The 3-substituted analogues 64 and 65 displayed no activity, which suggests that in both the carbamate and thiourea series the substitution at the 4-position of phenyl ring (A) is important for the antagonist activity.</p><p>The carbamate analogues 51–65 were prepared by reacting the α,α-diphenylpiperidino-4-methanol with aryl chloroformates, obtained from the reaction of phenols with triphosgene, in the presence of iPr2EtN. The non-commercially available phenols were prepared by conversion of the appropriate aryl fluoride into the corresponding phenol with 2-butyn-1-ol and potassium tert-butoxide in DMSO (Scheme 5).23</p><p>In summary, we systematically explored the SAR of the hit molecule SF-11 that led to the identification of selective and highly potent small molecule NPY Y2 receptor antagonists 16 (CYM 9484; IC50=19 nM) and 54 (CYM 9552; IC50=12 nM). The investigation of in vivo PK and further lead optimization of the series of compounds will be reported in due course.</p>",
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"content": "Highly potent and selective small molecule Neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC50 values of 19 nM and 12 nM respectively.",
"role": "assistant"
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science.healthver_entailment | science.healthver_entailment.3504 | [
{
"content": "Evaluate the given public health statement using the provided research abstract. Your goal is to determine the relationship between the claim and the abstract content.\n\n- \"decision\": Indicate whether the abstract \"SUPPORTS\", \"CONTRADICTS\", or provides \"INSUFFICIENT\" information regarding the claim.\n- \"justification\": List sentences from the abstract that back your decision. If the decision is \"INSUFFICIENT\", leave this list empty.\n\nStatement: There's a Mountain of Evidence That Hydroxychloroquine Is an Effective Treatment for COVID-19\n\nResearch Abstract:\nBackground: There is no effective therapy for COVID-19.\nHydroxychloroquine (HCQ) and chloroquine (CQ) have been used for its treatment but their safety and efficacy remain uncertain.\nObjective: We performed a systematic review to synthesize the available data on the efficacy and safety of CQ and HCQ for the treatment of COVID-19.\nMethods: Two reviewers searched for published and pre-published relevant articles between December 2019 to 8th June 2020.\nThe data from the selected studies were abstracted and analyzed for efficacy and safety outcomes.\nCritical appraisal of the evidence was done by Cochrane risk of bias tool and Newcastle Ottawa scale.\nThe quality of evidence was graded as per the GRADE approach.\nResults: We reviewed 12 observational and 3 randomized trials which included 10659 patients of whom 5713 received CQ/HCQ and 4966 received only standard of care.\nThe efficacy of CQ/HCQ for COVID-19 was inconsistent across the studies.\nMeta-analysis of included studies revealed no significant reduction in mortality with HCQ use [RR 0.98 95% CI 0.66-1.46] , time to fever resolution [mean difference -0.54 days (-1.19-011)] or clinical deterioration/development of ARDS with HCQ [RR 0.90 95% CI 0.47-1.71].\nThere was a higher risk of ECG abnormalities/arrhythmia with HCQ/CQ [RR 1.46 95% CI 1.04 to 2.06].\nThe quality of evidence was graded as very low for these outcomes.\nConclusions: The available evidence suggests that CQ or HCQ does not improve clinical outcomes in COVID-19.\nWell-designed randomized trials are required for assessing the efficacy and safety of HCQ and CQ for COVID-19.",
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"content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"Conclusions: The available evidence suggests that CQ or HCQ does not improve clinical outcomes in COVID-19.\"]}",
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science.chia_ner | science.chia_ner.1202 | [
{
"content": "Analyze the provided clinical trial criteria. Identify and extract distinct entities from the text.\n\nReturn the results as a JSON structure. Ensure the output is strictly in JSON format without any additional commentary.\n\nCriteria Text:\n\nPatients with liver cirrhosis, Hepatocellular Carcinoma or AFP >2 ULN or other malignancies.\nPatients with other factors causing liver diseases.\nPregnant and lactating women.\nPatients with concomitant HIV infection or congenital immune deficiency diseases.\nPatients with diabetes, autoimmune diseases.\nPatients with important organ dysfunctions.\nPatients with serious complications (e.g., infection, hepatic encephalopathy, hepatorenal syndrome, gastrointestinal bleeding.)\nPatients who receive antineoplastic or immunomodulatory therapy in the past 12 months.\nPatients with a previous use of IFN anti hepatitis B virus treatment or have NAs drug resistance.\nPatients who can't come back to clinic for follow-up on schedule.",
"role": "user"
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"content": "{\"Condition\": [\"Hepatocellular Carcinoma\", \"malignancies\", \"hepatorenal syndrome\", \"hepatic encephalopathy\", \"liver cirrhosis\", \"infection\", \"liver diseases\", \"organ dysfunctions\", \"gastrointestinal bleeding\", \"resistance\", \"HIV infection\", \"complications\", \"diabetes\", \"congenital immune deficiency diseases\", \"autoimmune diseases\"], \"Device\": [], \"Drug\": [\"IFN\", \"NAs drug\"], \"Measurement\": [\"AFP\"], \"Mood\": [], \"Multiplier\": [], \"Negation\": [], \"Observation\": [], \"Person\": [], \"Procedure\": [\"immunomodulatory therapy\", \"plastic or imm in th\"], \"Qualifier\": [\"serious\", \"important\", \"concomitant\", \"anti hepatitis B virus\"], \"ReferencePoint\": [], \"Scope\": [\"antineoplastic or immunomodulatory therapy\", \"infection, hepatic encephalopathy, hepatorenal syndrome, gastrointestinal bleeding\"], \"Temporal\": [\"past 12 months\"], \"Value\": [\"\\u003e2 ULN\"], \"Visit\": []}",
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science.craftchem_ner | science.craftchem_ner.3433 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nComparisonofDandEproviderepresentativeexamplesthatillustratethatpMAPKisfoundinonlyasubsetofallproliferating(Ki67-positive)cells.",
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"content": "[]",
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science.data_reco_mcq_sc | science.data_reco_mcq_sc.6147 | [
{
"content": "Explore the following research question and associated terms. Identify the most suitable dataset from the list provided. Use the dataset descriptions to guide your choice.\n\nInquiry: In this paper, we introduce a novel feature selection method, based on saliency-based feature selection. Our\n\nKeywords: feature selection text\n\nDataset Information:\nDeep Fashion3D: A novel benchmark and dataset for the evaluation of image-based garment reconstruction systems. Deep Fashion3D contains 2078 models reconstructed from real garments, which covers 10 different categories and 563 garment instances.\nAND Dataset: The AND Dataset contains 13700 handwritten samples and 15 corresponding expert examined features for each sample. The dataset is released for public use and the methods can be extended to provide explanations on other verification tasks like face verification and bio-medical comparison.\nCIFAR-10: The CIFAR-10 dataset (Canadian Institute for Advanced Research, 10 classes) is a subset of the Tiny Images dataset and consists of 60000 32x32 color images. The images are labelled with one of 10 mutually exclusive classes: airplane, automobile (but not truck or pickup truck), bird, cat, deer, dog, frog, horse, ship, and truck (but not pickup truck).\nSelQA: SelQA is a dataset that consists of questions generated through crowdsourcing and sentence length answers that are drawn from the ten most prevalent topics in the English Wikipedia.\n\nAvailable Datasets: A: Deep Fashion3D B: AND Dataset C: CIFAR-10 D: SelQA",
"role": "user"
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{
"content": "CIFAR-10",
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.3940 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nIn this note we consider setups in which variational objectives for Bayesian neural networks can be computed in closed form. In particular we focus on single-layer networks in which the activation function is piecewise polynomial (e.g. ReLU). In this case we show that for a Normal likelihood and structured Normal variational distributions one can compute a variational lower bound in closed form. In addition we compute the predictive mean and variance in closed form. Finally, we also show how to compute approximate lower bounds for other likelihoods (e.g. softmax classification). In experiments we show how the resulting variational objectives can help improve training and provide fast test time predictions.\n\nCited Works Summary:\n[1]: Bernoulli-logistic latent Gaussian models (bLGMs) are a useful model class, but accurate parameter estimation is complicated by the fact that the marginal likelihood contains an intractable logistic-Gaussian integral. In this work, we propose the use of fixed piecewise linear and quadratic upper bounds to the logistic-log-partition (LLP) function as a way of circumventing this intractable integral. We describe a framework for approximately computing minimax optimal piecewise quadratic bounds, as well a generalized expectation maximization algorithm based on using piecewise bounds to estimate bLGMs. We prove a theoretical result relating the maximum error in the LLP bound to the maximum error in the marginal likelihood estimate. Finally, we present empirical results showing that piece-wise bounds can be significantly more accurate than previously proposed variational bounds.",
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"content": "The approach most closely related to ours is probably the deterministic approximations in ref. (indeed they compute some of the same ReLU integrals that we do). While we focus on single-layer neural networks, the distinct advantage of their approximation scheme is that it can be applied to networks of arbitrary depth. Thus some of our results are potentially complementary to theirs. Reference also constructs deterministic variational objectives for the specific case of the ReLU activation function. Reference [1] considers quadratic piecewise linear bounds for the logistic-log-partion function in the context of Bernoulli-logistic latent Gaussian models. Finally, approaches for variance reduction in the stochastic variational inference setting include and .",
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science.craftchem_ner | science.craftchem_ner.4465 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nIntheadultCNS,thesubcellulardistributionofAnnexinA7dependsonthecelltype.",
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{
"content": "[]",
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science.scientific_papers_summarization_single_doc_pubmed | science.scientific_papers_summarization_single_doc_pubmed.6334 | [
{
"content": "Read the provided biomedical research paper and create a concise abstract. Ensure the abstract captures the main points of the paper.\n\nFull Paper:\nicu = intensive care unit ; ifn = interferon ; il = interleukin ; lps = lipopolysaccharide ; pcr = polymerase chain reaction ; tlr = toll - like receptor ; tnf = tumour necrosis factor .\nhg , te , and sf planned , drafted , read , and approved the final manuscript .\nthis article is part of a review series on infection , edited by steven opal .",
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"content": "international guidelines concerning the management of patients with sepsis , septic shock and multiple organ failure make no reference to the nature of the infecting organism . indeed \n , most clinical signs of sepsis are nonspecific . in contrast , in vitro data suggest that there are mechanistic differences between bacterial , viral and fungal sepsis , and imply that pathogenetic differences may exist between subclasses such as gram - negative and gram - positive bacteria . \n these differences are reflected in different cytokine profiles and mortality rates associated with gram - positive and gram - negative sepsis in humans . \n they also suggest that putative anti - mediator therapies may act differently according to the nature of an infecting organism . \n data from some clinical trials conducted in severe sepsis support this hypothesis . \n it is likely that potential new therapies targeting , for example , toll - like receptor pathways will require knowledge of the infecting organism . \n the advent of new technologies that accelerate the identification of infectious agents and their antimicrobial sensitivities may allow better tailored anti - mediator therapies and administration of antibiotics with narrow spectra and known efficacy .",
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science.scitldr_aic | science.scitldr_aic.352 | [
{
"content": "Review the provided sections from a computer science paper and distill the primary contribution into a single sentence. Provide only the summary sentence.\n\nSections:\n\nData augmentation (DA) is fundamental against overfitting in large convolutional neural networks, especially with a limited training dataset.\nIn images, DA is usually based on heuristic transformations, like geometric or color transformations.\nInstead of using predefined transformations, our work learns data augmentation directly from the training data by learning to transform images with an encoder-decoder architecture combined with a spatial transformer network.\nThe transformed images still belong to the same class, but are new, more complex samples for the classifier.\nOur experiments show that our approach is better than previous generative data augmentation methods, and comparable to predefined transformation methods when training an image classifier.\nConvolutional neural networks have shown impressive results in visual recognition tasks.\nHowever, for proper training and good performance, they require large labeled datasets.\nIf the amount of training data is small, data augmentation is an effective way to improve the final performance of the network BID6 ; BID9 ).\nIn images, data augmentation (DA) consists of applying predefined transformations such as flip, rotations or color changes BID8 ; BID3 ).\nThis approach provides consistent improvements when training a classifier.\nHowever, the required transformations are dataset dependent.\nFor instance, flipping an image horizontally makes sense for natural images, but produces ambiguities on datasets of numbers (e.g. 2 and 5).Several\nrecent studies investigate automatic DA learning as a method to avoid the manual selection of transformations. BID10 define\na large set of transformations and learn how to combine them. This approach\nworks well however, as it is based on predefined transformations, it prevents the model from finding other transformations that could be useful for the classifier. Alternatively\n, BID2 and BID12 generate new samples via a generative adversarial networks model (GAN) from the probability distribution of the data p(X), while BID0 learn the transformations of images, instead of generating images from scratch. These alternative\nmethods show their limits when the number of training samples is low, given the difficulty of training a high-performing generative model with a reduced dataset. BID5 learn the natural\ntransformations in a dataset by aligning pairs of samples from the same class. This approach produces\ngood results on easy datasets like MNIST however, it does not appear to be applicable to more complex datasets.Our work combines the advantages of generative models and transformation learning approaches in a single end-to-end network architecture. Our model is based on\na conditional GAN architecture that learns to generate transformations of a given image that are useful for DA. In other words, instead\nof learning to generate samples from p(X), it learns to generate samples from the conditional distribution p(X|X), withX a reference image. As shown in FIG0 , our\napproach combines a global transformation defined by an affine matrix with a more localized transformation defined by ensures that the transformed sample G(x i , z) is dissimilar from the input sample x i but similar to a sample x j from the same class. (b) Given an input image\nx i and a random noise vector z, our generator first performs a global transformation using a spatial transformer network followed by more localized transformations using a convolutional encoder-decoder network.a convolutional encoder-decoder architecture. The global transformations\nare learned by an adaptation of spatial transformer network (STN) BID7 ) so that the entire architecture is differentiable and can be learned with standard back-propagation. In its normal use, the purpose\nof STN is to learn how to transform the input data, so that the model becomes invariant to certain transformations. In contrast, our approach uses\nSTN to generate augmented samples in an adversarial way. With the proposed model we show\nthat, for optimal performance, it is important to jointly train the generator of the augmented samples with the classifier in an end-to-end fashion. By doing that, we can also add\nan adversarial loss between the generator and classifier such that the generated samples are difficult, or adversarial, for the classifier.To summarize, the contributions of this paper are: i) We propose a DA network that\ncan automatically learn to generate augmented samples without expensive searches for the optimal data transformations; ii) Our model trains jointly with\na classifier, is fully differentiable, trainable end-to-end, and can significantly improve the performance of any image classifier; iii) In low-data regime it outperforms\nmodels trained with strong predefined DA; iv) Finally, we notice that, for optimal\nperformance, it is fundamental to train the model jointly with the image classifier.\nIn this work, we have presented a new approach for improving the learning of a classifier through an automatic generation of augmented samples.\nThe method is fully differentiable and can be learned end-to-end.\nIn our experiments, we have shown several elements contributing to an improved classification performance.\nFirst, the generator and the classifier should be trained jointly.\nSecond, the combined use of global transformations with STN and local transformation with U-Net is essential to reach the highest accuracy levels.\nFor future work, we want to include more differentiable transformations such as deformations and color transformations and evaluate how these additional sample augmentations affect the final accuracy.",
"role": "user"
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"content": "Automatic Learning of data augmentation using a GAN based architecture to improve an image classifier",
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science.data_reco_mcq_sc | science.data_reco_mcq_sc.9019 | [
{
"content": "Explore the following research question and associated terms. Identify the most suitable dataset from the list provided. Use the dataset descriptions to guide your choice.\n\nInquiry: A deep ensemble-based method for object detection, where an adversarial learning strategy is proposed to optimize the\n\nKeywords: object detection images\n\nDataset Information:\nREDS: The realistic and dynamic scenes (REDS) dataset was proposed in the NTIRE19 Challenge. The dataset is composed of 300 video sequences with resolution of 720×1,280, and each video has 100 frames, where the training set, the validation set and the testing set have 240, 30 and 30 videos, respectively\nAPRICOT: APRICOT is a collection of over 1,000 annotated photographs of printed adversarial patches in public locations. The patches target several object categories for three COCO-trained detection models, and the photos represent natural variation in position, distance, lighting conditions, and viewing angle.\nImageNet: The ImageNet dataset contains 14,197,122 annotated images according to the WordNet hierarchy. Since 2010 the dataset is used in the ImageNet Large Scale Visual Recognition Challenge (ILSVRC), a benchmark in image classification and object detection.\nUNSW-NB15: UNSW-NB15 is a network intrusion dataset. It contains nine different attacks, includes DoS, worms, Backdoors, and Fuzzers.\n\nAvailable Datasets: A: REDS B: APRICOT C: ImageNet D: UNSW-NB15",
"role": "user"
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{
"content": "ImageNet",
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science.scientific_lay_summarisation_elife_single_doc_summ | science.scientific_lay_summarisation_elife_single_doc_summ.1953 | [
{
"content": "Transform the provided sections of a biomedical research paper into a digestible summary for a general audience. Focus on simplifying complex ideas while retaining key scientific insights.\n\nResearch Title: Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development\nContent Overview:\nAbstract:\nThe origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins. Throughout renal organogenesis, most kidney macrophages are perivascular and express F4/80 and CD206. These macrophages are enriched for mRNAs linked to developmental processes, such as blood vessel morphogenesis. Using antibody-mediated macrophage-depletion, we show macrophages support vascular anastomoses in cultured kidney explants. We also characterise a subpopulation of galectin-3+( Gal3+) myeloid cells within the developing kidney. Our findings may stimulate research into macrophage-based therapies for renal developmental abnormalities and have implications for the generation of bioengineered kidney tissues.\nIntroduction:\nMacrophages are professional phagocytes with roles in tissue development, immunity, regeneration, remodelling, and repair( Bosurgi et al., 2017; Eom and Parichy, 2017; Godwin et al., 2013; Stamatiades et al., 2016). In the adult kidney, macrophages can cause, prevent, and repair damage( Cao et al., 2015; Rogers et al., 2014). During organogenesis, evidence suggests that macrophages promote kidney growth( Alikhan et al., 2011; Rae et al., 2007), but details regarding their developmental localisation and functions are lacking. Characterising the roles for kidney macrophages may lead to the development of macrophage-based strategies to enhance renal maturation in cases of developmental abnormalities and premature birth. Kidney development begins when the caudal Wolffian duct is induced to branch, forming a ureteric bud that invades the metanephric mesenchyme by embryonic day( E) 11 in the mouse( Pichel et al., 1996; Saxén and Sariola, 1987). The ureteric bud undergoes rounds of iterative branching to form the adult collecting duct tree, while cells endogenous to the metanephric mesenchyme generate nephrons and stroma( Grobstein, 1955; Kobayashi et al., 2008; Epelman et al., 2014; Shakya et al., 2005; Short et al., 2014). Other kidney cell types, such as monocytes, macrophages, and most endothelial cells, derive from extra-renal sources( Epelman et al., 2014; Hoeffel et al., 2015; DeFalco et al., 2014; Sequeira-Lopez et al., 2015; Sims-Lucas et al., 2013). In embryonic development, macrophage progenitors arrive in organs in waves. The first wave is generated from yolk sac-derived primitive macrophage progenitors( Palis et al., 1999; Schulz et al., 2012), the second from yolk sac-derived erythro-myeloid progenitors( EMPs) that migrate and colonise the fetal liver( Hoeffel et al., 2015; Rantakari et al., 2016), and the third from haematopoietic stem cells( HSCs) that emerge in the aorta-gonad-mesonephros region( Medvinsky and Dzierzak, 1996; Sheng et al., 2015). Unlike yolk sac-derived primitive macrophage progenitors, both HSCs and EMPs in the foetal liver are thought to pass through a monocytic intermediate phase before differentiating into mature macrophages( Hoeffel et al., 2015; Hoeffel and Ginhoux, 2018; Schulz et al., 2012). Lineage tracing studies in mice suggest that kidney macrophages are initially derived from the yolk sac but are derived almost exclusively from foetal monocytes after birth( Epelman et al., 2014; Hoeffel et al., 2015; Munro and Hughes, 2017; Sheng et al., 2015). In the adult, macrophages and endothelial cells form anatomical and functional units that function to clear immune complexes from the renal blood( Stamatiades et al., 2016). In development, kidney macrophages closely associate with the epithelial tubules of nephrons( Rae et al., 2007), but their interactions with vascular endothelial cells have not been examined. In recent years, kidney vascularisation has been a focus of renal developmental research( Daniel et al., 2018; Halt et al., 2016; Hu et al., 2016; Munro et al., 2017a; Munro et al., 2017b); however, possible roles for macrophages in this process remain unexplored. We show that macrophages in the embryonic kidney restrict the early domain of nephron progenitor cells, frequently interact with blood vessels, are enriched for mRNAs linked to vascular development, and promote endothelial cross-connections.\nDiscussion:\nIn this report, we characterised macrophage arrival, localisation, and heterogeneity in the developing mouse kidney and show that macrophages support the assembly of the kidney and its vasculature. Kidneys depleted of macrophages contained discontinuous endothelial structures, while control-treated kidneys had characteristic net-like vascular plexuses. These data are consistent with macrophages having the capacity to promote vascular anastomoses, as has been described in other biological settings( Fantin et al., 2010; Liu et al., 2016). Blood vessels provide developing organs with oxygen and essential nutrients to promote growth( Chung and Ferrara, 2011). Studies have linked foetal macrophages with enhanced branching morphogenesis, nephrogenesis, and growth during kidney development( Alikhan et al., 2011; Rae et al., 2007; Sauter et al., 2014) and our results showing macrophages promote renal vascularisation may partly explain these links. While we demonstrate a close relationship between macrophages and developing renal blood vessels, important questions remain to be addressed. Future studies should examine the specific mechanisms by which macrophages mediate kidney vascularisation and should explore other potential roles for renal perivascular macrophages in the embryo. In the adult kidney, perivascular macrophages survey vascular transport for small immune complexes( Stamatiades et al., 2016). As the embryo is thought to be relatively sterile( Tissier, 1900), there are likely few immune complexes transported via the vasculature during development, but perivascular macrophages may nevertheless survey the bloodstream for factors such as maternal-derived antibodies that have crossed the placental barrier( Morphis and Gitlin, 1970). Further, we demonstrated that macrophages can engulf erythrocytes in the developing kidney, suggesting a possible role for renal perivascular macrophages in clearing cells carried via the vasculature. One way that macrophages shape developing tissues is via their roles in cell clearance( Wood and Martin, 2017); for example, macrophages clear excess neurons in the developing brain and spinal cord( Cuadros et al., 1993) and engulf dying cells in embryonic footplates to facilitate digit formation( Wood et al., 2000). Our findings indicate that macrophages play a similar role at the beginning of kidney organogenesis, as they prune the rostral domain of the early nephron progenitor population. Our study failed, however, to expose the precise mechanism( s) by which rostral nephron progenitors are cleared. We observed Six2+ nuclei of rostral nephron progenitors within the cell bodies of some macrophages, suggesting active phagocytosis of these cells, but it is unclear whether other mechanisms also contribute to their clearance; for instance, macrophages may generate signals and/or act as cellular chaperones to promote the caudal migration of these cells. A trophic role for macrophages in kidney development was first suggested by Rae et al., 2007, who demonstrated that treating cultured kidney explants with Csf1, a macrophage mitogen, results in enhanced renal growth and branching morphogenesis associated with increased macrophage numbers. Along with this finding, studies in the postnatal mouse revealed that increased activation of the Csf1/Csf1r pathway results in increased kidney weight and volume( Alikhan et al., 2011), whereas blockade of this pathway in the adult results in reduced kidney weight( Sauter et al., 2014). Our results add to these findings by showing that, in the absence of macrophages in vivo, the beginning of kidney development is delayed. Collectively, these studies suggest that macrophages act to enhance growth and maturation of renal tissue across the lifespan. The growth and maturation of renal organoids using current differentiation protocols is limited. Since blood vessels and phagocytic cells are important for renal organogenesis( Alikhan et al., 2011; Rae et al., 2007; Sauter et al., 2014), our results may have significant implications for the generation of kidney organoids. Endothelial cells, monocytes, and macrophages are thought to arrive in the developing kidney from extra-renal sources( Hoeffel et al., 2015; Kobayashi et al., 2014) and future studies might usefully compare organoid maturation when macrophages and blood vessels are exogenously added to these systems. In conclusion, we show that foetal kidney macrophages are a multifunctional cell type that frequently interact with newly forming renal blood vessels and encourage organogenesis. These results may inform future macrophage-based strategies for the prevention and treatment of neonatal and adult kidney diseases.",
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"content": "The kidneys clean our blood by filtering out waste products while ensuring that useful components , like nutrients , remain in the bloodstream . Blood enters the kidneys through a network of intricately arranged blood vessels , which associate closely with the ‘cleaning tubes’ that carry out filtration . Human kidneys start developing during the early phases of embryonic development . During this process , the newly forming blood vessels and cleaning tubes must grow in the right places for the adult kidney to work properly . Macrophages are cells of the immune system that clear away foreign , diseased , or damaged cells . They are also thought to encourage growth of the developing kidney , but how exactly they do this has remained unknown . Munro et al . therefore wanted to find out when macrophages first appeared in the embryonic kidney and how they might help control their development . Experiments using mice revealed that the first macrophages arrived in the kidney early during its development , alongside newly forming blood vessels . Further investigation using genetically modified mice that did not have macrophages revealed that these immune cells were needed at this stage to clear away misplaced kidney cells and help ‘set the scene’ for future development . At later stages , macrophages in the kidney interacted closely with growing blood vessels . As well as producing molecules linked with blood vessel formation , the macrophages wrapped around the vessels themselves , sometimes even eating cells lining the vessels and the blood cells carried within them . These observations suggested that macrophages actively shaped the network of blood vessels developing within the kidneys . Experiments removing macrophages from kidney tissue confirmed this: in normal kidneys , the blood vessels grew into a continuous network , but in kidneys lacking macrophages , far fewer connections formed between the vessels . This work sheds new light on how the complex structures in the adult kidney first arise and could be useful in future research . For example , adding macrophages to simplified , laboratory-grown ‘mini-kidneys’ could make them better models to study kidney growth , while patients suffering from kidney diseases might benefit from new drugs targeting macrophages .",
"role": "assistant"
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science.scicite_classification | science.scicite_classification.261 | [
{
"content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nReports of use of other multikinase inhibitors in sarcoma such as imatinib have not been very encouraging [22] or restricted to a smaller patient sub-population such as use of crizotinib in ALK driven tumors [23].",
"role": "user"
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{
"content": "Background",
"role": "assistant"
}
]
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science.bioasq_factoid_qa | science.bioasq_factoid_qa.951 | [
{
"content": "Given the following biomedical passages, answer the question succinctly. Ensure your response is precise and limited to the answer only.\n\nQuestion: Which type of cells protect Haematopoietic stem and progenitor cells (HSPCs) from ultraviolet-light-induced DNA damage in aquatic vertebrates?\n\nPassages: Haematopoietic stem and progenitor cells (HSPCs) require a specific microenvironment, the haematopoietic niche, which regulates HSPC behaviour1,2. The location of this niche varies across species, but the evolutionary pressures that drive HSPCs to different microenvironments remain unknown. The niche is located in the bone marrow in adult mammals, whereas it is found in other locations in non-mammalian vertebrates, for example, in the kidney marrow in teleost fish. Here we show that a melanocyte umbrella above the kidney marrow protects HSPCs against ultraviolet light in zebrafish. Because mutants that lack melanocytes have normal steady-state haematopoiesis under standard laboratory conditions, we hypothesized that melanocytes above the stem cell niche protect HSPCs against ultraviolet-light-induced DNA damage. Indeed, after ultraviolet-light irradiation, unpigmented larvae show higher levels of DNA damage in HSPCs, as indicated by staining of cyclobutane pyrimidine dimers and have reduced numbers of HSPCs, as shown by cmyb (also known as myb) expression. The umbrella of melanocytes associated with the haematopoietic niche is highly evolutionarily conserved in aquatic animals, including the sea lamprey, a basal vertebrate. During the transition from an aquatic to a terrestrial environment, HSPCs relocated into the bone marrow, which is protected from ultraviolet light by the cortical bone around the marrow. Our studies reveal that melanocytes above the haematopoietic niche protect HSPCs from ultraviolet-light-induced DNA damage in aquatic vertebrates and suggest that during the transition to terrestrial life, ultraviolet light was an evolutionary pressure affecting the location of the haematopoietic niche.",
"role": "user"
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{
"content": "melanocytes",
"role": "assistant"
}
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science.medmentions_ner | science.medmentions_ner.1787 | [
{
"content": "Analyze the provided paragraph from a scientific document. Your goal is to identify and extract relevant entities.\n\nFormat your findings as a JSON object, where each key represents a category of entities, and the corresponding value is a list of entities identified in that category. If no entities are found for a category, return an empty list.\n\nFocus on precision and ensure that the output is strictly in JSON format.\n\nDocument:\n\nResults of a Single Institution Experience with Dose-Escalated Chemoradiation for Locally Advanced Unresectable Non-Small Cell Lung Cancer We determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose-escalated chemoradiotherapy at the University of Pittsburgh Lung Cancer Program. The records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received four-dimensional CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log-rank and Cox regression analysis. For the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2- and 4- year OS was 56.0 and 30.7%, respectively. The 4- year LRC and FFDM were 43.9 and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in OS (p = 0.586), LRC (p = 0.440), or FFDM (p = 0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p = 0.037), planning target volume (PTV) over 450 cc (p < 0.001), heart V30 over 40% (p = -0.048), and esophageal mean dose over 20% (p = 0.024), V5 (p = -0.015), and V60 (p = -0.011). On multivariable analysis, PTV above 450 cc (52.2 vs. 25.3 months, p < 0.001) and esophageal V60 >20% (43.8 vs. 21.3 months, p = -0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5 and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V5 was ≤65 (7.4 vs. 23.8%, p = 0.03). Grade 2 or higher acute esophagitis was reduced if V60 ≤ 20% (62 vs. 81.3%, p = 0.018). The use of intensity-modulated radiation therapy was more frequent in stage IIIB compared to stage IIIA patients (56.5 vs. 39.5%, p = 0.048) and was associated with a higher lung V5 and V10. The outcomes of a program of dose-escalated chemoradiotherapy for unresectable stage IIIA and IIIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V60 and lung V5 were associated with lower morbidity and mortality.",
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{
"content": "{\"AnatomicalStructure\": [\"lung\", \"heart\"], \"Bacterium\": [], \"BiologicFunction\": [\"stage IIIA\", \"non-small cell lung cancer\", \"freedom from distant metastasis\", \"stage IIIB\", \"NSCLC\", \"Non-Small Cell Lung Cancer\", \"locoregional\", \"IIIB\", \"stage III NSCLC\", \"FFDM\", \"movement\", \"tumor\", \"esophagitis\"], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [], \"ClinicalAttribute\": [\"unresectable\", \"Unresectable\"], \"Eukaryote\": [], \"Finding\": [\"worse\", \"detected\"], \"Food\": [], \"HealthCareActivity\": [\"treated\", \"intensity-modulated radiation therapy\", \"follow-up\", \"Chemoradiation\", \"four-dimensional CT simulation scan\", \"chemoradiotherapy\"], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"Grade 2\", \"log-rank\", \"records\", \"Cox regression analysis\"], \"MedicalDevice\": [\"respiratory gating\"], \"Organization\": [], \"PopulationGroup\": [], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [\"retrospectively reviewed\", \"studies\"], \"SpatialConcept\": [\"Locally\", \"esophageal\"], \"Virus\": []}",
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science.bc7_litcovid_topic_classification | science.bc7_litcovid_topic_classification.2922 | [
{
"content": "Analyze the given paragraph from COVID-19 research. Determine the relevant topics discussed in the text. Your response should be a JSON array containing the identified topics. Ensure the output is a valid JSON array with no additional commentary.\n\nText:\n\nIn this paper, we considered a new mathematical model depicting the possibility of spread within a given general population. The model is constructed with five classes including susceptible, exposed, infected, recovered and deaths. We presented a detailed analysis of the suggested model including, the derivation of equilibrium points endemic and disease-free, reproductive number using the next generation matrix, the stability analysis of the equilibrium points and finally the positiveness of the model solutions. The model was extended to the concept of fractional differentiation to capture different memories including power law, decay and crossover behaviors. A numerical method based on the Newton was used to provide numerical solutions for different memories.",
"role": "user"
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{
"content": "[\"Epidemic Forecasting\"]",
"role": "assistant"
}
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science.scientific_lay_summarisation_plos_single_doc_summ | science.scientific_lay_summarisation_plos_single_doc_summ.15384 | [
{
"content": "Transform the following sections from a biomedical study into a simple summary for the general public. Focus on making the information accessible and easy to understand.\n\nResearch Heading: Causes and Consequences of Hyperexcitation in Central Clock Neurons\nContent:\nAbstract:\nHyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations( DLAMOs), have been observed in neurons of the suprachiasmatic nuclei( SCN), the site of the central mammalian circadian( ∼24-hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus.\nIntroduction:\nThe conventional theory of neuronal information processing is based on action potential( AP) firing[1],[2]. While signaling through APs is a ubiquitous form of neuronal communication throughout the nervous system, it is not the only mechanism through which neurons may signal. In particular, neurons that receive input that induces large inward currents( hyperexcitation) may display depolarization block, and be unable to fire APs due to voltage–gated sodium channel inactivation. For example, antipsychotic drugs can trigger depolarization block in midbrain dopamine neurons[3]–[5]. Depolarization block is also a feature of many mathematical models of neuronal dynamics[6],[7], including the canonical Hodgkin-Huxley[8] and Morris-Lecar[9] models. Furthermore, large inward currents can induce depolarized electrical states with low amplitude membrane oscillations( DLAMOs). Such depolarized states occur in intrinsically photosensitive retinal ganglion cells in the presence of bright light[10]. DLAMOs and depolarizing block occur spontaneously—not as the result of external stimulation—in neurons of the hypothalamic suprachiasmatic nuclei( SCN)[11]–[13]. Spontaneous depolarization block has also been reported in cerebellar nuclear neurons[14],[15]. These various depolarized states add complexity to the repertoire of neuronal communication. In the SCN, which function as the central mammalian circadian( ∼24-hour) pacemaker[16], depolarization block and DLAMOs occur only in a subset of SCN neurons and mostly during the latter half of the day[13]. Here, we study the ionic mechanisms that underlie these depolarized states in SCN neurons. We also seek to determine general principles for how neurons can spontaneously enter such states and the physiological role( s) they may play. Electrical activity of SCN neurons is not only important for sending timekeeping signals to other cells, but also for transmitting information from the external world to their intracellular molecular circadian clocks[17]. Thus, understanding the electrophysiology of SCN neurons is essential for understanding circadian timekeeping in mammals[18], and may also yield general insights into mechanisms for signaling from synapse to gene[19]. Our approach uses mathematical modeling in combination with experimental validation. We find that DLAMOs are caused by the interplay of L-type calcium and calcium-activated potassium( KCa) currents. During depolarized states, we predict that intracellular calcium concentration reaches high( but physiological) levels. We propose that these daily elevated calcium levels activate clock gene transcription during the day, which in turn increases the expression of KCa and potassium leak currents to hyperpolarize the membrane at dusk and night. We show that this additional feedback loop between membrane excitability and gene expression can promote rhythmicity of the intracellular circadian clock.\nDiscussion:\nPrevious studies have shown higher levels of Per1 expression in the SCN[36],[37] during the time of day when RMPs are more depolarized[38]. In this study we provide evidence that the depolarized RMPs reported in Belle et al.[13] correspond with high levels of steady-state intracellular calcium concentration that may be needed for activation of the Per1 gene through CREB[39],[40]. This is in line with Irwin and Allen[27], who show an increase in calcium levels in response to depolarization of SCN neurons, as well as Dolmetsch et al.[29], who show that high calcium levels are needed for CREB signaling. Further experimental work is needed to validate our predictions, including measurement of intracellular calcium levels in spontaneously depolarized SCN neurons and the specific levels of calcium needed to activate CREB signaling in these neurons. While the basic mechanism of circadian timekeeping in mammalian cells is a transcriptional-translational negative feedback loop, electrical activity has sometimes been considered part of the core timekeeping mechanism[41]–[43]. Our work generates the hypothesis that depolarized states in clock neurons are part of the intracellular timekeeping mechanism. Accordingly then, the molecular clock controls the transcription of potassium channels, which, when expressed, could take the electrical state of the neuron into and out of depolarization block or DLAMOs. Depolarized states trigger high calcium, which in turn triggers the transcription of Per1 and Per2. This hypothesis is consistent with and extends previously published data. In cerebellar granule cell cultures, Per1 expression was found to be dependent on the depolarization state of the neuron, and prevention of Ca2+ influx( by pharmacological blocking of voltage-gated calcium channels) reduced mPer1 induction[44]. Remarkably, cerebellar granule neurons also exhibit a spontaneous depolarized state at RMPs of −28 to 34 mV[14],[15]. In Drosophila, electrical silencing of pacemaker neurons stops the molecular clock[45],[46]. In SCN neurons, inhibiting Ca2+ influx[17] or CREB signaling[47] interferes with circadian rhythm generation. Here, we propose that in SCN neurons, calcium-activated potassium currents are diminished during the day, leading to higher calcium levels and more expression of PER1/PER2 at the expected phase. In addition, CREB is known to positively regulate large-conductance KCa( BK) channel expression in Drosophila[48], providing another potential mechanism for feedback. Mathematical modeling is an established tool for understanding the complex interaction of neuronal ion channels and calcium dynamics[49],[50]. Several models of SCN neurons and circadian clocks contain calcium as a key component[51]–[55]. Our model is the first to estimate calcium levels in hyperexcited SCN neurons and compare such estimates with experimental data on cytosolic calcium levels, as well as the increases in intracellular calcium from action potentials. We relied on measurements of the overall cytosolic calcium level, and found a simple exponential clearance was sufficient to reproduce our data. When further experimental data on calcium regulation( e. g. release from intracellular stores) in SCN neurons becomes available, these details should be incorporated into our mathematical models. In our model, we have focused on the effect of cytosolic calcium on KCa and potassium leak currents, based on previous reports of rhythmic regulation of these channels[32]–[34]. However, there is evidence that the circadian clock may also regulate A-type potassium and L-type calcium channels[12],[56], and the effects of this additional control could be considered in future models. Several experimental studies have used TTX to assess the role of sodium-dependent APs on circadian rhythmicity. Infusion of TTX into the SCN of freely moving rats disrupts behavioral rhythms but not internal circadian timekeeping[57]. In vitro application of TTX that abolishes AP firing in rat and hamster SCN slices does not affect the rhythm in SCN metabolism[58]. TTX also eliminates firing in SCN cultures[59], but does not block the cytosolic calcium rhythm[60]. Finally, single-cell bioluminescence measurements in SCN slice cultures indicate that TTX-sensitive APs are required for both robust clock gene expression rhythms in individual neurons and synchronization of these rhythms across cells[61]. Our simulation results( Figure S5) suggest that TTX dampens clock gene expression rhythms measured grossly across a population of SCN neurons primarily through accumulation of desynchronization rather than damping of individual oscillators. These simulations also predict that TTXLAMOs would only occur at certain times of day, which may help explain why these types of oscillations have not been widely reported in the literature outside of their initial discovery[12],[24]. Mizrak et al.[62] report that hyperexciting Drosophila clock neurons creates a morning-like expression profile for many circadian genes, while hyperpolarizing them creates an evening-like transcriptome. This underscores the different nature of neuronal signaling in depolarized versus conventional states. We predict that depolarized states in SCN neurons trigger transcription activation and can enhance rhythmicity, but future work is needed to understand how these depolarized states affect the dynamics of intracellular timekeeping in detailed mammalian clock models[63] and their other implications for neuronal information processing.",
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"content": "Daily rhythms in the behavior and physiology of mammals are coordinated by a group of neurons that constitute the central circadian ( ∼24-hour ) clock . Clock neurons contain molecular feedback loops that lead to rhythmic expression of clock-related genes . Much progress has been made in the past two decades to understand the genetic basis of the molecular circadian clock . However , the relationship between the molecular clock and the primary output of clock neurons—their electrical activity—remains unclear . Here , we explore this relationship using computational modeling of an unusual electrical state that clock neurons enter at a certain time of day . We predict that this state causes high concentration of calcium ions inside clock neurons , which activates transcription of clock genes . We demonstrate that this additional feedback promotes 24-hour gene expression rhythms . Thus , we propose that electrical activity is not just an output of the clock , but also part of the core circadian timekeeping mechanism that plays an important role in health and disease .",
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science.medmentions_ner | science.medmentions_ner.2418 | [
{
"content": "Analyze the provided paragraph from a scientific document. Your goal is to identify and extract relevant entities.\n\nFormat your findings as a JSON object, where each key represents a category of entities, and the corresponding value is a list of entities identified in that category. If no entities are found for a category, return an empty list.\n\nFocus on precision and ensure that the output is strictly in JSON format.\n\nDocument:\n\nDoes objective quality of physicians correlate with patient satisfaction measured by Hospital Compare metrics in New York State? It is unclear whether publicly reported benchmarks correlate with the quality of physicians and institutions. We investigated the association of patient satisfaction measures from a public reporting platform with the performance of neurosurgeons in New York State. We performed a cohort study involving patients undergoing neurosurgical operations from 2009-2013, who were registered in the Statewide Planning and Research Cooperative System (SPARCS) database. This cohort was merged with publicly available data from the CMS Hospital Compare website. A propensity adjusted regression analysis was used to investigate the association of patient satisfaction metrics with neurosurgeon quality, as measured by their individual rate of mortality and average length-of-stay (LOS). Overall, 166,365 patients underwent neurosurgical procedures during the study. Using a propensity adjusted multivariable regression analysis we demonstrated that undergoing neurosurgical operations in hospitals with a greater percentage of patient - assigned \" high \" score were associated with higher chance of being treated by a physician with superior performance in terms of mortality (OR 1.90; 95% CI, 1.86 to 1.95), and a higher chance of being treated by a physician with superior performance in terms of length-of-stay (LOS) (OR 1.24; 95% CI, 1.21 to 1.27). Similar associations were identified for hospitals with a higher percentage of patients, who claimed they would recommend these institutions to others. Merging a comprehensive all-payer cohort of neurosurgery patients in New York State with data from the CMS Hospital Compare website, we observed an association of superior hospital - level patient satisfaction measures with the objective performance of individual neurosurgeons in the corresponding hospitals.",
"role": "user"
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{
"content": "{\"AnatomicalStructure\": [], \"Bacterium\": [], \"BiologicFunction\": [], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [], \"ClinicalAttribute\": [], \"Eukaryote\": [], \"Finding\": [], \"Food\": [], \"HealthCareActivity\": [\"neurosurgical operations\", \"neurosurgery\", \"neurosurgical procedures\", \"registered\"], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"Statewide Planning and Research Cooperative System (SPARCS) database\", \"CMS Hospital Compare website\", \"Hospital Compare metrics\", \"patient satisfaction metrics\", \"multivariable regression analysis\", \"regression analysis\"], \"MedicalDevice\": [], \"Organization\": [\"hospitals\", \"hospital\"], \"PopulationGroup\": [\"cohort\", \"individual\", \"all-payer cohort\"], \"ProfessionalOrOccupationalGroup\": [\"neurosurgeon\", \"neurosurgeons\", \"physicians\", \"physician\"], \"ResearchActivity\": [\"study\"], \"SpatialConcept\": [\"New York State\"], \"Virus\": []}",
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science.pico_ner | science.pico_ner.1066 | [
{
"content": "Examine the following abstract and identify distinct entities. Focus on extracting entities related to participants, interventions, and outcomes.\n\nPresent your findings in a JSON format like: {\"Participant\": [\"example entity\", ...], \"Intervention\": [\"example entity\", ...], \"Outcome\": [\"example entity\", ...]}. If no entities are found for a category, use an empty list.\n\nAbstract Content:\n\nRandomised clinical trial of physiotherapy after open abdominal surgery in high risk patients . Postoperative physiotherapy has been shown to reduce the incidence of postoperative pulmonary complications after open abdominal surgery . This study aimed to determine if the addition of deep breathing exercises and secretion clearing techniques to a standardised physiotherapist-directed program of early mobilisation improved clinical outcomes in patients undergoing open abdominal surgery . Fifty-six patients undergoing open abdominal surgery , at high risk of developing postoperative pulmonary complications , were randomised before operation to an early mobilisation-only group or an early mobilisation-plus-deep breathing and coughing group . Mobility duration , frequency and intensity of breathing interventions were quantified for both groups . All outcomes were assessed by a blinded outcomes researcher using a standardised outcomes measurement tool developed specifically for this population . Outcomes included incidence of clinically significant postoperative pulmonary complications , fever , length of stay , and restoration of mobility . There were no significant differences between groups in mean age , anaesthetic time , perioperative morbidity , or postoperative mobility . Outcome data were available for 89 % of enrolled subjects . Overall incidence of postoperative pulmonary complications was 16 % . The incidence of postoperative pulmonary complications in the non-deep breathing and coughing group was 14 % , and the incidence of postoperative pulmonary complications in the deep breathing and coughing group was 17 % , ( absolute risk reduction -3 % , 95 % C1 -22 to 19 % ) . There was no significant difference between groups in the incidence of fever , physiotherapist time , or the number of treatments . This study suggests that , in this clinical setting , the addition of deep breathing and coughing exercises to a physiotherapist-directed program of early mobilisation does not significantly reduce the incidence of clinically significant postoperative pulmonary complications in high risk open abdominal surgery subjects .",
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{
"content": "{\"Intervention\": [\"mobilisation-plus-deep breathing\", \"and\", \"coughing exercises\", \"or an early\", \"secretion clearing techniques\", \". Mobility duration , frequency and intensity of breathing interventions were quantified for both groups . All outcomes were assessed by a blinded outcomes researcher using a standardised outcomes measurement tool developed specifically for this population .\", \"physiotherapy\", \"standardised physiotherapist-directed program\", \"Postoperative physiotherapy\", \"mobilisation-only group\", \"deep breathing\", \"randomised before operation to an early\", \"coughing group\", \"open abdominal surgery\", \"deep breathing exercises\"], \"Outcome\": [\"anaesthetic time\", \",\", \"number of treatments\", \"physiotherapist time\", \"clinically significant postoperative pulmonary complications\", \"fever\", \"length of stay\", \"Mobility duration\", \"mean age\", \"reduce the incidence\", \"postoperative pulmonary complications\", \"restoration of mobility\", \"perioperative morbidity , or postoperative mobility\", \"frequency and intensity of breathing interventions\"], \"Participant\": [\"high risk open abdominal surgery subjects\", \"patients undergoing open abdominal surgery\", \"high risk patients\"]}",
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science.scientific_papers_summarization_single_doc_pubmed | science.scientific_papers_summarization_single_doc_pubmed.10484 | [
{
"content": "Read the provided biomedical research paper and create a concise abstract. Ensure the abstract captures the main points of the paper.\n\nFull Paper:\nneurofibromatosis type - i ( nf-1 , von recklinghausen 's disease ) is an autosomal - dominant single - gene hereditary disorder of neural crest cells , involving neuroectoderm , mesoderm , and endoderm .\nit affects 1:3000 - 4000 individuals and is caused by a defect in the gene responsible for the production of the protein neurofibromin : the nf-1 gene .\nthe nf-1 gene is a tumor suppressor gene linked to the long arm of chromosome 17 .\nthe clinical manifestations of nf-1 are as follows : caf - au - lait spots , axillary or inguinal freckling , lisch nodules of the iris , neurofibromas , optic gliomas , and spinal skeletal deformities .\nthe latter manifest as acquired short , sharp , and angular ( usually thoracic ) scoliotic curves .\ndystrophic changes such as rib - penciling , vertebral scalloping , transverse process spindling , apical wedging , foraminal enlargement , and dural ectasia are classic features\nvarious procedures have been reported and entail anterior , posterior , and combined anterior / posterior approaches to establish arthrodesis and prevent curve progression .\nwe describe a case that highlights the operative management of an nf-1 patient with severe dystrophic thoracic kyphoscoliosis treated by a posterolateral spinal approach .\na 44-year - old patient with nf-1 presented to the department of neurosurgery with myelopathy caused by a 93 thoracic ( t5-t9 ) kyphoscoliosis , thoracic vertebral scalloping leading to a severe thinning of the vertebral bodies , profound stenosis by a bony ridge between two dural ectasias at t4-t5 anteriorly and auto fusion of t4-t7 [ figures 1 and 2 ] . magnetic resonance image of a 93 thoracic kyphoscoliosis and stenosis due to a bony ridge ( red circle ) between two dural ectasias at t4-t5 anteriorly and an autofusion of t4-t7 .\nnote the dural ctasias ( asterix ) and the vertebral scalloping ( yellow curve ) computed tomography image of the thoracic spine with a 93 kyphoscoliosis .\nnote the bony anterior autofusion of t4-t7 clinically , she had progressive sensory disturbances and upper motor signs .\noperative intervention , performed using intraoperative neuromonitoring , consisted of a posterolateral approach with posterior thoracic cord exposure , anterior decompression of the bony ridge on t4-t5 by a right costotransversectomy [ figure 3 ] at t4 and posterior fusion of c6-t12 with bilateral pedicle screws at the c6 , t11 , and t12 level as well as bilateral bridging rod instrumentation [ figures 4 and 5 ] .\ncadaver view of the anterior thoracic spinal cord with the thoracic nerve root lifted upward ( curved arrow ) after a performed right costotransversectomy at t4 .\nnote the detailed exposure of the anterior spinal cord with its epidural space ( white circle ) , corresponding veins ( black arrow ) , and the posterior longitudinal ligament ( white arrow ) .\nremark : the spinous process and the lamina have been removed for demonstrative purposes postoperative x - ray image showing the posterior fusion from c6 to t12 with bilateral pedicle screws at the c6 , t11 , and t12 level and bilateral bridging rods postoperative computed tomography image with posterior fusion of c6-t12 .\nnote the pedicle screws at the c6 , t11 , and t12 level as well as the resection of the bony ridge at t4-t5 ( red circle )\nit occurs usually in the low thoracic region and has a prevalence ranging from 2% to 69% in the literature .\netiological theories regarding nf-1-related scoliosis include erosion or infiltration of bone by neurofibromas , primary mesodermal dysplasia , osteomalacia , and endocrine disturbances .\nthis classification is based on the absence or presence of skeletal dysplasia , such as vertebral scalloping and associated dural ectasias , rib penciling , vertebral wedging , transverse process spindling , paraspinal or intraspinal soft tissue masses , apical rotation , foraminal enlargement , pedicle dysplasia , and widened interpediculate distance .\nthe literature states that the likelihood of curve progression and deterioration is proportional to the severity of skeletal dystrophy .\nstudies have shown that when a combination of three or more dysplastic features are present , the risk of curve deterioration was significantly increased in 85% of patients .\nnon - dystrophic curves can be managed as idiopathic scoliosis , dystrophic curves , however , need a more aggressive approach . a dystrophic curve pattern , as this was the case in our patient , classically presents as a short segment , sharply angulated , thoracic curve with three or more dystrophic elements .\nthey require aggressive treatment as there is a strong tendency for curve progression and clinical catastrophic deterioration .\ndystrophic scoliosis less than 20 should be closely monitored at 6 month intervals . in scoliosis , measuring 20-40 with less than 50 of kyphosis , a posterior spinal arthrodesis is feasible .\nhowever , when the scoliosis exceeds 40 and/or thoracic hyperkyphosis exceeds 50 , a combined anterior / posterior ( circumferential ) fusion is mandatory .\nneurological deficits are usually caused by hyperkyphosis and subsequent attenuation and deformation of the spinal cord . in those cases , an anterior decompression followed by circumferential fusion\nother contributory factors include intraspinal tumors , which have to be resected followed by a mechanical stabilization and bony fusion .\none of the difficulties encountered in nf - spinal surgery is the segmental instrumentation and fusion as there can be poor anchorage points for internal fixation due to vertebral destruction .\ndue to the high incidence of pseudarthrosis , fusion evaluation should be performed at 6 months and at regular intervals until solid arthrodesis is obtained . in case of failure ,\nthe neurological deficit was caused by a 93 thoracic ( t5-t9 ) kyphoscoliosis and stenosis due to a bony ridge between two dural ectasias at t4-t5 anteriorly [ figure 1 ] .\nfurthermore , there was an autofusion of t4-t7 [ figures 1 and 2 ] . due to the anterior t4-t7 autofusion , severe kyphosis , and the presence of dural actasias\nwe choose a posterolateral approach [ figure 3 ] instead with thoracic cord exposure , anterior decompression of the bony ridge on t4-t5 by a right costotransversectomy at t4 and posterior fusion of c6-t12 with bilateral pedicle screws at the c6 , t11 and t12 level as well as bilateral bridging rod instrumentation [ figures 4 and 5 ] .\nwe state that in selected cases of severe thoracic dystrophic kyphoscoliosis in nf - i , the posterolateral approach [ figure 3 ] is the only possible method to visualize the anterior thoracic spinal cord , perform anterior decompression , and to stabilize the thoracic deformity , because of the anterior dural ectasias and the kyphosis limiting an anterior procedure .",
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"content": "neurofibromatosis type - i ( nf - i ) is an autosomal - dominant hereditary disorder , in which spinal skeletal deformities are one of the manifestations and manifest as acquired abnormalities and present as short , sharp , and angular ( usually thoracic ) curves . \n the scoliosis can be severe requiring surgical intervention . \n the surgical procedure can be difficult because of scalloping of the vertebral bodies and dural ectasia . \n we state that in selected cases of severe thoracic dystrophic kyphoscoliosis in nf - i , the posterolateral approach is the only possible method to visualize the anterior thoracic spinal cord , perform anterior decompression , and to stabilize the thoracic deformity , because of the anterior dural ectasias and the kyphosis limiting an anterior procedure .",
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science.healthver_entailment | science.healthver_entailment.2385 | [
{
"content": "Evaluate the given public health statement using the provided research abstract. Your goal is to determine the relationship between the claim and the abstract content.\n\n- \"decision\": Indicate whether the abstract \"SUPPORTS\", \"CONTRADICTS\", or provides \"INSUFFICIENT\" information regarding the claim.\n- \"justification\": List sentences from the abstract that back your decision. If the decision is \"INSUFFICIENT\", leave this list empty.\n\nStatement: People with diabetes are among the groups most at risk for more severe complications to the novel coronavirus and its disease, COVID-19.\n\nResearch Abstract:\nObjective: To undertake a review and critical appraisal of published/preprint reports that offer methods of determining the effects of hypertension, diabetes, stroke, cancer, kidney issues, and high-cholesterol on COVID-19 disease severity.\nData sources: Google Scholar, PubMed, COVID-19 Open Research Dataset: a resource of over 128,000 scholarly articles, including over 59,000 articles with full text related to COVID-19, SARS-CoV-2, and coronaviruses.\nMethods: A search was conducted by two authors independently on the freely available COVID-19 Open Research Dataset (CORD-19).\nWe developed an automated search engine to screen a total of 59,000 articles in a few seconds.\nThe search engine was built using a retrieval function that ranks a set of documents based on the query terms appearing in each document regardless of their proximity within the document.\nFiltering of the articles was then undertaken using keywords and questions, e.g. \"Effects of diabetes on COVID/normal coronavirus/SARS-CoV-2/nCoV/COVID-19 disease severity, mortality?\".\nThe search terms were repeated for all the comorbidities considered in this paper.\nAdditional articles were retrieved by searching via Google Scholar and PubMed.\nFindings: A total of 54 articles were considered for a full review.\nIt was observed that diabetes, hypertension, and cholesterol levels possess an apparent relation to COVID-19 severity.\nOther comorbidities, such as cancer, kidney disease, and stroke, must be further evaluated to determine a strong relationship to the virus.\nReports associating cancer, kidney disease, and stroke with COVID-19 should be carefully interpreted, not only because of the size of the samples, but also because patients could be old, have a history of smoking, or have any other clinical condition suggesting that these factors might be associated with the poor COVID-19 outcomes rather than the comorbidity itself.\nSuch reports could lead many oncologists and physicians to change their treatment strategies without solid evidence and recommendations.\nFurther research regarding this relationship and its clinical management is warranted.\nAdditionally, treatment options must be examined further to provide optimal treatment and ensure better outcomes for patients suffering from these comorbidities.\nIt should be noted that, whether definitive measurements exist or not, the care of patients as well as the research involved should be largely prioritized to tackle this deadly pandemic.",
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"content": "{\"verdict\": \"SUPPORT\", \"evidence\": [\"It was observed that diabetes, hypertension, and cholesterol levels possess an apparent relation to COVID-19 severity.\"]}",
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science.covid_deepset_qa | science.covid_deepset_qa.874 | [
{
"content": "Analyze the following excerpt from a biomedical text. Identify the relevant information needed to respond to the inquiry. Provide only the necessary details in your answer.\n\nContext: Similarly, efficient priming of CTLs was observed against phage-displayed T-cell epitopes from Hepatitis B virus (Wan et al., 2001) and Candida albicans (Yang et al., 2005a; Wang et al., 2006 Wang et al., , 2014d , which, together with other types of immune responses, protected mice against systemic candidiasis. Vaccination with a combination of phagedisplayed peptides elicited antigen-specific CTLs that proved effective in reducing porcine cysticercosis in a randomized controlled trial (Manoutcharian et al., 2004; Morales et al., 2008) . While the correlates of vaccine-induced immune protection for infectious diseases, where they are known, are almost exclusively serum or mucosal antibodies (Plotkin, 2010) , \n\nIn certain vaccine applications, the filamentous phage has been used as a carrier for larger molecules that would be immunogenic even in isolation. Initially, the major advantages to phage display of such antigens were speed, ease of purification and low cost of production (Gram et al., 1993) . E. coli F17a-G adhesin (Van Gerven et al., 2008) , hepatitis B core antigen (Bahadir et al., 2011) , and hepatitis B surface antigen (Balcioglu et al., 2014) all elicited antibody responses when displayed on pIII, although none of these studies compared the immunogenicity of the phage-displayed proteins with that of the purified protein alone. Phage displaying Schistosoma mansoni glutathione S-transferase on pIII elicited an antibody response that was both higher in titer and of different isotypes compared to immunization with the protein alone (Rao et al., 2003) . Two studies of antiidiotypic vaccines have used the phage as a carrier for antibody fragments bearing immunogenic idiotypes. Immunization with phage displaying the 1E10 idiotype scFv (mimicking a Vibrio anguillarum surface epitope) elicited antibodies that protected flounder fish from Vibrio anguillarum challenge (Xia et al., 2005) . A chemically linked phage-BCL1 tumor-specific idiotype vaccine was weakly immunogenic in mice but extended survival time in a B-cell lymphoma model (Roehnisch et al., 2013) , and was welltolerated and immunogenic in patients with multiple myeloma (Roehnisch et al., 2014) . One study of DNA vaccination with an anti-laminarin scFv found that DNA encoding a pIII-scFv fusion protein elicited stronger humoral and cell-mediated immune responses than DNA encoding the scFv alone (Cuesta et al., 2006) , suggesting that under some circumstances, endogenous phage T-cell epitopes can enhance the immunogenicity of associated proteins. Taken together, the results of these studies show that as a particulate virus-like particle, the filamentous phage likely triggers different types of immune responses than recombinant protein antigens, and provide additional T-cell help to displayed or conjugated proteins. However, the low copy number of pIII-displayed proteins, as well as potentially unwanted phage-associated adjuvanticity, can make display of recombinant proteins by phage a suboptimal vaccine choice. Although our understanding of the immune response against the filamentous phage pales in comparison to classical model antigens such as ovalbumin, recent work has begun to shed light on the immune mechanisms activated in response to phage vaccination (Figure 1) . The phage particle is immunogenic without adjuvant in all species tested to date, including mice (Willis et al., 1993) , rats (Dente et al., 1994) , rabbits (de la Cruz et al., 1988) , guinea pigs (Frenkel et al., 2000; Kim et al., 2004) , fish (Coull et al., 1996; Xia et al., 2005) , non-human primates (Chen et al., 2001) , and humans (Roehnisch et al., 2014) . Various routes of immunization have been employed, including oral administration (Delmastro et al., 1997) as well as subcutaneous (Grabowska et al., 2000) , intraperitoneal (van Houten et al., 2006) , intramuscular (Samoylova et al., 2012a) , intravenous (Vaks and Benhar, 2011) , and intradermal injection (Roehnisch et al., 2013) ; no published study has directly compared the effect of administration route on filamentous phage immunogenicity. Antibodies are generated against only three major sites on the virion: (i) the surface-exposed N-terminal ∼12 residues of the pVIII monomer lattice (Terry et al., 1997; Kneissel et al., 1999) ; (ii) the N-terminal N1 and N2 domains of pIII (van Houten et al., 2010) ; and (iii) bacterial lipopolysaccharide (LPS) embedded in the phage coat (Henry et al., 2011) . In mice, serum antibody titers against the phage typically reach 1:10 5 -1:10 6 after 2-3 immunizations, and are maintained for at least 1 year postimmunization (Frenkel et al., 2000) . Primary antibody responses against the phage appear to be composed of a mixture of IgM and IgG2b isotypes in C57BL/6 mice, while secondary antibody responses are composed primarily of IgG1 and IgG2b isotypes, with a lesser contribution of IgG2c and IgG3 isotypes (Hashiguchi et al., 2010) . Deletion of the surface-exposed N1 and N2 domains of pIII produces a truncated form of this protein that does not elicit antibodies, but also results in a non-infective phage particle with lower overall immunogenicity (van Houten et al., 2010) . FIGURE 1 | Types of immune responses elicited in response to immunization with filamentous bacteriophage. As a virus-like particle, the filamentous phage engages multiple arms of the immune system, beginning with cellular effectors of innate immunity (macrophages, neutrophils, and possibly natural killer cells), which are recruited to tumor sites by phage displaying tumor-targeting moieties. The phage likely\n\nactivates T-cell independent antibody responses, either via phage-associated TLR ligands or cross-linking by the pVIII lattice. After processing by antigen-presenting cells, phage-derived peptides are presented on MHC class II and cross-presented on MHC class I, resulting in activation of short-lived CTLs and an array of helper T-cell types, which help prime memory CTL and high-affinity B-cell responses. Frontiers in Microbiology | www.frontiersin.org\n\nAlthough serum anti-phage antibody titers appear to be at least partially T-cell dependent (Kölsch et al., 1971; Willis et al., 1993; De Berardinis et al., 1999; van Houten et al., 2010) , many circulating pVIII-specific B cells in the blood are devoid of somatic mutation even after repeated biweekly immunizations, suggesting that under these conditions, the phage activates T-cell-independent B-cell responses in addition to highaffinity T-cell-dependent responses (Murira, 2014) . Filamentous phage particles can be processed by antigen-presenting cells and presented on MHC class II molecules (Gaubin et al., 2003; Ulivieri et al., 2008) and can activate T H 1, T H 2, and T H 17 helper T cells (Yang et al., 2005a; Wang et al., 2014d) . Anti-phage T H 2 responses were enhanced through display of CTLA-4 peptides fused to pIII (Kajihara et al., 2000) . Phage proteins can also be cross-presented on MHC class I molecules (Wan et al., 2005) and can prime two waves of CTL responses, consisting first of short-lived CTLs and later of long-lived memory CTLs that require CD4 + T-cell help (Del Pozzo et al., 2010) . The latter CTLs mediate a delayed-type hypersensitivity reaction (Fang et al., 2005; Del Pozzo et al., 2010) . The phage particle is self-adjuvanting through multiple mechanisms. Host cell wall-derived LPS enhances the virion's immunogenicity, and its removal by polymyxin B chromatography reduces antibody titers against phage coat proteins (Grabowska et al., 2000) . The phage's singlestranded DNA genome contains CpG motifs and may also have an adjuvant effect. The antibody response against the phage is entirely dependent on MyD88 signaling and is modulated by stimulation of several Toll-like receptors (Hashiguchi et al., 2010) , indicating that innate immunity plays an important but largely uncharacterized role in the activation of anti-phage adaptive immune responses. Biodistribution studies of the phage after intravenous injection show that it is cleared from the blood within hours through the reticuloendothelial system (Molenaar et al., 2002) , particularly of the liver and spleen, where it is retained for days (Zou et al., 2004) , potentially activating marginal-zone B-cell responses. Thus, the filamentous phage is not only a highly immunogenic carrier, but by virtue of activating a range of innate and adaptive immune responses, serves as an excellent model virus-like particle antigen. Long before the identification of filamentous phage, other types of bacteriophage were already being used for antibacterial therapy in the former Soviet Union and Eastern Europe (reviewed in Sulakvelidze et al., 2001) . The filamentous phage, with its nonlytic life cycle, has less obvious clinical uses, despite the fact that the host specificity of Inovirus and Plectrovirus includes many pathogens of medical importance, including Salmonella, E. coli, Shigella, Pseudomonas, Clostridium, and Mycoplasma species. In an effort to enhance their bactericidal activity, genetically modified filamentous phage have been used as a \"Trojan horse\" to introduce various antibacterial agents into cells. M13 and Pf3 phage engineered to express either BglII restriction endonuclease (Hagens and Blasi, 2003; Hagens et al., 2004) , lambda phage S holin (Hagens and Blasi, 2003) or a lethal catabolite gene activator protein (Moradpour et al., 2009) effectively killed E. coli and Pseudomonas aeruginosa cells, respectively, with no concomitant release of LPS (Hagens and Blasi, 2003; Hagens et al., 2004) . Unfortunately, the rapid emergence of resistant bacteria with modified F pili represents a major and possibly insurmountable obstacle to this approach. However, there are some indications that filamentous phage can exert useful but more subtle effects upon their bacterial hosts that may not result in the development of resistance to infection. Several studies have reported increased antibiotic sensitivity in bacterial populations simultaneously infected with either wild type filamentous phage (Hagens et al., 2006) or phage engineered to repress the cellular SOS response (Lu and Collins, 2009) . Filamentous phage f1 infection inhibited early stage, but not mature, biofilm formation in E. coli (May et al., 2011) . Thus, unmodified filamentous phage may be of future interest as elements of combination therapeutics against certain drug-resistant infections. More advanced therapeutic applications of the filamentous phage emerge when it is modified to express a targeting moiety specific for pathogenic cells and/or proteins for the treatment of infectious diseases, cancer and autoimmunity (Figure 2) . The first work in this area showed as proof-of-concept that phage encoding a GFP expression cassette and displaying a HER2specific scFv on all copies of pIII were internalized into breast tumor cells, resulting in GFP expression (Poul and Marks, 1999) . M13 or fd phage displaying either a targeting peptide or antibody fragment and tethered to chloramphenicol by a labile crosslinker were more potent inhibitors of Staphylococcus aureus growth than high-concentration free chloramphenicol (Yacoby et al., 2006; Vaks and Benhar, 2011) . M13 phage loaded with doxorubicin and displaying a targeting peptide on pIII specifically killed prostate cancer cells in vitro (Ghosh et al., 2012a) . Tumorspecific peptide:pVIII fusion proteins selected from \"landscape\" phage (Romanov et al., 2001; Abbineni et al., 2010; Fagbohun et al., 2012 Fagbohun et al., , 2013 Lang et al., 2014; Wang et al., 2014a) were able to target and deliver siRNA-, paclitaxel-, and doxorubicincontaining liposomes to tumor cells (Jayanna et al., 2010a; Wang et al., 2010a Wang et al., ,b,c, 2014b Bedi et al., 2011 Bedi et al., , 2013 Bedi et al., , 2014 ; they were non-toxic and increased tumor remission rates in mouse models (Jayanna et al., 2010b; Wang et al., 2014b,c) . Using the B16-OVA tumor model, Eriksson et al. (2007) showed that phage displaying peptides and/or Fabs specific for tumor antigens delayed tumor growth and improved survival, owing in large part to activation of tumor-associated macrophages and recruitment of neutrophils to the tumor site (Eriksson et al., 2009) . Phage displaying an scFv against β-amyloid fibrils showed promise as a diagnostic (Frenkel and Solomon, 2002) and therapeutic (Solomon, 2008) reagent for Alzheimer's disease and Parkinson's disease due to the unanticipated ability of the phage to penetrate into brain tissue (Ksendzovsky et al., 2012)\n\nInquiry: Why is the phage displaying an scFv against β-amyloid fibrils is a good diagnostic for Alzheimers and Parkinson's disease?",
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"content": "ability of the phage to penetrate into brain tissue (Ksendzovsky et al., 2012)",
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science.craftchem_ner | science.craftchem_ner.1233 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nMullerforproteinpurification.",
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"content": "[\"protein\"]",
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science.craftchem_ner | science.craftchem_ner.2774 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nYXWandRMEconceivedanddesignedtheexperiments.",
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science.scientific_lay_summarisation_elife_single_doc_summ | science.scientific_lay_summarisation_elife_single_doc_summ.2742 | [
{
"content": "Transform the provided sections of a biomedical research paper into a digestible summary for a general audience. Focus on simplifying complex ideas while retaining key scientific insights.\n\nResearch Title: Monkey EEG links neuronal color and motion information across species and scales\nContent Overview:\nAbstract:\nIt remains challenging to relate EEG and MEG to underlying circuit processes and comparable experiments on both spatial scales are rare. To close this gap between invasive and non-invasive electrophysiology we developed and recorded human-comparable EEG in macaque monkeys during visual stimulation with colored dynamic random dot patterns. Furthermore, we performed simultaneous microelectrode recordings from 6 areas of macaque cortex and human MEG. Motion direction and color information were accessible in all signals. Tuning of the non-invasive signals was similar to V4 and IT, but not to dorsal and frontal areas. Thus, MEG and EEG were dominated by early visual and ventral stream sources. Source level analysis revealed corresponding information and latency gradients across cortex. We show how information-based methods and monkey EEG can identify analogous properties of visual processing in signals spanning spatial scales from single units to MEG – a valuable framework for relating human and animal studies.\nIntroduction:\nHow do results from human magnetoencephalography( MEG) and electroencephalography( EEG) experiments relate to those obtained from animals in invasive electrophysiology? It is generally well understood how potential changes in large populations of neurons can propagate through tissue types and lead to detectable electric potentials and associated magnetic fields outside the head( Pesaran et al., 2018). Yet, in typical MEG and EEG experiments, we have little clue which specific cellular and circuit mechanisms contribute to the recorded signals( Cohen, 2017). This can be attributed to several factors. First, the reconstruction of cortical sources from non-invasive signals is generally limited and based on assumptions( Darvas et al., 2004). Second, invasive and non-invasive electrophysiology are largely separate research fields. Comparable experiments performed on both levels and in the same species are rare, with few recent exceptions( Bimbi et al., 2018; Godlove et al., 2011; Reinhart et al., 2012; Shin et al., 2017; Snyder et al., 2015; Snyder et al., 2018). Third, studies employing invasive and non-invasive methods in parallel suffer from sparse sampling of recording sites. Massively parallel invasive recordings in multiple brain regions have only recently become viable( Dotson et al., 2017; Jun et al., 2017; Siegel et al., 2015), and EEG recordings in awake behaving animals have so far been limited to relatively few electrodes. This sparsity limits specificity when drawing conclusions from one level to the other. In summary, the mapping between measurement scales is severely underconstrained, both theoretically when trying to infer cortical sources of non-invasively measured activity, and experimentally by the lack of sufficiently comparable data. Thus, key for linking different scales are comparable large-scale recordings on all levels to provide high specificity and eventually trace the origins of large-scale phenomena back to their underlying cellular mechanisms. Importantly, this includes non-invasive recordings in animals. These allow to bridge the gap between invasive animal electrophysiology and non-invasive human experiments by permitting to disentangle similarities and differences due to species membership from those due to measurement technique. An especially suitable candidate for this is monkey EEG, making use of evolutionary proximity and promising to better connect the rich literature in non-human primate neurophysiology with human studies. A powerful tool to link data from different measurement scales is the abstraction from measured activity itself to its information content, as enabled by multivariate decoding methods. Representational similarity analysis( RSA) compares the representational structure of signals( Cichy et al., 2014; Kriegeskorte et al., 2008a). However, as decoding approaches have inherent difficulties to identify the sources of decodable information( Carlson et al., 2018; Liu et al., 2018), it is necessary to employ thoughtful control analyses or experiments( Cichy et al., 2015) to disambiguate different possible mechanisms underlying large-scale information structure. This crucially relies on empirical knowledge about processes on the circuit-scale. To bridge the gap between invasive and non-invasive electrophysiology, in the present study, we developed and employed fully human-comparable high-density monkey EEG. We presented identical color and motion stimuli to both human participants and macaque monkeys and combined large-scale recordings on multiple scales, including invasive electrophysiology from six areas across the macaque brain, monkey EEG and human MEG with multivariate decoding and representational similarity analysis. We found color and motion direction information not only in invasive signals, but also in EEG and MEG. We show how motion and color tuning in human MEG can be traced back to the properties of individual units. Our results establish a proof of principle for using large-scale electrophysiology across species and measurement scales to link non-invasive recordings to circuit-level activity.\nDiscussion:\nConsistent with earlier reports( An et al., 2012; Mendoza-Halliday et al., 2014; Siegel et al., 2015), we found color and motion information in all areas we measured, rather than in a small amount of specialized areas. Nonetheless, the amount of information strongly depended on the area. Interestingly, the motion direction decoding accuracies we found were lower than previously reported in both area MT and prefrontal cortex( Mendoza-Halliday et al., 2014). This can largely be attributed to differences in the paradigm and analysis strategy: First, rather than decoding from large pseudo-populations, we used small, simultaneously recorded populations. Second, we report averaged single trial probabilities, which tended to be smaller but more robust than the corresponding discrete classification results. Third, the rapid succession of very short stimuli likely limited cortical processing of each stimulus. Fourth, our paradigm only involved passive fixation. Especially in higher-order areas we would expect representations to be strengthened, and altered, according to task demands in a more engaging cognitive task. Stimulus features showing a spatial organization at the scale of cortical columns, such as orientation, can in principle be decoded from EEG and MEG( Cichy et al., 2015). This implies that other, similarly topographical representations should be equally accessible. Indeed, a clustering of both color( Conway and Tsao, 2009; Roe et al., 2012; Tanigawa et al., 2010) and motion direction( Albright et al., 1984; Li et al., 2013; Tanigawa et al., 2010) has been reported in several areas of the visual system. This suggests that our successful decoding of stimulus color and motion direction was not attributable to confounding factors, but likely stemmed from true feature-related signals. Crucially, even though we recorded invasively in many areas, our results do not unequivocally identify the sources of visual information in MEG and EEG. First, neither color nor motion direction representations are limited to the areas we recorded from. Secondly, partially due to the simple feature spaces used for our stimuli, many areas are expected to show highly similar tuning properties. Based on RSA, we can therefore only conclude that the non-invasively measured information stems from areas with tuning similar to V4 or IT. It is reasonable to assume that earlier visual areas strongly contributed to this, which is corroborated by our source level searchlight analysis revealing strong information peaks in occipital cortex. Furthermore, it has been shown that for example area V1 exhibits a more bimodal motion direction tuning( i. e. orientation or axis tuning) than area MT( Albright, 1984), matching the results found here in V4. There is, however, previous evidence that the structure of color representations decodable from area V1 using fMRI is not in agreement with perceptual similarity( Brouwer and Heeger, 2013), contrary to area V4, and contrary to the representations we found in MEG and EEG, suggesting that these color representations might not be explained by V1 activity alone. Notably, in area MT cortical columns with opposite preferred motion directions along the same axis lie spatially close to each other( Albright et al., 1984; Born and Bradley, 2005). This could, in principle, lead to a diminished decodability of opposite motion directions from mass signals such as EEG, MEG or fMRI. In such a scenario, the source of bimodal motion direction tuning might still lie in area MT. However, this would require columns with opposite preferred motion directions to be close to uniformly distributed at the relevant spatial scale. While several recent fMRI studies have focused on motion axis decoding( Schneider et al., 2019; Zimmermann et al., 2011), motion direction has been successfully decoded from BOLD signals in area MT( Kamitani and Tong, 2006). Given that motion representations are prevalent across visual cortex( An et al., 2012), we consider it unlikely that MT was a dominant source of the bimodally tuned motion signals we measured in EEG and MEG. In sum, this suggests that the information decoded from non-invasive signals originated in a mixture of several early visual areas. Recordings from additional visual areas using the same paradigm are required to further clarify this. Future studies may also expand the stimulus space- a limitation of the present proof-of-principle study. Manipulating other stimulus features in order to maximize differences between areas will allow to further dissociate representations in specific parts of the visual system. We utilized human-comparable monkey EEG as a bridge technology to link invasive animal electrophysiology to human MEG. High electrode density and methods identical to those used in human M/EEG enabled us to perform source reconstruction and directly relate measures across species. The few available previous studies measuring EEG in nonhuman primates were typically restricted to only a few electrodes( Bimbi et al., 2018; Snyder et al., 2015; Snyder et al., 2018) and used diverging methods such as skull-screw electrodes, or both( Godlove et al., 2011; Musall et al., 2014; Reinhart et al., 2012; Whittingstall and Logothetis, 2009; Woodman et al., 2007). We show how monkey EEG can serve as a missing link to enable the disentangling of species differences from differences in measurement modality. In isolation, our observation of bimodal motion direction tuning in human MEG could not directly inform conclusions about the relative contributions of dorsal and ventral stream areas. Finding the same result in monkey EEG allowed us to infer that it was not due to a decreased influence of MT-like areas in the human, but rather a sign of a general dominance of V4-like tuning in non-invasive signals. State-of-the-art animal electrophysiology requires large technical efforts and comes at a significant ethical cost. When applied in addition to ongoing invasive experiments, the marginal cost of monkey EEG is comparably small. It is non-invasive, depends mostly on standard human neuroscience tools, and does not necessitate further animal training. This is far outweighed by the potential benefits of establishing a database for linking invasive and non-invasive electrophysiology and for enhancing comparability between the fields. Notably, another possibility to achieve this goal is given by invasive electrophysiological recordings in human patients, that are however severely constrained by the requirement for medical necessity. In the current work, we used an information-based approach to compare brain areas, measurement scales, and species. Such analyses are powerful tools to relate very different signals based on their information contents. This may not only include data from different measurement techniques, such as MEG and fMRI( Cichy et al., 2014; Cichy et al., 2016a), or species( Cichy et al., 2014; Kriegeskorte et al., 2008b), but also cognitive or computational models( Cichy et al., 2016b; Wardle et al., 2016). Furthermore, instead of comparing representations of simple sensory stimuli, the same framework can be applied to complex task conditions( Hebart et al., 2018). We would like to highlight that our framework of cross-species and cross-scale comparisons is not limited to information-based analyses. For example we anticipate that it will be highly interesting to compare and pinpoint specific spectral signatures of circuit activity in signals on all scales( Donner and Siegel, 2011; Siegel et al., 2012). This has been successful in some cases( Sherman et al., 2016; Shin et al., 2017), but could significantly benefit from the present large scale approach to gain further specificity. In the long term, with sufficient knowledge about mechanistic signatures on all scales, this could facilitate the establishment of transfer functions between circuit activity and non-invasive human electrophysiology( Cohen, 2017; Donner and Siegel, 2011; Siegel et al., 2012). It is important to note that such transfer can only be possible based on knowledge on all scales. As has been noted before( Sprague et al., 2018), macro-scale signals alone always suffer from an ill-posed inverse problem when trying to infer micro-scale properties. The approach of dense recordings on all scales, as outlined here, allows to bridge this gap by constraining inferences. Such developments would allow quick and inexpensive access to circuit function in the human brain, both for basic research and in clinical practice( Siegel et al., 2012). In sum, we show that color and motion direction can be decoded from non-invasive electrophysiology in humans and monkeys. Our results suggest that such simple stimulus representations are dominated by signals from early ventral stream areas. This inference serves as a proof-of-principle for, and was enabled by, using high-density monkey EEG as a bridge technology to link scales and species.",
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"content": "Neurons carry information in the form of electrical signals , which we can listen to by applying sensors to the scalp: the resulting recordings are called an EEG . Electrical activity within the brain also generates a weak magnetic field above the scalp , which can be measured using a technique known as MEG . Both EEG and MEG only require a few dozen sensors , placed centimeters away from the brain itself , but they can reveal the precise timing and rough location of changes in neural activity . However , the brain consists of billions of neurons interconnected to form complex circuits , and EEG or MEG cannot reveal changes in activity of these networks in fine detail . In animals , and in patients undergoing brain surgery , scientists can use hair-thin microelectrodes to directly record the activity of individual neurons . Yet , it is difficult to know how activity measured inside the brain relates to that measured outside . To find out , Sandhaeger et al . had monkeys and healthy human volunteers perform the same task , where they had to watch a series of colored dots moving across a screen . The brain of the human participants was monitored using MEG; in the monkeys , EEG provided an indirect measure of brain activity , while microelectrodes directly revealed the activity of thousands of individual neurons . All three recordings contained information about movement and color . Moreover , the monkey EEG bridged the gap between direct and indirect recordings . Sandhaeger et al . identified signals in the monkey EEG that corresponded to the microelectrode recordings . They also spotted signals in the human MEG that matched the monkey EEG . Linking non-invasive measures of brain activity with underlying neural circuits could help to better understand the human brain . This approach may also allow clinicians to interpret EEG and MEG recordings in patients with brain disorders more easily .",
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science.chemsum_single_document_summarization | science.chemsum_single_document_summarization.32969 | [
{
"content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nSynthesis and Nitric Oxide Releasing Properties of Novel Fluoro S-Nitrosothiols\n\nContent Extracts:\n\n<p>Nitric oxide (NO), an endogenous signaling molecule,1–3 has been extensively studied for its vasodilatory,4 antithrombotic,5 immune modulatory,6 antimicriobial,7 anticancer8 and wound healing9 properties. However, due to its high reactivity, the intravascular lifetime of NO is very short (~ 2 s).10 Therefore, precursor molecules (NO donors) are commonly utilized to generate NO in situ for chemical and biochemical studies. So far, various NO donors have been reported,11 including S-nitrosothiols, N-diazeniumdiolates and their derivatives, metal nitrosyls, and N-nitrosamines, as well as organic nitrates and nitrites. Current NO donors are also widely investigated as promising medicinal and therapeutic agents for disease treatments.12–14</p><p>Fluorine-containing compounds have significant potential applications in medical and materials chemistry.15, 16 In pharmaceuticals, almost 150 fluorinated drugs have successfully reached the market since the first fluorine-containing drug (fludrocortisone) was approved in 1955.16 Currently, 20% ~ 30% administered drugs contain fluorine atoms or fluoroalkyl groups.16 Fluorocarbon-based materials also have been widely applied in clinical biomaterials,17 affinity chromatography,18 enzyme immobilization,19 crystal engineering20 and supermolecular chemistry.21 Overall, the development of fluorinated compounds and materials with desired functionalities is of continuous interest and has significance in all branches of chemistry.</p><p>In the recent development of NO-releasing polymers for use in preparing implanted antimicrobial and thromboresistant biomedical devices (e.g., intravascular catheters, subcutaneous cannula, etc.), chemical leaching of the NO donor and its decomposition products has become a critical concern, owing to possible toxicity issues.22 Very recently, our group reported the incorporation of a novel fluorinated NO donor (S-nitroso-N-pentafluoropropionyl-penicillamine, C2F5-SNAP) into polyvinylidene fluoride for preparation of fluoropolymer-based biomaterials that exhibit NO release and significant antimicrobial properties.23 Due to the specific fluorous-fluorous interactions present between the fluorinated NO donor and the fluoropolymer, leaching of the fluorinated NO donor and the corresponding decomposition products was demonstrated to be quite low (< 10%, total), compared to that observed in the use of non-fluorinated NO donors. Thus, the development of new fluorinated NO donors is of great interest for potentially creating fluoropolymer-based NO release biomaterials from which chemical leaching will be greatly reduced for potential applications of biomedical implants and devices.</p><p>To the best of our knowledge, fluorinated S-nitrosothiol type NO donors have not received much attention in the medical and biomaterials research fields. Indeed, to date, only the C2F5-SNAP molecule has been reported as a fluorinated NO donor.23 However, the C2F5-SNAP NO donor was found to be quite unstable even upon storage within a freezer, resulting in the difficulty in handling and storage of this species.23 In contrast, the non-fluorinated S-nitrosoN-acetylpenicillamine (SNAP, see Fig. 1) has great stability, and has extensively been doped into various polymers for the long-term NO release over several months.22 Therefore, there is a need to develop new and relatively stable fluorinated structural analogs of SNAP as NO donors for fluoropolymer-based biomedical devices applications.</p><p>Herein, we consider the amine-based nucleophilic addition chemistry of thiolactone (see Fig. 1), which has been widely used to incorporate free thiol moieties as the precursors of S-nitrosothiols.24–27 3-Acetamido-4,4-dimethylthietan-2-one (gem-dimethyl thiolactone) was selected as the thiolactone to imitate the structure of SNAP. To prevent the strong electron withdrawing effects from fluorine or fluoroalkyl groups on the stability of S-N bond, we consider fluorinated benzylamine derivatives as nucleophiles. Specifically, the phenyl ring acts as a linker to diminish the strong electron withdrawing effects from fluoro/trifluoromethyl groups. We hypothesize that a nucleophilic ring opening of the thiolactone in the presence of fluorinated benzylamines should yield amide-based tertiary free thiols, which can be subsequently nitrosylated into fluorinated S-nitrosothiols (see Fig. 1).</p><p>In total, 12 fluorinated benzylamines with various degrees of fluorine substitution and 2 non-fluorinated benzylamines were utilized in the synthesis of the new amide-based S-nitrosothiols shown in Scheme 1. The gem-dimethyl thiolactone intermediate was easily obtained from the reaction between D-penicillamine and excess acetic anhydride. In the presence of various benzylamines as nucleophiles, a ring opening of the gem-dimethyl thiolactone yielded amide-based free thiol 2 intermediates. With pure thiol intermediates 2 in hand, a nitrosylation reaction using NaNO2 in presence of strong acid under dark conditions yielded the pure target products 3a-3n as greenish powders. NO donors 3a-3n were obtained with total yields of between 21 % - 30 % in three steps (see Section 2 in SI).</p><p>Although S-nitrosothiols are known to be relatively unstable due to the inherently weak S-N bond (25 – 31 kcal/mol),28, 29 SNAP is very stable at room temperature. For the previously prepared C2F5-SNAP NO donor, due to the presence of fluorinated groups, C2F5-SNAP was found to be unstable at room temperature and even slowly decompose at - 20 ˚C.23 All new targets 3a-3n were found to be stable during the vacuum drying process at room temperature in the dark. Additionally, they remained stable after being stored at - 20 ˚C over several months. For example, 1H NMR studies of 3l indicated that no decomposition of 3l was observed after storage for 40 days at −20 ˚C under dark conditions (see Fig. S1). Hence, the presence of fluoro/trifluoromethyl groups on the aromatic ring in targets 3a-3n do not appear to decrease the stability of the resulting S-nitrosothiols as was observed for C2F5-SNAP. This result is also consistent with the literature finding that tertiary S-nitrosothiols are known to be thermally stable. 29</p><p>To further investigate the NO release profiles from 3a-3n, we carried out kinetic studies of their photolytic and thermal decompositions. For example, the steady-state photolysis of 3k (150 μM) was carried out under 350 nm irradiation in a mixture of PBS and DMSO (50:50, v/v) at 23 ˚C. The UV-Vis spectra of its photodecomposition are shown in Fig. 2a, in which the characteristic UV-Vis band of the nO → π* transition (342 nm) continuously decreases and eventually flattens. The kinetic profile was analyzed using the absorbance changes at 342 nm (Fig. 2a insert), and was fitted to a first-order rate equation giving an observed rate constant kobs = (1.214 ± 0.052)×10−2 s−1 (t1/2 ~ 57 s). The corresponding rate constants and half-lives for the photodecomposition of the other NO donors synthesized in this work are summarized in Table 1. All exhibit first-order decomposition with half-lives between 50 to 80 s under light irradiation. Compared to the photostability of SNAP (t1/2 ~ 46 s), 3a-3n exhibit slower photodecomposition rates. Targets 3m and 3n have similar decomposition rate constants to 3a-3l, indicating that substitution groups on the phenyl ring do not influence the photolytic release rate of NO.</p><p>Thermal decomposition studies of 3a-3n at 37 ˚C were also performed in a mixture of PBS and DMSO (50:50, v/v). The absorbance data vs. time for the decomposition of 3k at 342 nm (see Fig. 2b) was monitored and this kinetic data was fitted to a zero-order rate equation, yielding an observed rate constant kobs of (1.446 ± 0.001) × 10−4 μM/min. All of the thermal decomposition kinetic data for compounds 1 and 3a-3n are reported in Table 2. NO donors 3a-3n are less stable in solution when compared to SNAP. NO donors 3d-3e and 3j-3l decomposed via a zero-order reaction model, similar to SNAP. But the others, 3a-3c, 3f-3i and 3m-3n, exhibit first-order decomposition kinetics.</p><p>To understand these different kinetic behaviors, we also performed computational calculations (see Section 5 in SI). Interestingly, the transition state for the homolysis of the S-N bond resulting in NO release does not exist. We found experimentally that the NO release was mainly determined by the calculated binding dissociation enthalpy (BDE) of S-N bond. Compared to SNAP, 3e, 3l and 3m have slightly lower BDE (see Table 3S) for the S-N bond. Thus, 3e, 3l and 3m are less stable than SNAP, consistent with our kinetic results under the thermal decomposition.</p><p>Furthermore, the emitted NO gas released by each new donor was accurately quantitated by an NOA chemiluminescence method. For instance, the photolysis of 3k (1.50 × 10−7 mol) within a NOA reaction cell was conducted in a mixture of PBS and DMSO (50:50, v/v) under 350 nm lamp irradiation, in which the corresponding NO gas signal was monitored by the NOA analyzer (see Fig. 3a). Three independent photolysis reactions gave the average NO generation yield of 98 ± 2 %. These results indicate that NO donor 3k can stoichiometrically release NO.</p><p>In addition to NO gas, the corresponding disulfide is reported to be the product derived from the decomposition of S-nitrosothiols.30 To further examine the disulfide formation, products derived from both the photo and thermal decomposition of 3k (2.98 mM) in DMSO-d6 were analyzed by 1H NMR spectroscopy (see Fig. 4). Before the decomposition, methide and gem-dimethyl groups in 3k had chemical shifts at ~ 5.30, 1.98 and 1.96 ppm. After photolysis for 2 h, 3k was completely decomposed, to cleanly yield the disulfide, with the methide resonance at ~ 4.65 ppm and gem-dimethyl groups at ~ 1.33 and 1.25 ppm. This disulfide was further confirmed by HRMS results (m/z (ESI): calculated for [M+H]+ = 731.1966; found = 731.1965). Interestingly, a partial thermal decomposition of 3k was observed after 4 d at 37 ˚C in the dark (see Fig. 4), yielding a mixture of 3k and its corresponding disulfide. These data provide evidence that 3k can be employed as a pure NO donor, to stoichiometrically release NO and the corresponding disulfide. The mechanism of NO-release from S-nitrosothiols has been well-studied under heat, irradiation, and Cu+ mediated reduction conditions.28, 30 A homolysis of the weak S-N bond could yield equal moles of NO and a thiyl radical. Thiyl radical intermediates are typically reactive, subsequently resulting in a rapid dimerization to yield the corresponding disulfide.28, 30 Finally, a possible NO generation pathway for NO donors 3 is summarized in Fig. 3b, based on our NO measurement and disulfide characterization.</p><p>To summarize, a novel family of fluorinated S-nitrosothiols has been reported herein. The presence of fluorine or fluoroalkyl groups on the benzylamide does not influence the stability of the S-N bond. Kinetic studies of their photolytic and thermal decomposition reactions were conducted. The stoichiometric release of NO and the corresponding disulfide formation from decomposition was monitored by NO chemiluminescence measurements and 1H NMR spectroscopy, respectively. Detailed theoretical calculations on the relationship between structure and stability of these new fluorinated NO donors are currently underway. We anticipate that these new species will have applications as useful NO release agents, potentially for incorporation into fluorinated biopolymers for preventing infection and/or thrombosis on surfaces of various medical devices. Such studies are now ongoing in our laboratory.</p>",
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"content": "A series of new fluoro S-nitrosothiols is reported as potential nitric oxide (NO) donors. A three-step synthesis and the NO releasing kinetic profiles of these species are presented. The stoichiometric release of NO, with the clean formation of corresponding disulfides, confirms that these new species can facilitate their application as NO donors for various applications including creating novel antimicrobial and thromboresistant fluoropolymer-based medical devices.",
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science.craftchem_ner | science.craftchem_ner.2109 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nThisisalsoinkeepingwithpreviousstudiesthatshowthatsitosterolisadirectinhibitorofthisenzymeinvitro[39].",
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{
"content": "[\"sitosterol\", \"inhibitor of this enzyme\"]",
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science.craftchem_ner | science.craftchem_ner.3455 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nArrowsmarkmembranelocalizationoftheproteinandasterisksmarkcellswithelevatedlevelsofcytoplasmicbeta-cateninorAjuba.",
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"content": "[\"protein\"]",
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.2669 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nLocality-sensitive hashing (LSH), introduced by Indyk and Motwani in STOC '98, has been an extremely influential framework for nearest neighbor search in high-dimensional data sets. While theoretical work has focused on the approximate nearest neighbor problems, in practice LSH data structures with suitably chosen parameters are used to solve the exact nearest neighbor problem (with some error probability). Sublinear query time is often possible in practice even for exact nearest neighbor search, intuitively because the nearest neighbor tends to be significantly closer than other data points. However, theory offers little advice on how to choose LSH parameters outside of pre-specified worst-case settings. We introduce the technique of confirmation sampling for solving the exact nearest neighbor problem using LSH. First, we give a general reduction that transforms a sequence of data structures that each find the nearest neighbor with a small, unknown probability, into a data structure that returns the nearest neighbor with probability @math , using as few queries as possible. Second, we present a new query algorithm for the LSH Forest data structure with @math trees that is able to return the exact nearest neighbor of a query point within the same time bound as an LSH Forest of @math trees with internal parameters specifically tuned to the query and data.\n\nCited Works Summary:\n[1]: The past decade has been marked by the (continued) explosion of diverse data content and the fast development of intelligent data analytics techniques. One problem we identified in the mid-2000s was similarity search of feature-rich data. The challenge here was achieving both high accuracy and high efficiency in high-dimensional spaces. Locality sensitive hashing (LSH), which uses certain random space partitions and hash table lookups to find approximate nearest neighbors, was a promising approach with theoretical guarantees. But LSH alone was insufficient since a large number of hash tables were required to achieve good search quality. Building on an idea of Panigrahy, our multi-probe LSH method introduced the idea of intelligent probing. Given a query object, we strategically probe its neighboring hash buckets (in a query-dependent fashion) by calculating the statistical probabilities of similar objects falling into each bucket. Such intelligent probing can significantly reduce the number of hash tables while achieving high quality. In this paper, we revisit the problem motivation, the challenges, the key design considerations of multi-probe LSH, as well as discuss recent developments in this space and some questions for further research.\n\n[2]: Although Locality-Sensitive Hashing (LSH) is a promising approach to similarity search in high-dimensional spaces, it has not been considered practical partly because its search quality is sensitive to several parameters that are quite data dependent. Previous research on LSH, though obtained interesting asymptotic results, provides little guidance on how these parameters should be chosen, and tuning parameters for a given dataset remains a tedious process. To address this problem, we present a statistical performance model of Multi-probe LSH, a state-of-the-art variance of LSH. Our model can accurately predict the average search quality and latency given a small sample dataset. Apart from automatic parameter tuning with the performance model, we also use the model to devise an adaptive LSH search algorithm to determine the probing parameter dynamically for each query. The adaptive probing method addresses the problem that even though the average performance is tuned for optimal, the variance of the performance is extremely high. We experimented with three different datasets including audio, images and 3D shapes to evaluate our methods. The results show the accuracy of the proposed model: the recall errors predicted are within 5 from the real values for most cases; the adaptive search method reduces the standard deviation of recall by about 50 over the existing method.",
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"content": "We note that the adaptive method of [2] does not adapt search depth to the distance distribution from the query point @math . In fact, choosing good parameters for LSH and especially multi-probe LSH was mentioned by [1] as a challenge in the paper celebrating their VLDB 10-year Best Paper Award.",
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science.scientific_lay_summarisation_elife_single_doc_summ | science.scientific_lay_summarisation_elife_single_doc_summ.725 | [
{
"content": "Transform the provided sections of a biomedical research paper into a digestible summary for a general audience. Focus on simplifying complex ideas while retaining key scientific insights.\n\nResearch Title: The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs\nContent Overview:\nAbstract:\nTranslation is a core cellular process carried out by a highly conserved macromolecular machine, the ribosome. There has been remarkable evolutionary adaptation of this machine through the addition of eukaryote-specific ribosomal proteins whose individual effects on ribosome function are largely unknown. Here we show that eukaryote-specific Asc1/RACK1 is required for efficient translation of mRNAs with short open reading frames that show greater than average translational efficiency in diverse eukaryotes. ASC1 mutants in S. cerevisiae display compromised translation of specific functional groups, including cytoplasmic and mitochondrial ribosomal proteins, and display cellular phenotypes consistent with their gene-specific translation defects. Asc1-sensitive mRNAs are preferentially associated with the translational ‘closed loop’ complex comprised of eIF4E, eIF4G, and Pab1, and depletion of eIF4G mimics the translational defects of ASC1 mutants. Together our results reveal a role for Asc1/RACK1 in a length-dependent initiation mechanism optimized for efficient translation of genes with important housekeeping functions.\nIntroduction:\nRibosomes are universal protein-synthesizing machines that are highly conserved in their structure and function throughout all kingdoms of life. However, each domain of life has evolved unique ribosomal proteins that are added to the conserved core. The fundamental tasks of ribosomes— deciphering the genetic code and synthesizing peptide bonds— are the same in all organisms, so the functions of these ‘extra’ ribosomal proteins are intriguing, yet almost entirely unknown. Eukaryotic ribosomes contain 13 domain-specific proteins that may play roles in translation initiation, which is both more complicated and more highly regulated in eukaryotes than in prokaryotes( Ban et al., 2014; Sonenberg and Hinnebusch, 2009). Recruitment of prokaryotic ribosomes to mRNAs requires only three initiation factors, IF1, 2, and 3, and relies on base-pairing between the RNA of the small ribosomal subunit and the anti-Shine-Delgarno sequence of the mRNA( Boelens and Gualerzi, 2002). In contrast, translation initiation in eukaryotes requires at least 12 initiation factors and proceeds by a complex series of steps beginning with recognition of the mRNA 5′ cap structure, followed by unwinding of mRNA secondary structure, recruitment of the small( 40S) ribosomal subunit, scanning, recognition of the initiation codon, and finally, joining of the large( 60S) ribosomal subunit to form a functional ribosome( Aitken and Lorsch, 2012). Although the eukaryotic ribosome is generally considered to be a passive player during canonical initiation, several of its proteins have been implicated in mRNA recruitment. For example, RPL38 is required for the translation of the Hox body-patterning genes during embryonic development, allowing spatiotemporal regulation of gene expression through translational control( Kondrashov et al., 2011). Other proteins including RPS25, RPL40, and RACK1 are essential for the translation of viral mRNAs that are recruited to the ribosome via alternative initiation pathways( Cherry et al., 2005; Landry et al., 2009; Lee et al., 2013; Majzoub et al., 2014). The eukaryote-specific ribosomal protein RACK1 is a WD40-repeat β-propeller protein that binds the solvent-exposed face of the 40S subunit near the mRNA exit channel, in close proximity to proteins that contact the mRNA during translation initiation( Pisarev et al., 2008; Sengupta et al., 2004). In addition to its function as a core ribosomal protein, in mammalian cells, RACK1 has been found in complex with several proteins involved in signal transduction including protein kinase C, Src kinase, and cAMP phosphodiesterase, among many others( Adams et al., 2011). The location of RACK1 on the ribosome together with its interactions with signaling proteins suggests a possible role in conveying stimulus-dependent information to the translation machinery( Nilsson et al., 2004). However, signaling pathways in yeast and human have diverged significantly compared to genes required for ribosomal function( Stuart et al., 2003), suggesting that RACK1 might have another, more conserved function during translation. Loss of RACK1 causes widespread and pleiotropic defects in many organisms. Deletion of the RACK1 homolog in budding yeast, ASC1, leads to slow growth, loss of invasive growth, loss of cell wall integrity, and decreased 60S subunit levels, among many described effects( Li et al., 2009; Melamed et al., 2010; Valerius et al., 2007; Yoshikawa et al., 2011). In metazoans, RACK1 is required for cell migration, neural tube closure, and control of post-synaptic excitation in the brain( Kiely et al., 2009; Ron et al., 1999; Wehner et al., 2011; Yaka et al., 2002). These cellular functions may explain why homozygous RACK1 loss-of-function mutations cause early developmental lethality in mouse and flies( Kadrmas et al., 2007; Volta et al., 2013). However, it is not known whether and how the effects of RACK1 on ribosome function contribute to the myriad cellular and organismal phenotypes observed in RACK1/ASC1 mutants( Gibson, 2012). Here we have examined the translational functions of Asc1/RACK1 genome-wide by ribosome footprint profiling in yeast ASC1 mutants. We show that Asc1 is required for the efficient translation of short mRNAs, including those encoding cytoplasmic and mitochondrial ribosomal proteins. This requirement is specific as deletion of other ribosomal proteins does not cause similar translation defects. Using translational reporters we demonstrate that length per se determines translational sensitivity to Asc1, thus confirming a role for Asc1 in the translational privileging of short mRNAs, which is a dominant trend in genome-wide translational efficiency data from diverse eukaryotes. Remarkably, mRNA enrichment with proteins that mediate the formation of a ‘closed loop’ during translation— eIF4E, eIF4G, and Pab1— is strongly biased towards short mRNAs and predicts Asc1-sensitivity, suggesting a role for Asc1 in closed-loop-dependent ribosome recruitment. Consistent with this prediction, we find that depletion of the central closed loop factor eIF4G mimics the translational effects of mutating ASC1. Finally, we show that loss of ASC1 reduces mitochondrial translation and renders cells unable to use alternative carbon sources that require enhanced mitochondrial function, demonstrating the functional significance of translational perturbation in ASC1 mutants. Together, our results reveal a role for Asc1 in the enhanced translation of short mRNAs and establish a direct connection between gene-specific effects of Asc1 on translation and defects in cellular physiology. Furthermore, because mitochondria are essential for energy generation and regulation of many cellular networks, our results suggest that the pleiotropic phenotypes associated with the Asc1/RACK1 protein should be re-examined in the context of mitochondrial health.\nDiscussion:\nHere we have demonstrated that the eukaryote-specific ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs, a category that includes functionally related groups of genes required for vital cellular processes( e. g. cytoplasmic and mitochondrial ribosomal proteins). A correlation between ORF length and translation efficiency or ribosome density has been observed since the advent of genome-wide translation profiling( Arava et al., 2003; Ingolia et al., 2009) and we observed this relationship in data collected from diverse eukaryotes including yeast, nematodes, mice, and humans( Guo et al., 2010; Stadler and Fire, 2011). To account for this trend, it was proposed that the rate of translation initiation is higher for short ORFs( Arava et al., 2005; Shah et al., 2013), but the mechanism( s) underlying length-dependent initiation rate differences were unknown. It has been suggested that the increased probability of mRNA circularization by diffusion could make initiation more efficient on short mRNAs( Chou, 2003; Guo et al., 2015). Our results add an additional nuance to these physical models — the presence of a ribosome-dependent regulatory mechanism that specifically enhances the translation of short mRNAs by promoting the formation and/or function of the closed loop. Our analyses reveal a clear trend that short mRNAs preferentially associate with closed loop factors in vivo, and consistent with these observations, short mRNAs form more stable closed loop complexes than longer mRNAs in vitro( Amrani et al., 2008). A challenge for the future will be to determine how the mRNA, the closed loop factors, and the ribosome cooperate to privilege the translation of short mRNAs. How might Asc1/RACK1 promote closed loop formation? RACK1’s placement on the solvent exposed side of the head of the small subunit puts it in close proximity to the mRNA exit channel, in a position with the potential to interact with the mRNA-bound closed loop factors during initiation. Intriguingly, eIF4G co-purifies with Asc1 from yeast lysates under stringent conditions in which most other initiation factors do not( Gavin et al., 2002; 2006), suggesting that Asc1 may interact directly with the closed loop via eIF4G. Our results also raise the possibility that translation of many mRNAs could be co-regulated by mechanism( s) that target Asc1/RACK1’s function in closed-loop-dependent initiation. Moving forward, it will be important to determine how the many signaling pathways that have been linked to Asc1/RACK1 impact the translation of closed-loop-dependent mRNAs. More generally, our study highlights the fact that individual ribosomal proteins can contribute to efficient translation of subsets of mRNAs with important consequences for cellular physiology. In particular we show that loss of the non-essential ribosomal protein Asc1/RACK1 causes a concerted decrease in MRP expression that leads to mitochondrial insufficiency. Given the central role of mitochondria in energy and metabolite production in eukaryotic cells, it is not surprising that mitochondrial defects elicit pleiotropic consequences( Calvo and Mootha, 2010; Fleming et al., 2001; Kushnir et al., 2001; Shoffner et al., 1990; Vafai and Mootha, 2012). In light of our findings, many of Asc1/RACK1’s ascribed cellular functions should be re-evaluated for potential connections to mitochondrial dysfunction. Finally, it is intriguing that several distinct mutations in human ribosomal proteins and ribosome biogenesis factors result in anemia, the cause of which is currently the source of much debate( Freed et al., 2010; Narla et al., 2011). Given that many forms of heritable anemia have been traced to defects in mitochondrial iron metabolism( Dailey and Meissner, 2013; Huang et al., 2011), it will be interesting to see whether translation of nuclear-encoded mitochondrial proteins is affected in these diseases and whether these defects contribute to pathogenesis.",
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"content": "Ribosomes are structures within cells that are responsible for making proteins . Molecules called messenger RNAs ( or mRNAs ) , which contain genetic information derived from the DNA of a gene , pass through ribosomes that then “translate” that information to build proteins . Although all living cells contain ribosomes , the protein building blocks that make up the structure of the ribosome are not the same in all species . Furthermore , the exact roles that each building block plays during translation are not known . The ribosomes of plants , animals , and budding yeast contain the same protein , known as Asc1 in budding yeast and RACK1 in plants and animals . Thompson et al . have now explored the role of Asc1 in yeast cells by measuring translation in the absence of Asc1 using a technique called ribosome footprint profiling . This analysis revealed that cells lacking Asc1 translate fewer short mRNA molecules than normal cells . Short mRNAs encode small proteins that tend to play important ‘housekeeping’ roles in the cell — by forming the structural building blocks of ribosomes , for example . It has been observed previously that short mRNAs are translated at a higher rate than longer mRNAs on average , although the reasons behind this bias are still mysterious . The findings of Thompson et al . suggest that the ribosome itself may discriminate between short and long mRNAs and that the Asc1 protein is involved in calibrating the ribosome’s preference for short mRNAs . Cells need differing amounts of small proteins in different growth conditions . It will therefore be interesting to investigate whether mRNA length discrimination can be regulated by Asc1 and/or other components of the ribosome to tune gene expression to the environment .",
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science.chia_ner | science.chia_ner.802 | [
{
"content": "Analyze the provided clinical trial criteria. Identify and extract distinct entities from the text.\n\nReturn the results as a JSON structure. Ensure the output is strictly in JSON format without any additional commentary.\n\nCriteria Text:\n\nPatients will be excluded if they have had exposure to a total daily dose of MET 1000 mg bid for at least 2 weeks in the past 3 months;\nPatients will be excluded if they could not tolerate MET during the recommended titration schedule outlined in the protocol;\nMajor neurological or medical illnesses that affect weight gain (e.g., unstable thyroid disease) or require a systemic medication that might impact weight or glucose regulation (e.g., diabetes mellitus [insulin], chronic renal failure [steroids]);\nFasting glucose = 126 mg/dL on 2 occasions during screening indicating need for prompt treatment;\nIf lab results are available in the last 6 months, then a serum creatinine =1.3 mg/dL on 2 occasions during screening and/or follow-up, indicating potential impairment of renal functioning;\nPregnant or breast feeding;\nChildren and caregivers who are unable to complete assessments for any reason;",
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"content": "{\"Condition\": [\"diabetes mellitus\", \"not tolerate\", \"chronic renal failure\", \"thyroid disease\"], \"Device\": [], \"Drug\": [\"steroids\", \"insulin\", \"MET\"], \"Measurement\": [\"serum creatinine\", \"Fasting glucose\"], \"Mood\": [], \"Multiplier\": [\"1000 mg bid\", \"2\", \"2 o\"], \"Negation\": [], \"Observation\": [], \"Person\": [], \"Procedure\": [], \"Qualifier\": [\"unstable\"], \"ReferencePoint\": [], \"Scope\": [], \"Temporal\": [\"at least 2 weeks in the past 3 months\"], \"Value\": [\"=1.3 mg/dL\", \"= 126 mg/dL\"], \"Visit\": []}",
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science.scitldr_aic | science.scitldr_aic.1424 | [
{
"content": "Review the provided sections from a computer science paper and distill the primary contribution into a single sentence. Provide only the summary sentence.\n\nSections:\n\nOpen-domain question answering (QA) is an important problem in AI and NLP that is emerging as a bellwether for progress on the generalizability of AI methods and techniques.\nMuch of the progress in open-domain QA systems has been realized through advances in information retrieval methods and corpus construction.\nIn this paper, we focus on the recently introduced ARC Challenge dataset, which contains 2,590 multiple choice questions authored for grade-school science exams.\nThese questions are selected to be the most challenging for current QA systems, and current state of the art performance is only slightly better than random chance.\nWe present a system that reformulates a given question into queries that are used to retrieve supporting text from a large corpus of science-related text.\nOur rewriter is able to incorporate background knowledge from ConceptNet and -- in tandem with a generic textual entailment system trained on SciTail that identifies support in the retrieved results -- outperforms several strong baselines on the end-to-end QA task despite only being trained to identify essential terms in the original source question.\nWe use a generalizable decision methodology over the retrieved evidence and answer candidates to select the best answer.\nBy combining query reformulation, background knowledge, and textual entailment our system is able to outperform several strong baselines on the ARC dataset.\nThe recently released AI2 Reasoning Challenge (ARC) and accompanying ARC Corpus is an ambitious test for AI systems that perform open-domain question answering (QA).\nThis dataset consists of 2590 multiple choice questions authored for grade-school science exams; the questions are partitioned into an Easy set and a Challenge set.\nThe Challenge set comprises questions that cannot be answered correctly by either a Pointwise Mutual Information (PMI-based) solver, or by an Information Retrieval (IR-based) solver.\nalso note that the simple information retrieval (IR) methodology (Elasticsearch) that they use is a key weakness of current systems, and conjecture that 95% of the questions can be answered using ARC corpus sentences.ARC has proved to be a difficult dataset to perform well on, particularly its Challenge partition: existing systems like KG 2 achieve 31.70% accuracy on the test partition.\nOlder models such as DecompAttn BID27 and BiDAF that have shown good performance on other datasets -e.g. SQuAD BID29 ] -perform only 1-2% above random chance.\n1 The seeming intractability of the ARC Challenge dataset has only very recently shown signs of yielding, with the newest techniques attaining an accuracy of 42.32% on the Challenge set BID35 .\n2 An important avenue of attack on ARC was identified in Boratko et al. [2018a,b] , which examined the knowledge and reasoning requirements for answering questions in the ARC dataset.\nThe authors note that \"simple reformulations to the query can greatly increase the quality of the retrieved sentences\".\nThey quantitatively measure the effectiveness of such an approach by demonstrating a 42% increase in score on ARC-Easy using a pre-trained version of the DrQA model BID7 .\nAnother recent tack that many top-performing systems for ARC have taken is the use of natural language inference (NLI) models to answer the questions .\nThe NLI task -also sometimes known as recognizing textual entailment -is to determine whether a given natural language hypothesis h can be inferred from a natural language premise p.\nThe NLI problem is often cast as a classification problem: given a hypothesis and premise, classify their relationship as either entailment, contradiction, or neutral.\nNLI models have improved state of the art performance on a number of important NLP tasks BID27 and have gained recent popularity due to the release of large datasets BID4 BID46 BID43 .\nIn addition to the NLI models, other techniques applied to ARC include using pre-trained graph embeddings to capture commonsense relations between concepts BID51 ; as well as the current state-of-theart approach that recasts multiple choice question answering as a reading comprehension problem that can also be used to fine-tune a pre-trained language model BID35 .ARC\nChallenge represents a unique obstacle in the open domain QA world, as the questions are specifically selected to not be answerable by merely using basic techniques augmented with a high quality corpus. Our\napproach combines current best practices: it retrieves highly salient evidence, and then judges this evidence using a general NLI model. While\nother recent systems for ARC have taken a similar approach BID26 BID25 , our extensive analysis of both the rewriter module as well as our decision rules sheds new light on this unique dataset.In order to overcome some of the limitations of existing retrieval-based systems on ARC and other similar corpora, we present an approach that uses the original question to produce a set of reformulations. These\nreformulations are then used to retrieve additional supporting text which can then be used to arrive at the correct answer. We couple\nthis with a textual entailment model and a robust decision rule to achieve good performance on the ARC dataset. We discuss\nimportant lessons learned in the construction of this system, and key issues that need to be addressed in order to move forward on the ARC dataset.\nOf the systems above ours on the leaderboard, only BID26 report their accuracy on both the dev set (43.29%) and the test set (36.36%).\nWe suffer a similar loss in performance from 36.37% to 33.20%, demonstrating the risk of overfitting to a (relatively small) development set in the multiplechoice setting even when a model has few learnable parameters.\nAs in this paper, BID26 pursue the approach suggested by Boratko et al. [2018a,b] in learning how to transform a naturallanguage question into a query for which an IR system can return a higher-quality selection of results.\nBoth of these systems use entailment models similar to our match-LSTM BID41 model, but also incorporate additional co-attention between questions, candidate answers, and the retrieved evidence.\nBID35 present an an encouraging result for combating the IR bottleneck in opendomain QA.\nBy concatenating the top-50 results of a single (joint) query and feeding the result into a neural reader optimized by several lightly-supervised 'reading strategies', they achieve an accuracy of 37.4% on the test set even without optimizing for single-answer selection.\nIntegrating this approach with our query rewriting module is left for future work.\nIn this paper, we present a system that answers science exam questions by retrieving supporting evidence from a large, noisy corpus on the basis of keywords extracted from the original query.\nBy combining query rewriting, background knowledge, and textual entailment, our system is able to outperform several strong baselines on the ARC dataset.\nOur rewriter is able to incorporate background knowledge from ConceptNet and -in tandem with a generic entailment model trained on SciTail -achieves near state of the art performance on the end-to-end QA task despite only being trained to identify essential terms in the original source question.There are a number of key takeaways from our work: first, researchers should be aware of the impact that Elasticsearch (or a similar tool) can have on the performance of their models.\nAnswer candidates should not be discarded based on the relevance score of their top result; while (correct) answers are likely critical to retrieving relevant results, the original AI2 Rule is too aggressive in pruning candidates.\nUsing an entailment model that is capable of leveraging background knowledge in a more principled way would likely help in filtering unproductive search results.\nSecond, our results corroborate those of BID26 and show that tuning to the dev partition of the Challenge set (299 questions) is extremely sensitive.\nThough we are unable to speculate on whether this is an artifact of the dataset or a more fundamental concern in multiple-choice QA, it is an important consideration for generating significant and reproducible improvements on the ARC dataset.",
"role": "user"
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"content": "We explore how using background knowledge with query reformulation can help retrieve better supporting evidence when answering multiple-choice science questions.",
"role": "assistant"
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science.craftchem_ner | science.craftchem_ner.3887 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nAbnormalMuscleMitochondrialPhenotypeinPGC-1alpha-/-Mice",
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"content": "[]",
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science.bioasq_factoid_qa | science.bioasq_factoid_qa.670 | [
{
"content": "Given the following biomedical passages, answer the question succinctly. Ensure your response is precise and limited to the answer only.\n\nQuestion: Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?\n\nPassages: MARS: improving multiple circular sequence alignment using refined sequences.\nWe present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed.\nWe present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences.\nExperimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency.\nRESULTS We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences.\nA solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program.<br><b>RESULTS</b>: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences.\nMARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences.\nMARS: improving multiple circular sequence alignment using refined sequences.",
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{
"content": "MARS",
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science.covid_deepset_qa | science.covid_deepset_qa.1661 | [
{
"content": "Analyze the following excerpt from a biomedical text. Identify the relevant information needed to respond to the inquiry. Provide only the necessary details in your answer.\n\nContext: Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation (Wood et al., 2011; Essaidi-Laziosi et al., 2018) . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer (Imperiale and Jiang, 2015) , further contributing to chronic activation of inflammation when they infect the airway (Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017) . With that note, human papilloma virus (HPV), a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies (de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015) . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection (Chi et al., 2011; Ford et al., 2013; Papi et al., 2013) . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance (Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b) . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV (Yan et al., 2016; Guibas et al., 2018) and certain CoV (including the recently emerged COVID-19 virus) (Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020) , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection (Yan et al., 2016; Tan et al., 2019) . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium (Ampomah et al., 2018; Tan et al., 2019) . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway (Guibas et al., 2018) . Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections (Vasileiou et al., 2017; Zheng et al., 2018) ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M (OSM) which causes tight junction opening (Pothoven et al., 2015; Tian et al., 2018) . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases (Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018) . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 (ANGPTL4) and bactericidal/permeabilityincreasing fold-containing family member A1 (BPIFA1) are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018) . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment (Diver et al., 2019) . In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present (Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019) . In addition, viral infection may disrupt biofilm colonies in the upper airway (e.g., Streptococcus pneumoniae) microbiome to be release into the lower airway and worsening the inflammation (Marks et al., 2013; Chao et al., 2014) . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth (Siegel et al., 2014; Mallia et al., 2018) . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms (Singanayagam et al., 2018 (Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019) . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles (Teo et al., 2018) . These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases (Wark et al., 2013; Singanayagam et al., 2018) . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome (Bakken et al., 2011) . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism (with literature evidence) Oxidative stress ROS production (RV, RSV, IFV, HSV)\n\nAs RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation (see text for abbreviations). that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection (Griggs et al., 2017) . Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown (Peng et al., , 2019 Qiu et al., 2018) . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 (DNAH5) and multiciliate differentiation And DNA synthesis associated cell cycle protein (MCIDAS) (Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model (Zhu et al., 2020) . Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells (Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a) . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation (Zhu et al., 2009) . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases (Tan et al., 2014) . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation (Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018) . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases (Wardzynska et al., 2020) . Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids (Kim et al., 2017) . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections (Hsu et al., 2016 (Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations (Moheimani et al., 2018) . Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections (Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018) . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes (Cardenas et al., 2019; Gomez, 2019) .\n\nInquiry: What have recent epigenetic studies indicated?",
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"content": "the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes (Cardenas et al., 2019; Gomez, 2019) .",
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science.scientific_lay_summarisation_plos_single_doc_summ | science.scientific_lay_summarisation_plos_single_doc_summ.4402 | [
{
"content": "Transform the following sections from a biomedical study into a simple summary for the general public. Focus on making the information accessible and easy to understand.\n\nResearch Heading: The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection\nContent:\nAbstract:\nThe genus Orthopoxviridae contains a diverse group of human pathogens including monkeypox, smallpox and vaccinia. These viruses are presumed to be less dependent on host functions than other DNA viruses because they have large genomes and replicate in the cytoplasm, but a detailed understanding of the host factors required by orthopoxviruses is lacking. To address this topic, we performed an unbiased, genome-wide pooled RNAi screen targeting over 17, 000 human genes to identify the host factors that support orthopoxvirus infection. We used secondary and tertiary assays to validate our screen results. One of the strongest hits was heat shock factor 1( HSF1), the ancient master regulator of the cytoprotective heat-shock response. In investigating the behavior of HSF1 during vaccinia infection, we found that HSF1 was phosphorylated, translocated to the nucleus, and increased transcription of HSF1 target genes. Activation of HSF1 was supportive for virus replication, as RNAi knockdown and HSF1 small molecule inhibition prevented orthopoxvirus infection. Consistent with its role as a transcriptional activator, inhibition of several HSF1 targets also blocked vaccinia virus replication. These data show that orthopoxviruses co-opt host transcriptional responses for their own benefit, thereby effectively extending their functional genome to include genes residing within the host DNA. The dependence on HSF1 and its chaperone network offers multiple opportunities for antiviral drug development.\nIntroduction:\nThe Poxviridae family is comprised of several human pathogens in the Orthopoxvirus genus, including monkeypox( MPXV) and smallpox( Variola), which was eradicated through vaccination with vaccinia( VACV). With a dramatic increase in human MPXV cases in Africa, the rise of VACV-like orthopoxvirus infection in South America, and concerns about the weaponization of smallpox, it is important to design new strategies for the treatment and prevention of these diseases[1],[2]. To this end, one valuable method to understand the mechanism of disease is to determine the virus-host interactions necessary for orthopoxvirus infection. Orthopoxviruses are large double-stranded DNA viruses with a unique lifecycle in the cytoplasm of the host cell. The viruses enact a cascade of transcriptional responses, with early gene expression occurring from the stages of viral entry to uncoating, intermediate gene expression after DNA replication, followed by late gene expression until the end of the virus lifecycle[3],[4]. Early in infection, orthopoxviruses express factors that cleave host mRNAs, effectively preventing the expression of most host genes[4],[5]. Poxviruses are also known to use host proteins during their lifecycle. This includes the use of the proteasome to facilitate viral uncoating and DNA replication, the ribosome to translate mRNAs, and specific host factors to help drive late viral transcription events[6]–[9]. Several RNAi screens have been performed in recent years and have expanded our knowledge of the host proteins involved in orthopoxvirus replication. Moser et al. performed a screen of kinase genes in Drosophila cells and found that modulation of the actin cytoskeleton by AMPK is important for VACV entry[10]. Mercer et al. screened the 7, 000 genes comprising the ‘druggable genome’ and revealed the role of the proteasome in viral uncoating and of the Cullin3 ubiquitin ligase in initiating viral DNA replication[9]. Finally, Sivan et al. performed two siRNA screens targeting over 18, 000 genes to reveal the importance of nuclear pore genes in viral morphogenesis[11]. All of these important new insights were based on an arrayed RNAi screen format. Notably, these screens generated hit lists with some overlap on the protein or functional level, but also significant numbers of unique hits. This is presumably due to substantial false negative rates, false positive rates, and the distinct model systems and readouts used to assess VACV infection, suggesting that more host protein factors remain to be discovered. Here, we used two complimentary and unbiased assays to identify host proteins necessary for orthopoxvirus infection. First, we developed a pooled-cell lentiviral shRNA screen in human cells based on screening formats previously utilized to determine pathways important in cancer biology[12],[13]. Strengths of the pooled screen format are the ease of scaling to larger screening sets and the ability to enable multiple screening paradigms. Furthermore, cells are cultured in standard low-throughput format, rather than in multiwell plates, and thus can be easily passaged and otherwise manipulated. As a second assay, we used RNASeq to analyze the host transcriptional responses elicited by poxviral infection. These data identified host mRNAs that were upregulated during infection, suggesting that they may facilitate virus infection. By comparing the data from these two orthogonal datasets, we identified proteins involved in the heat shock response as critical factors for orthopoxvirus infection. In particular, we found that heat shock factor 1( HSF1), the ancient master regulator of the cytoprotective heat shock response, is necessary for orthopoxvirus infection. We find that depletion and knockout of HSF1 or its pharmacologic inhibition significantly reduces VACV infection. Moreover, the principal targets of HSF1 transcription are upregulated during VACV infection, even as global host gene expression is suppressed. Our findings define a set of host factors that are necessary for orthopoxvirus infection and suggest that poxviruses have evolved to utilize host stress responses to their own advantage.\nDiscussion:\nHere we identify HSF1, the master regulator of the host transcriptional response to proteotoxic cellular stress, as a critical host factor for orthopoxvirus infection. Identifying HSF1 as important resulted from the combined use of two unbiased experimental approaches: RNASeq and pooled shRNA screening. Pooled shRNA libraries have not yet been widely used to identify host factors important for virus replication, but may be a useful tool for probing the virus-host interaction on a genomic scale. While pooled screening is subject to the same false hit rates and cell toxicity issues as comparable arrayed format screens, our results show that both screening approaches identify components of similar cellular pathways. Of our high-confidence hits, half( HSF1, JAG1, TNPO3, SKI) have a nuclear function or signal to transcription factors, which is interesting for a cytoplasmic virus. We also have a strong correlation with recently published host factors necessary for orthopoxvirus infection. Sivan et al recently described the importance of nuclear pore proteins in viral morphogenesis; we identified the nuclear import protein TNPO3 in our screen. JAG1, a Notch signaling molecule, is regulated by the Wnt pathway. The Wnt pathway was recently published to be important for Myxoma leporipoxvirus infection[60]. We also identified ITGB1BP1, or ICAP1, which specifically binds to the cytoplasmic domain of beta1 integrin. Beta1 integrin was recently shown to interact with VACV on the cell surface and signal through PI3K/Akt to facilitate VACV entry[61]. Previously published RNAi screens for necessary host factors during poxvirus infection of mammalian cells all also identified members of the heat shock response pathway, however the candidate genes were not validated or further developed in those publications[9],[11],[60]. Our screen was the only one to identify the master regulator of the pathway, HSF1, as important. The reason that our screen identified HSF1 and other screens did not is not immediately apparent, but it is notable that all of the screens enforce the idea that HSPs are important for viral replication. The activation of HSF1 helps unify a mechanism for how poxviruses control the expression of many host proteins that they utilize. Earlier reports established that several heat shock proteins associate with VACV proteins during infection. HSP90 interacts with VACV core protein 4a( A10L), and colocalizes with the viral factory during specific stages of the virus lifecycle[62]. Evidence suggests several viral proteins are bound by HSP70/72[63]. HSP27( HSPB1) binds to three VACV proteins in protein-interaction studies: a truncated TNF-α receptor-like protein( VACV-WR002), C2L kelch-like protein( VACV-WR026) and I4L ribonucleoside-diphosphate reductase large subunit( VACV-WR073)[64]. Upregulation of HSF1 transcription provides a mechanism for how VACV and other poxviruses ensure sufficient levels of multiple chaperones through the activation of a single host protein. While other studies have shown that poxviruses can activate host transcription processes[65], our study suggests that the activation of HSF1 aids orthopoxvirus replication on multiple levels. In addition to the involvement of HSPs as mentioned in the previous paragraph, HSC70, HSP72 and HSP90 have been shown to be packaged within virions[66]–[68], suggesting an importance for chaperones in early stages of virus infection. The continuous usage of host cell chaperones at multiple( if not all) stages of the virus lifecycle shows that poxviruses use the heat shock response to extend their genome, activating HSF1 to transcribe essential factors that are encoded by the host. A prediction of this genome extension hypothesis would be that some members of the family Poxviridae will have evolved to include one or more HSF1-stimulated genes in their own genome, reducing their dependence on host-production of HSPs. Consistent with this, genus Mulluscipoxvirus( Molluscum contagiosum; accession number AAC55141) and genus Crocodylipoxvirus( Nile crocodilepox virus; accession number YP_784220) encode proteins with homology to the DNAJ/HSP40 chaperone family. Interestingly, other large, cytoplasmically replicating DNA viruses encode HSPs in their genome. This is most striking in the case of mimiviruses, which express HSP70( MIMI_L254), HSP40/DNAJ( MIMI_R269, MIMI_gp0838) and DNAK( MIMI_L393) homologs, suggesting the requirement for large amounts of these HSPs during viral replication is consistent across cytoplasmic large DNA viruses[69],[70]. How orthopoxviruses activate HSF1 is an interesting question for future study. In unstressed cells, HSF1 is in an inactive form in the cytoplasm, bound to several proteins including HSP90 and HSP70. There are several proposed mechanisms of activation of HSF1, including the idea that recruitment of HSP90 and/or HSP70 away from HSF1 in the cytoplasm allows the free HSF1 to become post-translationally modified and translocate to the nucleus to begin transcribing genes[30],[41]–[43]. HSF1 may be activated during VACV infection when cytosolic HSP90 is recruited to the viral factory, as has been previously shown[62]. Poxviruses also encode kinases, which may act to directly phosphorylate and activate HSF1 during VACV infection. Finally, orthopoxviruses may indirectly activate HSF1 by stimulating the MAPK signaling pathway[71], which in turn strongly drives HSF1 activity[72]. Understanding these mechanisms may provide insight into how an invading virion can manipulate the levels of a selective set of host proteins while also deploying proteins that reduce the general level of host mRNAs. Together, these data unify previously disparate observations regarding individually identified heat shock proteins and poxvirus infection. Earlier studies had illustrated the importance of individual members of the heat-shock response, but had not established whether poxviruses co-opted existing proteins or whether a heat-shock response was activated. Both our shRNA screening data and transcriptomic analysis implicate HSF1 activation as an important aspect of the orthopoxvirus lifecycle. This has implications not only for understanding viral evolution but also offers potential antiviral targets. Furthermore, our studies underscore that the HSF1 pathway is a viable target for broad-spectrum antiviral development, as it is a core cellular process used by multiple viruses, including HIV and EBV[73],[74]. A more complete understanding of how perturbing cellular homeostasis benefits viral replication will be important for illuminating the biology of virus-host interactions and for recognizing new therapeutic possibilities.",
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"content": "Orthopoxviruses bring in many of the factors they need for replication and impair the host cell by preventing the expression of host proteins . Although orthopoxviruses are less reliant on the host than some viruses , host factors are still required for infection . Here , we report results from two genome-scale approaches that identify host proteins used by orthopoxviruses during infection . These approaches showed that the master regulator of the heat shock response , heat shock factor 1 ( HSF1 ) , is a critical host factor for orthopoxvirus replication . HSF1-regulated genes are some of the only host genes with expression maintained or increased following virus infection . Our studies show that orthopoxviruses enter the cell and activate a host transcription pathway as part of its own replication process . These proteins are then utilized by the virus during infection and packaged into the virion , essentially extending the viral genome to include genes co-opted from the host nuclear DNA . This is supported by the existence of heat shock proteins in the viral genome of non-orthopoxvirus genera . We further show that small-molecule inhibitors of HSF1 and HSF1-transcribed genes are effective inhibitors of orthopoxvirus replication , suggesting a new avenue for antiviral development .",
"role": "assistant"
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science.craftchem_ner | science.craftchem_ner.3348 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nSectionswerefixedin4%paraformaldehydefor10minatroomtemperature,blocked,andstainedwithantibodies.",
"role": "user"
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"content": "[]",
"role": "assistant"
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science.anat_em_ner | science.anat_em_ner.179 | [
{
"content": "Analyze the provided text from a biomedical study. Your task is to detect and list entities based on predefined categories.\n\nPresent your results in a JSON format: {\"AnatomicalEntity\": [\"entity1\", \"entity2\", ...]}. Each category should have a corresponding list of identified entities. \n\nText:\n\nPreliminary evidence for a pyridine nucleotide cycle in Bordetella pertussis.\nPreliminary evidence that Bordetella pertussis has a functional pyridine nucleotide cycle was the observation that [14C]-nicotinic acid was rapidly metabolized during its uptake by the bacteria to pyridine nucleotides and nicotinamide. Nicotinamide deamidase activity, necessary for the completion of the cycle by conversion of nicotinamide to nicotinic acid, was found in a soluble extract (20 000 X g supernatant) of B. pertussis cell lysates.",
"role": "user"
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{
"content": "{\"AnatomicalEntity\": [\"extract\", \"cell lysates\", \"supernatant\"]}",
"role": "assistant"
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science.chemsum_single_document_summarization | science.chemsum_single_document_summarization.20053 | [
{
"content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nAn Orthosteric Inhibitor of the Ras-Sos Interaction\n\nContent Extracts:\n\n<p>Aberrant receptor tyrosine kinase (RTK) signaling is a major underlying cause of various developmental disorders and hyperproliferative diseases.1 A primary transduction mechanism by which RTK signals are propagated involves the ligand-dependent activation of the small guanine nucleotide binding protein Ras (Fig. 1a).2 The rate-limiting step in this activation process is the conversion of Ras-GDP to Ras-GTP through an exchange reaction that is catalyzed by the Ras specific guanine nucleotide exchange factor Sos.3 Accordingly, the design of inhibitors that target Sos-mediated Ras activation should constitute an effective strategy for experimental and therapeutic intervention.4</p><p>Structural and biochemical analyses of Ras-Sos interactions have demonstrated the involvement of multiple inter- and intra-molecular interactions that act in concert to destabilize the nucleotide-bound state of Ras.3 A key element of this catalytic process is the disruption of direct and water-mediated interactions between Ras and guanine nucleotide by the insertion of a helical hairpin from Sos into the switch regions of Ras (Fig. 1b). Since the αH helix is the only portion of the hairpin that makes direct contact with Ras, we reasoned that α-helical mimics of αH could interfere with Ras-Sos interaction. Computational5 and experimental mutational6 analyses identified F929 and N944 as residues that contribute most strongly to the binding of αH to Ras (Supplementary Results, Supplementary Table 2). Thus, we initiated the design of stabilized helices that mimic the full length (929–944) Sos αH helix. To this end we utilized the hydrogen bond surrogate (HBS) approach to design stabilized α-helical peptides (Fig. 1c).7 The HBS strategy affords preorganized α-helices in which the N-terminal main chain hydrogen bond between the C=O of the ith amino acid residue and the NH of the i+4th amino acid residue is replaced with a carbon-carbon bond. HBS helices have been previously shown to target their chosen protein receptors with high affinity and specificity.8,9</p><p>Synthetic mimics of the wild-type Sos αH (929–944) were only partially soluble in aqueous buffers at 25 µM and higher concentrations. We therefore optimized the native peptide sequence by incorporating charged residues at non-interfacial positions to enhance solubility. During this iterative design process, we also simultaneously examined the sequences for their helical content by circular dichroism spectroscopy and their potential to inhibit Ras/Sos association in an in vitro nucleotide exchange assay.10 Replacement of non-essential hydrophobic residues and substitution of β-branched residues, which have low helix-forming propensities,11 with suitable residues that favor the helical conformation resulted in an optimized sequence FEGIYRLELLKAEEAN. Detailed discussion of our peptide design strategy along with properties of various sequences is included as Supplementary Results. HBS helices were synthesized as previously described (Supplementary Fig. 1).12 The key step in the synthesis of these compounds consists of a ring-closing metathesis reaction between two appropriately placed alkene groups on the resin bound peptide. One of the olefin coupling partners is installed by appending 4-pentenoic acid to the N-terminal amino acid residue, while the other olefin is incorporated as an N-allyl group at the i+4 position.</p><p>The optimized HBS helix, HBS 3, was judged to be 56% helical in 10% trifluoroethanol in phosphate buffered saline (Supplementary Fig. 3). When assayed in a cell-free nucleotide exchange reaction, this compound displayed a potent inhibitory effect as compared to a control analog HBS 7 in which three residues that are important for interaction (F929, E942, N944) were substituted for alanine (Fig. 1d and Supplementary Fig. 4).6 Circular dichroism spectroscopy confirmed that alanine substitutions do not affect the α-helicity of HBS 7. We find that HBS 3 alone does not trigger the exchange of mantGDP from Ras (Supplementary Fig. 4); this observation is consistent with structural and biochemical studies indicating the requirement for multiple contact points between Sos and Ras to affect guanine nucleotide exchange.3,6,13 Dissociation constants for binding of HBS 3 and HBS 7 to Ras were determined by fluorescence polarization assay using fluorescein-labeled peptides with GDP bound Ras and under conditions known to promote nucleotide dissociation (Supplementary Methods). HBS 3 targets nucleotide-free Ras with a KD of 28 ± 4.8 µM and GDP-bound Ras with a KD of 158 ± 16 µM (Supplementary Fig. 5). By comparison, the reported KD value for the interaction of nucleotide-bound Ras with the catalytic domain of Sos is 14.5 µM.10 Whether this difference reflects the restricted number of contacts formed between HBS 3 and Ras relative to the catalytic domain of Sos or a distinct mode of binding remains to be established. HBS 7 binds Ras with a ten-fold lower affinity (273 ± 8.5 µM), indicating the specificity of HBS 3–Ras interactions (Supplementary Fig. 5a).</p><p>To further characterize the interaction of the peptide with Ras, we performed 1H-15N HSQC NMR titration experiments with HBS 3 and uniformly 15N-labeled recombinant Ras.14 Addition of HBS 3 to 150 μM Ras in 1:3 and 1:5, Ras:HBS 3 ratios provided a concentration-dependent shift in resonances of several Ras residues (Supplementary Fig. 6a). Specifically, addition of HBS 3 led to shifts in resonances of residues corresponding to the shallow cleft into which the native Sos αH helix binds (Fig. 2a and Supplementary Fig. 6b-c). This cleft consists of switch I (residues 25–40) and switch II (residues 56–75) regions, and spans the nucleotide-binding pocket, supporting our prediction that HBS 3 can act as a direct mimic of αH. Shifts in peaks corresponding to residues that flank switch I and switch II regions were also observed (Supplementary Fig. 6b).</p><p>To assess the capacity of the designed αH helix mimetic to antagonize the RTK-mediated Ras activation, we first monitored the cellular uptake of fluorescein-conjugate derivatives by fluorescence microscopy. Cells incubated with HBS 3 or HBS 7 displayed an intense intracellular fluorescence signal in comparison to cells treated with fluorescein alone (Supplementary Fig. 7a-b), validating the suitability of HBS 3 and its derivatives for cell-based assays. It is noteworthy that unconstrained analog 3 has low cell permeability consistent with earlier reports documenting the inferior biological activity of unconstrained peptides relative to their constrained counterparts.9,15 The cellular uptake of fluorescein-labeled HBS 3 is significantly reduced at 4 °C as compared to 37 °C (Supplementary Fig. 7b), suggesting that the stabilized helix does not passively diffuse into the cell but rather is internalized through an energy-dependent mechanism. The identity of this mechanism remains to be established.</p><p>We next sought to determine whether the treatment of cells with HBS 3 can modulate Sos-mediated Ras activation in response to ligand-dependent receptor stimulation. Serum-starved HeLa cells were treated for 12 hours with HBS 3 or control peptides (3 and HBS 7) and then stimulated with EGF. Cellular levels of Ras-GTP were monitored by the Raf1 Ras-binding domain (RBD) pull-down assay.16 Consistent with previous reports EGF stimulation resulted in a twenty-fold increase in Ras activation. The extent of Ras activation was significantly reduced in the presence of HBS 3 (Fig. 2b\nand\nSupplementary Fig. 8). In contrast, incubation of cells with control peptides did not appreciably affect the levels of Ras activation. Notably, at the concentration and incubation times tested, the peptides did not alter the level or phosphorylation status of EGFR upon EGF treatment (Supplementary Fig. 9), suggesting that HBS 3 targets Ras activation downstream of EGFR.</p><p>To further ascertain that the observed cellular effects of HBS 3 are mediated through the direct inhibition of Ras-Sos interaction and not through receptor targeting or modulation of interactions upstream of Ras/Sos complex formation, we utilized a SosCat-CAAX construct in which the catalytic domain of Sos is tagged to the CAAX motif of Ras. This construct has been previously shown to anchor Sos to the membrane and activate Ras independent of growth factor stimulation.17 Treatment with HBS 3 resulted in an approximately 5-fold reduction in Ras-GTP levels when compared to untreated serum-starved HeLa cells expressing SosCat-CAAX (Fig. 2c\nand\nSupplementary Fig. 8). Taken together with the lack of apparent effect of HBS 3 on EGFR activation, this result provides a strong indication that the inhibition of Sos-mediated Ras activation by HBS 3 is a consequence of its interference with Sos-Ras interaction.</p><p>The activation of Ras leads to stimulation of various signal transduction pathways.18 To determine whether the inhibitory effect of HBS 3 on Ras can modulate downstream signaling events, we focused on the activation of the ERK cascade, a well-documented Ras effector pathway implicated in cell proliferation and differentiation.19 Serum-starved HeLa cells were pretreated with the indicated peptides and then stimulated with EGF for various time intervals. We monitored the resulting variations in the levels of ERK phosphorylation by blotting the cell lysates with phospho-ERK-specific antibodies. Significantly, HBS 3 reduced the extent and duration of ERK activation post EGF addition (Fig. 2 d-e and Supplementary Fig. 8).19 In comparison to HBS 3, the unconstrained counterpart and the specificity control have no apparent effect on ERK activation. The capacity of HBS 3 to induce inhibition of ERK activation suggests that it could in principle be equally effective in compromising other Ras effector pathways downstream of the Ras-Sos interaction.</p><p>Binding of Sos to Ras triggers a substantial conformational reorganization involving switch I and switch II regions of Ras.3 This organization exposes the nucleotide binding pocket and facilitates exchange. We find that a rationally designed stabilized α-helix that mimics a key element from Ras-binding domain of Sos can inhibit Sos-induced activation of Ras and regulate MAPK signaling in cultured cells. Significantly, the unconstrained peptide derivative remains inactive highlighting the remarkable potential of stabilized helices and helix mimetics in inhibiting previously untargeted protein-protein interactions.15,20–22</p><p>Overstimulation of Ras signaling is an inevitable consequence of constitutively active RTKs and accounts for a plethora of molecular changes that underlie various cancers and other diseases.23,24 The present study identifies a strategy for intercepting at a key control point the pathway linking multiple RTKs to Ras signaling – Sos-mediated Ras activation. Adaptation of this strategy for therapeutic intervention may therefore offer a unique opportunity to pan-target a wide spectrum of disorders associated with aberrant RTK function.</p>",
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"content": "Mimics of \\xce\\xb1-helices on protein surfaces have emerged as powerful reagents for antagonizing protein-protein interactions, which are difficult to target with small molecules. Herein we describe the design of a cell-permeable synthetic \\xce\\xb1-helix based on the guanine nucleotide exchange factor Sos that interferes with Ras-Sos interaction and downregulates Ras signaling in response to receptor tyrosine kinase activation.",
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science.healthver_entailment | science.healthver_entailment.1245 | [
{
"content": "Evaluate the given public health statement using the provided research abstract. Your goal is to determine the relationship between the claim and the abstract content.\n\n- \"decision\": Indicate whether the abstract \"SUPPORTS\", \"CONTRADICTS\", or provides \"INSUFFICIENT\" information regarding the claim.\n- \"justification\": List sentences from the abstract that back your decision. If the decision is \"INSUFFICIENT\", leave this list empty.\n\nStatement: Does heat prevent COVID-19? No, Absolutely not\n\nResearch Abstract:\nBACKGROUND: Corona Virus Disease-2019 (COVID-19) has spread widely throughout the world since the end of 2019.\nNucleic acid testing (NAT) has played an important role in patient diagnosis and management of COVID-19.\nIn some circumstances, thermal inactivation at 56 °C has been recommended to inactivate Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) before NAT.\nHowever, this procedure could theoretically disrupt nucleic acid integrity of this single-stranded RNA virus and cause false negatives in real-time polymerase chain reaction (RT-PCR) tests.\nMETHODS: We investigated whether thermal inactivation could affect the results of viral NAT.\nWe examined the effects of thermal inactivation on the quantitative RT-PCR results of SARS-CoV-2 particularly with regard to the rates of false-negative results for specimens carrying low viral loads.\nWe additionally investigated the effects of different specimen types, sample preservation times and a chemical inactivation approach on NAT.\nRESULTS: Our work showed increased Ct values in specimens from diagnosed COVID-19 patients in RT-PCR tests after thermal incubation.\nMoreover, about half of the weak-positive samples (7 of 15 samples, 46.7%) were RT-PCR negative after heat inactivation in at least one parallel testing.\nThe use of guanidinium-based lysis for preservation of these specimens had a smaller impact on RT-PCR results with fewer false negatives (2 of 15 samples, 13.3%) and significantly less increase in Ct values than heat inactivation.\nCONCLUSION: Thermal inactivation adversely affected the efficiency of RT-PCR for SARS-CoV-2 detection.\nGiven the limited applicability associated with chemical inactivators, other approaches to ensure the overall protection of laboratory personnel need consideration.",
"role": "user"
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"content": "{\"verdict\": \"NEI\", \"evidence\": []}",
"role": "assistant"
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science.scireviewgen_multidoc_summarization | science.scireviewgen_multidoc_summarization.3657 | [
{
"content": "Craft a cohesive chapter for a literature review using the abstracts provided. Focus on the chapter's theme, weaving together insights and findings from the abstracts. Highlight key points and note any research gaps.\nLiterature Review Title: Adaptive Critic Nonlinear Robust Control: A Survey \nChapter Title: VII. COMPARISON REMARKS BETWEEN ADP-BASED ROBUST CONTROL AND H ∞ CONTROL DESIGNS \n1. Abstract of Cited Paper (BIB001): In this paper we present an online gaming algorithm based on policy iteration to solve the continuous-time (CT) two-player zero-sum game with infinite horizon cost for nonlinear systems with known dynamics. That is, the algorithm learns online in real-time the solution to the game design HJI equation. This method finds in real-time suitable approximations of the optimal value, and the saddle point control policy and disturbance policy, while also guaranteeing closed-loop stability. The adaptive algorithm is implemented as an actor/critic structure which involves simultaneous continuous-time adaptation of critic, control actor, and disturbance neural networks. We call this online gaming algorithm ‘synchronous’ zero-sum game policy iteration. A persistence of excitation condition is shown to guarantee convergence of the critic to the actual optimal value function. Novel tuning algorithms are given for critic, actor and disturbance networks. The convergence to the optimal saddle point solution is proven, and stability of the system is also guaranteed. Simulation examples show the effectiveness of the new algorithm. \n2. Abstract of Cited Paper (BIB002): In this paper, a new iterative adaptive dynamic programming (ADP) method is proposed to solve a class of continuous-time nonlinear two-person zero-sum differential games. The idea is to use the ADP technique to obtain the optimal control pair iteratively which makes the performance index function reach the saddle point of the zero-sum differential games. If the saddle point does not exist, the mixed optimal control pair is obtained to make the performance index function reach the mixed optimum. Stability analysis of the nonlinear systems is presented and the convergence property of the performance index function is also proved. Two simulation examples are given to illustrate the performance of the proposed method. \n3. Abstract of Cited Paper (BIB003): SUMMARY ::: ::: In this paper, we present an online learning algorithm to find the solution to the H ∞ control problem of continuous-time systems with input constraints. A suitable nonquadratic functional is utilized to encode the input constraints into the H ∞ control problem, and the related H ∞ control problem is formulated as a two-player zero-sum game with a nonquadratic performance. Then, a policy iteration algorithm on an actor–critic–disturbance structure is developed to solve the Hamilton–Jacobi–Isaacs (HJI) equation associated with this nonquadratic zero-sum game. That is, three NN approximators, namely, actor, critic, and disturbance, are tuned online and simultaneously for approximating the HJI solution. The value of the actor and disturbance policies is approximated continuously by the critic NN, and then on the basis of this value estimate, the actor and disturbance NNs are updated in real time to improve their policies. The disturbance tries to make the worst possible disturbance, whereas the actor tries to make the best control input. A persistence of excitation condition is shown to guarantee convergence to the optimal saddle point solution. Stability of the closed-loop system is also guaranteed. A simulation on a nonlinear benchmark problem is performed to validate the effectiveness of the proposed approach. Copyright © 2012 John Wiley & Sons, Ltd. \n4. Abstract of Cited Paper (BIB004): The problem of H∞ state feedback control of affine nonlinear discrete-time systems with unknown dynamics is investigated in this paper. An online adaptive policy learning algorithm (APLA) based on adaptive dynamic programming (ADP) is proposed for learning in real-time the solution to the Hamilton-Jacobi-Isaacs (HJI) equation, which appears in the H∞ control problem. In the proposed algorithm, three neural networks (NNs) are utilized to find suitable approximations of the optimal value function and the saddle point feedback control and disturbance policies. Novel weight updating laws are given to tune the critic, actor, and disturbance NNs simultaneously by using data generated in real-time along the system trajectories. Considering NN approximation errors, we provide the stability analysis of the proposed algorithm with Lyapunov approach. Moreover, the need of the system input dynamics for the proposed algorithm is relaxed by using a NN identification scheme. Finally, simulation examples show the effectiveness of the proposed algorithm. \n5. Abstract of Cited Paper (BIB005): In this paper, the problem of H ∞ control design for affine nonlinear discrete-time systems is addressed by using adaptive dynamic programming (ADP). First, the nonlinear H ∞ control problem is transformed into solving the two-player zero-sum differential game problem of the nonlinear system. Then, the critic, action and disturbance networks are designed by using neural networks to solve online the Hamilton-Jacobi-Isaacs (HJI) equation associating with the two-player zero-sum differential game. When novel weight update laws for the critic, action and disturbance networks are tuned online by using data generated in real-time along the system trajectories, it is shown that the system states, all neural networks weight estimation errors are uniformly ultimately bounded by using Lyapunov techniques. Further, it is shown that the output of the action network approaches the optimal control input with small bounded error and the output of the disturbance network approaches the worst disturbance with small bounded error. At last, simulation results are presented to demonstrate the effectiveness of the new ADP-based method. \n6. Abstract of Cited Paper (BIB006): Abstract In this paper, the continuous-time input-constrained nonlinear H ∞ state feedback control under event-based environment is investigated with adaptive critic designs and neural network implementation. The nonlinear H ∞ control issue is regarded as a two-player zero-sum game that requires solving the Hamilton–Jacobi–Isaacs equation and the adaptive critic learning (ACL) method is adopted toward the event-based constrained optimal regulation. The novelty lies in that the event-based design framework is combined with the ACL technique, thereby carrying out the input-constrained nonlinear H ∞ state feedback via adopting a non-quadratic utility function. The event-based optimal control law and the time-based worst-case disturbance law are derived approximately, by training an artificial neural network called a critic and eventually learning the optimal weight vector. Under the action of the event-based state feedback controller, the closed-loop system is constructed with uniformly ultimately bounded stability analysis. Simulation studies are included to verify the theoretical results as well as to illustrate the event-based H ∞ control performance. \n7. Abstract of Cited Paper (BIB007): In this paper, the ${H}_{\\infty }$ optimal control problem for a class of continuous-time nonlinear systems is investigated using event-triggered method. First, the ${H}_{\\infty }$ optimal control problem is formulated as a two-player zero-sum (ZS) differential game. Then, an adaptive triggering condition is derived for the ZS game with an event-triggered control policy and a time-triggered disturbance policy. The event-triggered controller is updated only when the triggering condition is not satisfied. Therefore, the communication between the plant and the controller is reduced. Furthermore, a positive lower bound on the minimal intersample time is provided to avoid Zeno behavior. For implementation purpose, the event-triggered concurrent learning algorithm is proposed, where only one critic neural network (NN) is used to approximate the value function, the control policy and the disturbance policy. During the learning process, the traditional persistence of excitation condition is relaxed using the recorded data and instantaneous data together. Meanwhile, the stability of closed-loop system and the uniform ultimate boundedness (UUB) of the critic NN’s parameters are proved by using Lyapunov technique. Finally, simulation results verify the feasibility to the ZS game and the corresponding ${H}_{\\infty }$ control problem.\n\nReview Chapter:",
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"content": "As is shown in previous sections, the wide existence of uncertain parameters or disturbances of the dynamical plant always leads to the necessity of designing robust controllers. There exists a class of H ∞ control methods , which focuses on constructing the worst-case control law for specified plants including additive disturbances or dynamical uncertainties. From the point of minimax optimization, the H ∞ control problem can be formulated as a two-player zerosum differential game. In order to obtain a controller that minimizes the cost function in the worst-case disturbance, it incorporates the requirement of finding the Nash equilibrium solution corresponding to the Hamilton-Jacobi-Isaacs (HJI) equation. However, it is intractable to acquire the analytic solution for general nonlinear systems. This issue is similar to the difficulty of solving the HJB equation in nonlinear optimal regulation design discussed in the previous sections. Hence, using the idea of ADP, iterative methods have been developed to solve the H ∞ control problems. Similar to the adaptive critic optimal regulation, this is known as the adaptive-critic-based H ∞ control design (see BIB003 BIB001 BIB002 BIB004 BIB005 BIB006 BIB007 BIB008 and the related references therein). Consider a class of continuous-time affine nonlinear systems with external perturbations described bẏ where v(t) ∈ R q is the perturbation vector with v(t) ∈ L 2 [0, ∞), z(t) ∈ R p is the objective output, and h(·) is differentiable in its argument. In nonlinear H ∞ control design, we need to find a feedback control law u(x) such that the closed-loop dynamics is asymptotically stable and has L 2 -gain no larger than , that is where Q(x) 2 = x T (t)Qx(t) and Q, R, and P are symmetric positive definite matrices with appropriate dimensions. If the condition (75) is satisfied, the closed-loop system is said to have L 2 -gain no larger than . Note that the solution of H ∞ control problem is the saddle point of zero-sum game theory and is denoted as a pair of laws (u * , v * ), where u * and v * are called the optimal control and the worst-case disturbance, respectively. Based on BIB003 BIB001 BIB002 BIB004 BIB005 BIB006 BIB007 BIB008 , we generally let the utility be and define the infinite horizon cost function as The design goal is to find the feedback saddle point solution (u * , v * ), such that the Nash condition holds, where the asterisked symbol J * (x 0 ) represents the optimal cost. For an admissible control u ∈ A ( ), if the related cost function (77) is continuously differentiable, then its infinitesimal version is the nonlinear Lyapunov equation with J (0) = 0. Define the Hamiltonian of system (74a) as According to Bellman's optimality principle, the optimal cost function J * (x) guarantees the so-called HJI equation The saddle point solution (u * , v * ) satisfies the stationary condition BIB005 , which can be used to obtain the optimal control law and the worst-case disturbance law as follows: Considering the two formulas in (82), the HJI equation becomes the form with J * (0) = 0. Note that the HJI equation (83) is difficult to solve in theory. This inspires us to devise an approximate control strategy to overcome the difficulty by virtue of ADP. Incorporating the critic neural network, the approximate values of the control and disturbance laws arê The closed-loop system is also proven to be UUB with the approximate control (84a) and disturbance law (84b). Recently, there are also some results of event-triggered H ∞ control based on ADP BIB007 , BIB008 . Therein, the H ∞ control problem for continuous-time affine nonlinear systems was investigated with network-based event-triggering formulation. The ADP-based robust control and ADP-based H ∞ control methods are both developed to cope with the external perturbations. Basically, both of them concern with the uncertainties or disturbances and guarantee the robustness of the controlled plants. However, there are also some apparent differences between them, listed as follows. 1) The design objective of ADP-based robust control and ADP-based H ∞ control is not totally the same. Achieving robust stability is the single task of the robust control design while attaining certain L 2 -gain performance level is the additional objective of the H ∞ control design. It means that, the H ∞ control scheme is established with the purpose of disturbance attenuation. 2) The cost functions, or specifically the utilities are defined differently. In ADP-based robust control design, we define a modified utility in terms of the state variable reflecting the bound of the uncertainty and the control variable. However, in ADP-based H ∞ control design, what we give is an utility composed of the state, control, and disturbance variables. As a result, the ADP method is employed to solve the modified HJB equation in the former while it is adopted to cope with the HJI equation in the latter. 3) The feedback controller in the ADP-based robust control design is not the same as the H ∞ control design. In the robust control framework, the uncertain term is not incorporated to the expression of the feedback controller. However, the H ∞ method contains another law called disturbance except the control law, which also should be formulated during the design process. Though there exist great distinctions, it is certainly convinced that the ADP method is applicable to both robust control and H ∞ control problems. The involvement of ADP to robust and H ∞ designs bring the adaptive and selflearning properties into the traditional control methods. Hence, with ADP formulation, the adaptive, learning, and intelligent systems are widely constructed under uncertain environment. All of these research demonstrates the necessity and significance of adaptive-critic-based nonlinear robust control designs.",
"role": "assistant"
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science.scientific_papers_summarization_single_doc_pubmed | science.scientific_papers_summarization_single_doc_pubmed.8852 | [
{
"content": "Read the provided biomedical research paper and create a concise abstract. Ensure the abstract captures the main points of the paper.\n\nFull Paper:\nthe von meyenburg complex ( vmc ) was first described in 1918 and is characterized by multiple bile duct hamartomas .\nthese are benign developmental malformations composed of dilated intrahepatic bile ductules embedded in fibrous stroma .\n, the majority are discovered incidentally , but may present a diagnostic dilemma when the patient is undergoing staging imaging for known primary malignancy .\nwe describe a case of vmc with ultrasound , contrast enhanced ultrasound ( ceus ) , computed tomography ( ct ) , and magnetic resonance ( mr ) imaging correlation .\nan 81-year - old man was admitted with a one - week history of abdominal pain and constipation . on clinical examination\ncontrast - enhanced ct images ( siemens sensation 16 slice ) were acquired in the portal venous phase ( 60 s following administration of contrast ) , demonstrating a focal sigmoid stricture and proximal large bowel obstruction .\nmultiple low - density lesions of varying sizes were identified within the liver , which were non - enhancing in the portal venous phase [ figure 1 ] .\na sigmoid malignancy was likely , but the majority of liver lesions were near fluid density ( 3 - 20hu ) and not entirely typical for metastases .\nan 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .\naxial enhanced ct image of the abdomen , at the level of the porta , demonstrate multiple fluid density lesions ( arrows ) of varying sizes within the liver .\nb - mode ultrasound demonstrated multiple hyperechoic lesions [ figure 2 ] of varying sizes throughout the liver , none of which displayed signal with color doppler ultrasound .\nthe hepatic lesions were further interrogated with ceus , using sonovue ( bracco spa milan ) as the microbubble contrast agent , on a siemens s2000 ( siemens ag , erlangen ) , with a 4 mhz transducer and imaged using a low mechanical index technique ( cps , siemens ag , erlangen ) .\nno appreciable vascularity was seen within the hepatic lesions in all three phases of the study ( arterial , early portal venous , and late portal venous phase ) with imaging performed for 3 min [ figure 3 ] .\nthe patient proceeded to laparotomy where a hartmann 's procedure was performed and multiple liver biopsies were obtained .\nb - mode ultrasound image of the liver shows several hyperechoic focal lesions ( arrows ) .\nan 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .\ncontrast enhanced ultrasound of the liver in the late portal venous phase ( 1 min 30 sec following injection of contrast ) demonstrates non - enhancing lesions ( arrow ) .\nhistology of the resected colon confirmed moderately differentiated adenocarcinoma invading through the muscularis propria , but not penetrating the serosal surface .\nhistology of the focal lesions demonstrated expanded portal tracts with dense stroma , containing dilated bile ducts ; a few of which contained inspissated bile [ figure 4 ] .\na dilated congested blood vessel within the specimens was presumed to be responsible for the hepatic nodularity .\nan 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .\nhemotoxylin and eosin stained biopsy specimen shows dilated ducts with inspissated bile ( arrow ) in an expanded and fibrotic portal tract .\nmr imaging was performed to further evaluate the liver and to identify any lesions characteristic of metastases .\nmultiple hepatic lesions were again visualized and displayed moderate to high t2 ( tr : 2410 ; te : 103 ) signal intensity [ figure 5 ] and t1 hypointensity with no contrast enhancement [ figure 6 ] .\nthe multiple liver lesions displayed decreasing signal intensity [ figure 7 ] with increasing b - values on diffusion - weighted imaging , indicating free diffusion .\nthe imaging findings were in keeping with vmc in addition to simple cysts ; metastases being less likely .\nan 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex . in t2-weighted mr sequence of the liver\nan 81-year - old man with colon cancer and lesions in the liver diagnosed as von meyenburg complex .\npost - contrast t1-weighted sequence demonstrate multiple non - enhancing lesions ( arrow ) throughout the liver .\nan 81-year - old man with adenocarcinoma of the colon and hepatic lesions later diagnosed as von meyenburg complex .\ndiffusion weighted images of the liver at different b - values reveal negative correlation between the signal intensity of the focal liver lesions ( arrow ) compared to the b - value , in keeping with free diffusion , which favors benign disease .\nsurveillance imaging 3 years post - surgery demonstrated identical appearances of the liver , with no new abnormalities present and no disease recurrence .\nvon meyenburg complex ( vmc ) is an uncommon abnormality and affected patients are usually asymptomatic , although jaundice and portal hypertension may arise as a result of mass effect .\nthe imaging findings of vmc have been documented through case reports and a single case series .\nthe biliary hamartomas of vmc may be single or multiple , ranging in size from 1 to 15 mm ; not all lesions are identifiable on imaging and given the small size of the lesions , definitive characterization may be difficult . in\nthe presence of multiple low - density lesions within the liver , differentiation from metastases remains the key clinical question , particularly in the presence of a known primary .\nsonographic appearances of vmc are varied , being described as multiple hypoechoic lesions , hyperechoic lesions and also a mixture of both hypo- and hyper - echoic lesions .\nit has been postulated that lesional reflectivity may be dependent on the size and number of the dilated bile ducts and degree of fibrosis .\nother features of vmc include the presence of a comet tail artifact and association with liver cysts .\ncontrast enhanced ultrasound ( ceus ) allows a true assessment of lesional vascularity , with no escape of contrast through the interstitium .\nthis enables dynamic visualization of the lesion of interest through arterial , venous , and delayed phases .\nberry et al . , reported a case of multiple vmcs that did not demonstrate contrast enhancement in all phases ; exclusion of hypovascular metastases was not possible .\nhohmann et al . , highlighted the presence of enhancement in a biliary hamartoma on ceus with \nwashout in the delayed phase . however , this was a single biliary hamartoma , measuring 5 mm , which may have affected interpretation .\n, has suggested that all metastases invariably display arterial vascularity on ceus albeit transiently , despite hypovascular appearances on ct and mr imaging .\nthis particular phenomenon is only evident through continuous dynamic observation unique to ceus examination . in the present case , none of the lesions demonstrated contrast enhancement throughout all phases of the study , confirming the avascular nature of the abnormality .\non contrast enhanced ct , biliary hamartomas are predominantly of low attenuation , and may demonstrate an irregular border .\nthe majority of cases reported suggest that vmc does not exhibit contrast enhancement , although one case of homogeneous enhancement has been reported .\nevaluation of lesional contrast enhancement on ct is not truly dynamic , unlike the evaluation of lesional enhancement on contrast ultrasound , and so ct scanning can not definitively differentiate vmc from metastatic disease .\nall agree that vmcs appear hypointense on t1-weighted imaging and are hyperintense on heavily t2-weighted sequences with similar signal intensity to the spleen , but less than liver cysts ; our observations corroborate these findings . however , mr enhancement characteristics are difficult to establish with contradicting reports showing both enhancement and no enhancement on gadolinium - enhanced t1-weighted sequences .\nmore recently , diffusion - weighted imaging ( dwi ) has gained recognition for its potential to differentiate metastatic lesions , showing restricted diffusion , from benign lesions , demonstrating free diffusion .\nalthough there are no published reports on dwi for vmc , our findings of free diffusion support a benign diagnosis .\nmultiple cysts typically appear as anechoic areas with posterior acoustic shadowing on ultrasound and display very high t2 signal characteristics , with no enhancement with contrast . in abscess formation , peripheral enhancement ,\nwhile vmc has been described as a benign condition , there have been isolated reports of hepatic malignancies on a background of vmc , including hepatocellular carcinoma and cholangiocarcinoma , but given the paucity of reports , a clear association with vmc has not yet been established .\nwe report a case of von meyenburg 's complex that has been investigated with us , ceus , ct , and mri .\nb - mode ultrasound and ct do not help to differentiate hepatic metastases from vmc . however , lack of enhancement on ceus , increased signal intensity on heavily t2-weighted mr sequences and free diffusion on dwi all favor benign disease , but currently biopsy must remain the gold standard for diagnosis .",
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"content": "the von meyenburg complex ( vmc ) is an uncommon congenital malformation and is characterized by benign bile duct hamartomas . \n these are usually discovered incidentally and may represent a diagnostic dilemma when liver metastases are suspected . \n mri of vmc shows distinct imaging characteristics , but reporting of lesional contrast enhancement has been inconsistent , whilst microbubble contrast enhanced ultrasound provides real - time evaluation of soft tissue vascularity . \n given the diagnostic uncertainty over imaging in vmc , biopsy is often recommended as the definitive diagnosis . \n we report a biopsy proven case of vmc on a background of primary colonic malignancy investigated with ultrasound , contrast enhanced ultrasound , computed tomography ct , and magnetic resonance imaging mri , and review the key imaging features .",
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science.scicite_classification | science.scicite_classification.1692 | [
{
"content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\n…or species’means and treated analytically as measurement error (Careau et al. 2008), but researchers have since demonstrated that individual differences in baseline metabolic rate can persist over the lifetime of individuals (Nespolo and Franco 2007; Burton et al. 2011; White et al. 2013).",
"role": "user"
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{
"content": "Background",
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science.bioasq_general_qa | science.bioasq_general_qa.238 | [
{
"content": "Review the provided biomedical excerpts and respond to the question concisely. Ensure your answer is derived solely from the given context and avoid adding any extraneous information.\n\nQuestion: How is yellow fever virus transmitted?\n\nExcerpts: Yellow Fever (YF) is an acute viral communicable disease transmitted by an arbovirus of the flavivirus genus. It is primarily a zoonotic disease, especially the monkeys. Worldwide, an estimated 200 000 cases of yellow fever occurred each year, and the case-fatality rate is ~15%. Forty-five endemic countries in Africa and Latin America, with a population of close to 1 billion, are at risk. Up to 50% of severely affected persons from YF die without treatment\nyellow fever virus (YFV) are transmitted between arthropod vectors and vertebrate hosts. While barriers limiting arbovirus population diversity have been observed in mosquitoes, whether barriers exist in vertebrate hosts is unclear. To investigate whether arboviruses encounter bottlenecks during dissemination in the vertebrate host, we infected immunocompetent mice and immune-deficient mice lacking alpha/beta interferon (IFN-α/β) receptors (IFNAR⁻/⁻ mice) with a pool of genetically marked viruses to evaluate dissemination and host barriers\nRe-emergence of vector-borne diseases such as dengue and yellow fever, which are both transmitted by the Aedes aegypti mosquito, has been correlated with insecticide resistance.\nArthropod-borne viruses are important emerging pathogens world-wide. Viruses transmitted by mosquitoes, such as dengue, yellow fever, and Japanese encephalitis viruses, infect hundreds of millions of people and animals each year. Global surveillance of these viruses in mosquito vectors using molecular based assays is critical for prevention and control of the associated diseases\nfever and dengue fever are mosquito-borne infectious diseases transmitted by Aedes aegyptii, the presence of yellow fever in Sudan and dengue fever in Saudi Arabia are threats to Egypt with the reemerging of Ae. aegyptii in Southern Egypt, larvae control is feasible than flying adults\ndengue virus (DENV) and yellow fever virus (YFV), that originated in sylvatic cycles maintained in non-human primates and forest-dwelling mosquitoes have emerged repeatedly into sustained human-to-human transmission by Aedes aegypti mosquitoes\nSylvatic cycles of both viruses remain active, and where the two viruses overlap in West Africa they utilize similar suites of monkeys and Aedes mosquitoes\nFirst, the sylvatic cycle of YFV originated in Africa and was introduced into the New World, probably as a result of the slave trade, but is absent in Asia; in contrast, sylvatic DENV likely originated in Asia and has spread to Africa but not to the New World. Second, while sylvatic YFV can emerge into extensive urban outbreaks in humans, these invariably die out, whereas four different types of DENV have established human transmission cycles that are ecologically and evolutionarily distinct from their sylvatic ancestors\nFinally, transmission of YFV among humans has been documented only in Africa and the Americas, whereas DENV is transmitted among humans across most of the range of competent Aedes vectors, which in the last decade has included every continent save Antarctica\nMosquito-transmitted diseases such as malaria, dengue, yellow fever and filariasis are the main contributors to this burden\nyellow fever (YFV) viruses is increasing in many parts of the world. The viruses are primarily transmitted by Aedes aegypti, a highly domesticated mosquito species that is notoriously difficult to control.\nThe first of these to be discovered was yellow fever virus in 1901, and three to four new species are still being found every year\nThe causative agent of yellow fever is an arbovirus of the Flaviviridae family transmitted by infected Aedes mosquitoes, particularly in Africa. In the Central African Republic since 2006, cases have been notified in the provinces of Ombella-Mpoko, Ouham-Pende, Basse-Kotto, Haute-Kotto and in Bangui the capital. As the presence of a vector of yellow fever virus (YFV) represents a risk for spread of the disease, we undertook entomological investigations at these sites to identify potential vectors of YFV and their abundance\nfamily Flaviviridae, includes a number of important arthropod-transmitted human pathogens such as dengue viruses, West Nile virus, Japanese encephalitis virus and yellow fever virus\nReports of the detection of these viruses with no recognized pathogenic role in humans are increasing in mosquitoes collected around the world, particularly in those sampled in entomological surveys targeting pathogenic flaviviruses. The presence of six potential flaviviruses, detected from independent European arbovirus surveys undertaken in the Czech Republic, Italy, Portugal, Spain and the UK between 2007 and 2010, is reported in this work\nYellow Fever virus (YFV) is an important arboviral pathogen in much of sub-Saharan Africa and the tropical Americas. It is the prototype member of the genus Flavivirus and is transmitted primarily by Aedes (Stegomyia) mosquitoes. The incidence of human infections in endemic areas has risen in recent years. Prompt and dependable identification of YFV is a critical component of response to suspect cases\nHealth-care professionals can help travelers by providing accurate pre-travel counseling for mosquito-transmitted diseases such as malaria, yellow fever, and dengue fever. Governments and international organizations will benefit from knowledge survey among health professionals in this field to promote the development of travel health profession\nUnited States made 12 million visits to developing countries in Asia, South America, Central America, Oceania, the Middle East, and Africa.\nYellow fever is a serious illness public health importance and is transmitted by mosquitoes of the genera Haemagogus and Sabethes in the rural and forest environments, and by Aedes aegypti in the urban setting\nMany specialist human viruses also have mammalian or avian origins. Indeed, a substantial proportion of mammalian viruses may be capable of crossing the species barrier into humans, although only around half of these are capable of being transmitted by humans and around half again of transmitting well enough to cause major outbreaks. A",
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"content": "Yellow fever virus is transmitted by mosquitoes and is restricted to Africa, Central and South America and the Caribbean. \nYellow fever virus is a flavivirus, and there is only one antigenic type. It was taken to the Americas by the early slave traders, and nowadays reported in Africa, America, Asia and Europe. Yellow fever virus is transmitted by two different cycles: \n-from human to human by the mosquito Aedes aegypti; which is well-adapted to breeding around human habitations; the infection can be maintained in this way as ‘urban’ yellow fever.\n-from infected monkeys to humans by mosquitoes such as Haemagogus. This is ‘jungle’ yellow fever and is seen in Africa and South America.\n\nYellow fever is not transmitted directly from human to human by day-to-day contact, but transmission from ill patients to healthcare workers has been reported, notably after needlestick injury.",
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science.pico_ner | science.pico_ner.248 | [
{
"content": "Examine the following abstract and identify distinct entities. Focus on extracting entities related to participants, interventions, and outcomes.\n\nPresent your findings in a JSON format like: {\"Participant\": [\"example entity\", ...], \"Intervention\": [\"example entity\", ...], \"Outcome\": [\"example entity\", ...]}. If no entities are found for a category, use an empty list.\n\nAbstract Content:\n\nThe effect of aging on circulating levels of proinflammatory cytokines during septic shock . Norasept II Study Investigators . BACKGROUND As the proportion of the population that is older continues to rise , infection in older people has become an important healthcare problem . Although aging is associated with multiple abnormalities in immune function , the effect of aging on the production of proinflammatory cytokines has not been well studied under conditions of clinical stress . OBJECTIVES The aim of this study was to examine the effect of aging on circulating levels of the proinflammatory cytokines in a large cohort of septic shock patients . We hypothesized that aging would be associated with a diminished proinflammatory cytokine response to sepsis . DESIGN Patients with septic shock who were enrolled in the placebo limb of the North American Sepsis Trial ( NORASEPT II ) study were analyzed . SETTING The intensive care units of 105 hospitals in the United States and Canada . PARTICIPANTS Nine hundred and thirty patients presenting to hospital within 12 hours of the onset of septic shock . MEASUREMENTS Interleukin-6 ( IL-6 ) , tumor necrosis factor-alpha ( TNF-alpha ) , soluble tumor necrosis factor-receptor-55 ( sTNF-R55 ) , and soluble tumor necrosis factor-receptor-75 ( sTNF-R75 ) concentrations were measured at enrollment . The study population was broken down into five age groups as follows : less than 50 years ( group one ) , 50 to 64 years ( group two ) , 65 to 74 years ( group three ) , 75 to 84 years ( group four ) , and 85 or older ( group five ) . Clinical , demographic , and cytokine data were extracted to describe each age group . RESULTS Data were available for 930 patients . The patients ' mean age ( +/- SD ) was 59 +/- 17 years ( range , 18 to 102 ) . There were 280 patients in group one , 242 in group two , 210 in group three , 150 in group four , and 48 in group five . The primary diagnoses ; clinical characteristics ; and IL-6 , sTNF-R55 , and sTNF-R75 levels were similar among the five age groups . The TNF-alpha levels were significantly higher , however , in the oldest group of patients ( group five ) . The 28-day survival was 49 % in patients over the age of 75 and 58 % in those under 75 years ( P = .03 ) . There was no gender difference in survival or cytokine levels . CONCLUSIONS Contrary to our expectations , we found that aging was not associated with a decline in the circulating levels of proinflammatory cytokines .",
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"content": "{\"Intervention\": [\"Norasept II\", \"placebo\", \"North American Sepsis Trial ( NORASEPT II )\"], \"Outcome\": [\"sTNF-R75 levels\", \"Clinical , demographic , and cytokine data\", \"survival\", \"cytokine levels\", \"sTNF-R55\", \"soluble tumor necrosis factor-receptor-55 ( sTNF-R55 )\", \"gender difference\", \"28-day survival\", \"tumor necrosis factor-alpha ( TNF-alpha )\", \"circulating levels of the proinflammatory cytokines\", \"proinflammatory\", \"IL-6\", \"soluble tumor necrosis factor-receptor-75 ( sTNF-R75 )\", \"primary diagnoses\", \"circulating levels of proinflammatory cytokines\", \"TNF-alpha levels\", \"Interleukin-6 ( IL-6\", \"clinical characteristics\"], \"Participant\": [\"280\", \"Nine hundred and thirty\", \"210\", \"59 +/- 17 years\", \"150\", \"50 to 64 years\", \"85 or older\", \"242\", \"48\", \"older\", \"75 to 84 years\", \"930\", \"65 to 74 years\", \"less than 50 years\", \"septic shock\"]}",
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science.medmentions_ner | science.medmentions_ner.2421 | [
{
"content": "Analyze the provided paragraph from a scientific document. Your goal is to identify and extract relevant entities.\n\nFormat your findings as a JSON object, where each key represents a category of entities, and the corresponding value is a list of entities identified in that category. If no entities are found for a category, return an empty list.\n\nFocus on precision and ensure that the output is strictly in JSON format.\n\nDocument:\n\nPrenatal Diagnosis of Lysosomal Storage Disorders Using Chorionic Villi Prenatal enzymatic diagnosis for an array of lysosomal storage disorders (LSDs) can be performed accurately, provided that a confirmed diagnosis by biochemical/molecular study in the index case is available and a strict defined protocol, specific to each individual disorder is followed. The present chapter describes the protocols for reliable and accurate prenatal enzymatic diagnoses by fluorometric and spectrophotometric methods of lysosomal storage disorders: Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandhoff, GM1, Mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy, and Batten diseases using uncultured chorionic villi samples. The biological reference intervals for enzyme levels in normal and affected fetuses are given for interpretation of prenatal results. It is imperative to establish normal reference interval in each laboratory to take into account the local environment, technical variations, and different ethnicities. Besides, enzyme activity in the fetus should be represented as percentage of the mean activity of enzyme of normal fetuses. The pitfalls and challenges in prenatal diagnosis as well as technical problems in performing enzyme assays are also discussed to help the reader in standardization and performing the assays for correct diagnosis.",
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"content": "{\"AnatomicalStructure\": [\"fetus\", \"Chorionic Villi\", \"fetuses\", \"uncultured chorionic villi\"], \"Bacterium\": [], \"BiologicFunction\": [\"Pompe\", \"Sandhoff\", \"activity of enzyme\", \"GM1\", \"Batten diseases\", \"disorder\", \"Fabry\", \"LSDs\", \"Lysosomal Storage Disorders\", \"Gaucher\", \"Wolman\", \"Tay Sach\", \"Metachromatic leukodystrophy\", \"enzyme activity\", \"Krabbe\", \"lysosomal storage disorders\", \"Mucoplysaccharidoses\"], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [], \"ClinicalAttribute\": [], \"Eukaryote\": [], \"Finding\": [\"diagnosis\", \"results\", \"index case\"], \"Food\": [], \"HealthCareActivity\": [\"fluorometric\", \"Prenatal enzymatic diagnosis\", \"assays\", \"spectrophotometric methods\", \"enzyme assays\", \"Prenatal Diagnosis\", \"enzyme levels\", \"prenatal enzymatic diagnoses\", \"prenatal diagnosis\"], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"defined protocol\", \"interpretation\", \"protocols\"], \"MedicalDevice\": [], \"Organization\": [\"laboratory\"], \"PopulationGroup\": [\"ethnicities\"], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [\"biochemical/molecular study\", \"standardization\"], \"SpatialConcept\": [\"local environment\"], \"Virus\": []}",
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science.chemprot_re | science.chemprot_re.875 | [
{
"content": "Examine the provided text and determine the interactions between chemical entities and genes. Focus on identifying any connections present.\n\nPresent your findings in a structured JSON format. Each relationship should be represented as an array entry. If no interactions are detected, return an empty array.\n\nText Content:\n\nValidation of an in vitro exposure system for toxicity assessment of air-delivered nanomaterials. To overcome the limitations of in vitro exposure of submerged lung cells to nanoparticles (NPs), we validated an integrated low flow system capable of generating and depositing airborne NPs directly onto cells at an air-liquid interface (ALI). The in vitro exposure system was shown to provide uniform and controlled dosing of particles with 70.3% efficiency to epithelial cells grown on transwells. This system delivered a continuous airborne exposure of NPs to lung cells without loss of cell viability in repeated 4h exposure periods. We sequentially exposed cells to air-delivered copper (Cu) NPs in vitro to compare toxicity results to our prior in vivo inhalation studies. The evaluation of cellular dosimetry indicated that a large amount of Cu was taken up, dissolved and released into the basolateral medium (62% of total mass). Exposure to Cu NPs decreased cell viability to 73% (p<0.01) and significantly (p<0.05) elevated levels of lactate dehydrogenase, intracellular reactive oxygen species and interleukin-8 that mirrored our findings from subacute in vivo inhalation studies in mice. Our results show that this exposure system is useful for screening of NP toxicity in a manner that represents cellular responses of the pulmonary epithelium in vivo.",
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"content": "[[\"Cu\", \"INDIRECT-UPREGULATOR\", \"lactate dehydrogenase\"], [\"Cu\", \"INDIRECT-UPREGULATOR\", \"interleukin-8\"]]",
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science.bc7_litcovid_topic_classification | science.bc7_litcovid_topic_classification.1170 | [
{
"content": "Analyze the given paragraph from COVID-19 research. Determine the relevant topics discussed in the text. Your response should be a JSON array containing the identified topics. Ensure the output is a valid JSON array with no additional commentary.\n\nText:\n\nBACKGROUND: Long-term care (LTC) homes have been the epicentre of the coronavirus disease 2019 (COVID-19) pandemic in Canada to date. Previous research shows that for-profit LTC homes deliver inferior care across a variety of outcome and process measures, raising the question of whether for-profit homes have had worse COVID-19 outcomes than nonprofit homes. METHODS: We conducted a retrospective cohort study of all LTC homes in Ontario, Canada, from Mar. 29 to May 20, 2020, using a COVID-19 outbreak database maintained by the Ontario Ministry of Long-Term Care. We used hierarchical logistic and count-based methods to model the associations between profit status of LTC homes (for-profit, nonprofit or municipal) and COVID-19 outbreaks in LTC homes, the extent of COVID-19 outbreaks (number of residents infected), and deaths of residents from COVID-19. RESULTS: The analysis included all 623 Ontario LTC homes, comprising 75 676 residents; 360 LTC homes (57.7%) were for profit, 162 (26.0%) were nonprofit, and 101 (16.2%) were municipal homes. There were 190 (30.5%) outbreaks of COVID-19 in LTC homes, involving 5218 residents and resulting in 1452 deaths, with an overall case fatality rate of 27.8%. The odds of a COVID-19 outbreak were associated with the incidence of COVID-19 in the public health unit region surrounding an LTC home (adjusted odds ratio [OR] 1.91, 95% confidence interval [CI] 1.19-3.05), the number of residents (adjusted OR 1.38, 95% CI 1.18-1.61), and older design standards of the home (adjusted OR 1.55, 95% CI 1.01-2.38), but not profit status. For-profit status was associated with both the extent of an outbreak in an LTC home (adjusted risk ratio [RR] 1.96, 95% CI 1.26-3.05) and the number of resident deaths (adjusted RR 1.78, 95% CI 1.03-3.07), compared with nonprofit homes. These associations were mediated by a higher prevalence of older design standards in for-profit LTC homes and chain ownership. INTERPRETATION: For-profit status is associated with the extent of an outbreak of COVID-19 in LTC homes and the number of resident deaths, but not the likelihood of outbreaks. Differences between for-profit and nonprofit homes are largely explained by older design standards and chain ownership, which should be a focus of infection control efforts and future policy.",
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"content": "[\"Prevention\"]",
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science.genia_ner | science.genia_ner.782 | [
{
"content": "Analyze the provided text excerpt from a scientific document. Identify and extract distinct entities based on predefined categories.\n\nDeliver the results as a JSON structure where each key represents an entity category, and the associated value is a list of identified entities. If no entities are found for a category, return an empty list.\n\nText Excerpt:\n\nLineage-specific activation of STAT3 by interferon-gamma in human neutrophils. Binding of interferon-gamma (IFN-gamma) to its heterodimeric receptor induces activation of the tyrosine kinases JAK1 and JAK2 followed by tyrosine phosphorylation of STAT1alpha. Selective activation of STAT1alpha at the IFN-gamma receptor is achieved by specific interaction between a cytosolic tyrosine motif including Y440 in the IFN-gamma receptor alpha-chain and the SH2 domain of STAT1alpha. We demonstrate that, in addition to STAT1alpha, STAT3 is also activated by IFN-gamma in human neutrophils. The activation of STAT3 was not found in human eosinophils, monocytes, and HL-60 cells, although the STAT3 protein was expressed in these cells. The cell type-specific activation of STAT3 by IFN-gamma was also observed in neutrophils that are differentiated in vitro from human CD34 + hematopoietic stem cells. These results indicate that a single cytokine receptor can activate different STAT family members in a cell-specific manner, which might result in cell-specific gene transcription.",
"role": "user"
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"content": "{\"CellLine\": [\"HL - 60 cells\"], \"CellType\": [\"monocytes\", \"human CD34 + hematopoietic stem cells\", \"human neutrophils\", \"neutrophils\", \"human eosinophils\"], \"DNA\": [], \"Protein\": [\"Y440\", \"interferon - gamma\", \"cytosolic tyrosine motif\", \"IFN - gamma\", \"IFN - gamma receptor alpha - chain\", \"STAT1alpha\", \"tyrosine kinases\", \"SH2 domain\", \"IFN - gamma receptor\", \"STAT family members\", \"STAT3 protein\", \"JAK1\", \"interferon - gamma (IFN - gamma)\", \"cytokine receptor\", \"STAT3\", \"JAK2\"], \"RNA\": []}",
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science.chemsum_single_document_summarization | science.chemsum_single_document_summarization.6605 | [
{
"content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nA photochemical C=C cleavage process: toward access to backbone N-formyl peptides\n\nContent Extracts:\n\n<p>All costs related to the publication of this open access article were entirely funded by the Beilstein-Institut.</p><p>This article is part of the thematic issue \"Late-stage diversification of peptides\".</p>\n\nFindings\n<p>The photochemistry of nitroaromatic functional groups has a rich history that dates back decades [1–5]. Photochemical pathways allow access to diverse and interesting target structures [6–10], though photocleavage of C–X bonds for use as photoremovable protecting groups [11–12] has been the major thrust of the development of 2-nitroaryl compounds. Various 2-nitrobenzyl derivatives are used to photocage heteroatom functional groups, including alcohols, amines, carboxylic acids, and phosphates [11]. Typical photochemical pathways result in cleavage of a benzylic C–X bond following initial benzylic H-atom abstraction [11,13]. In contrast, photorelease systems based on C–C or C=C bond photocleavage are quite rare [14–15]. We recently reported a vinylogous analogue of this photo-deprotection process, which allowed photocleavage of alkenyl sp2 C–X bonds, rather than benzylic sp3 C–X cleavage [16–17]. We now report that further studies into this reaction demonstrate two mechanistically distinct photocleavage pathways, with selectivity dependent on pH. In addition to an anticipated alkenyl sp2 C–X bond cleavage pathway, we identified a new photochemical reaction pathway, prevalent under neutral and acidic reaction conditions, which leads to formyl products from formal oxidative cleavage of a C=C bond.</p><p>Our interest in vinylogous analogues of 2-nitroaryl photoreactive groups stems from studies into alkenylboronic acid reagents for Chan–Lam-type modification of peptide backbone N–H bonds, directed by a proximal histidine residue (Figure 1C, step, i + iv → ii) [18–20]. Subsequent investigations validated the use of photoreactive boronic acids as an approach to reversible backbone N–H modification via photocleavage of an alkenyl C–N bond [16–17]. Traditional 2-nitroaryl groups allow cleavage of benzylic C–X bonds (e.g. C–O cleavage, Figure 1A) through H-atom abstraction from a photoexcited intermediate, which produces an oxonium-type intermediate (in brackets). Hydrolysis of this intermediate then affords an alcohol product. Recently [16–17], we demonstrated that vinylogous analogues of this mechanism (Figure 1B) provide entry into similar photo-uncaging chemistries for amide release.</p>\n\n\n<p>Uncaging of peptide backbone N–H bonds from Chan–Lam-type modification.</p>\n\nFindings\n<p>Figure 1C shows an example of this concept applied to a peptide substrate. Reaction of the peptide i with an alkenylboronic acid reagent iv in the presence of a copper(II) salt in water provides access to the backbone N–H alkenylation product ii, directed by a neighboring histidine residue. Upon exposure to 365-nm light, photocleavage of the caging group (red) was observed, producing the free peptide i. Irradiation longer than 10 minutes were sometimes necessary for maximal yield of photo-deprotected product i [16]. Furthermore, byproducts or transiently stable intermediates were sometimes indicated by HPLC and/or NMR of these photocleavage reactions [16–17]. These observations prompted a more detailed study of the components present during photocleavage reactions of small-molecule models, leading to the identification of the N-formyl product iii, a possible intermediate on the path to product i via imide hydrolysis.</p><p>To better understand the mechanism of photocleavage and the appearance of the formyl product iii, we first identified the 2-nitroaryl-derived byproducts produced in this reaction. Model compound 1 was subjected to aqueous photocleavage in the presence of triethylamine, and the resulting reaction mixture was purified by reversed-phase HPLC (Figure 2). We isolated a nitroso product 3, in addition to two other major identifiable components of the crude reaction: quinoline N-oxide (4) and quinolinone (5). The compounds 4 and 5 are C9 compounds possibly derived from thermal or photochemical rearrangement of compound 3 or another intermediate. The yield of each product was calculated by NMR and verified by isolation (Figure 2). To test the generality of this process with other functional groups, we prepared and tested alkenyl ether 6 as a model of C–O-bond cleavage. Photoirradiation of the ether 6 similarly provided a mixture of C9-containing products 3, 4, and 5. Under these reaction conditions, the C–X cleavage products (MeOH or 2) were observed, but no formyl products were formed. The C9 byproducts – the nitroso 3, and related compounds 4 and 5 are all consistent with the classical C–X cleavage mechanism and with hydrolysis of the presumed oxonium intermediate 6', but are inconsistent with the production of formyl products.</p>\n\n\n<p>Photocleavage of compounds 1 and 6 under basic conditions. Yield of products was calculated from crude 1H NMR using residual CD3OD peaks as internal standard.</p>\n\nFindings\n<p>In contrast, photoirradiation of the same alkenyl ether 6 under acidic conditions at pH 4.0 provided a mixture of methanol (53%) and methyl formate (38%, 7) as determined by NMR, the latter product is the result of formal oxidative C=C cleavage (Figure 3a). Alkenyl amide 1 at pH 4.0 similarly gave mixtures of the C–N cleavage product 2 and C=C cleavage product 8. We examined product selectivity in the irradiation of alkenyl amide 1 across a range of pH and found a significant correlation (Figure 3b–d). The formyl product 8 predominated at acidic and neutral pH. The amount of 8 decreased with increasing pH, and above pH 10 the C–X cleavage product 2 became the major product. Unfortunately, no products other than the formyl compound were isolated after photocleavage of compound 1 or 6 in acidic conditions. Instead, when irradiation of alkenyl amide 1 was conducted in acetone, crude NMR analysis indicated the appearance of product 8 as well as new peaks in the aromatic region.</p>\n\n\n<p>(a) Photocleavage of compound 6 under acidic conditions. Yields determined by 1H NMR using residual CD3OD as an internal standard. (b–d) Selectivity of photocleavage of alkenyl amide 1 as a function of pH. Product percentage of N-formyl 8 was assessed by crude NMR (c) and graphed (d). Formation of N-formyl-N-methyl acetamide 8 during photocleavage of compound 1. Conditions: 1 (1.8 μmol) was dissolved in MeOD-d4 (200 μL) and deuterated buffer (400 μL). The solution was irradiated at 365 nm for 2 min. (e) Photocleavage reaction of 1 in acetone.</p>\n\nFindings\n<p>Following acetylation of the reaction mixture, we were able to isolate small quantities of O-acetyl N-hydroxyindole (9, Figure 3e), although the initial byproduct N-hydroxyindole itself proved too unstable to be isolated. It is noteworthy within this context that hydroxyindole is a C8 compound, consistent with transfer of the C1 formyl group to compound 8. The formation of amide 2 at elevated pH could, in theory, derive from hydrolysis of the initially formed formyl product 8 (i.e. Figure 1C). However, the appearance of primarily C9 byproducts in the formation of amide 2 at elevated pH precludes pathways involving the intermediacy of 8. To provide additional support for this analysis, and to assess the stability of N-formyl amides formed in this reaction, we irradiated alkenyl amide 10, which contains a 2-phenylethyl substituent that allowed easier isolation of N-formyl 11 (Figure 4). After irradiation, the product 11 was isolated in 28% yield, the modest yield reflecting the instability in water and on silica of this compound. The purified N-formyl 11 was then dissolved in buffer (pH 8), and its hydrolysis to amide 12 was assessed (Figure 4, inset). We observed clean first-order kinetics to give amide 12 with a half-life (t1/2) of 6.4 h.</p>\n\n\n<p>Preparation and hydrolysis kinetics (inset) of N-formyl product 11. Dashed line: first-order decay fit used in calculating the rate constant.</p>\n\nFindings\n<p>The observation of N-formyl products can be rationalized with a bifurcating mechanism (Figure 5). Following photoactivation, H-atom abstraction and nucleophilic addition of water would produce the key intermediate B. Such hemi-aminal compounds would be unstable under basic conditions, readily forming aldehyde products 3. However, related hemi-aminal compounds are quite stable under non-basic conditions, and the motif is even contained in some natural products, such as zampanolide [21] and spergualin [22]. We propose a competing electrocyclization pathway, affording the heterocycle D, a pathway which should not be base-catalyzed, and thus may be reasonably predominant under appropriate conditions. From heterocycle D, a C–C cleavage would produce the N-formyl product 8 and a re-aromatized C8 heterocyclic byproduct E. Rearrangement to hydroxyindole (F) would then account for the isolation of the acetylated analogue 9.</p>\n\n\n<p>Proposed mechanism for the formation of aldehyde 3 and N-formyl product 8.</p>\n\nFindings\n<p>The photochemical pathway described here represents a formal oxidative olefin cleavage of vinylogous nitroaryl-modified amides and ethers. The pathway adds to the diversity of photochemical pathways known for 2-nitrophenyl systems, and the concept described here might be useful for the synthetic unmasking of relatively sensitive imido structures. For chemical biology applications, the results point to a far more diverse photochemistry than previously assumed for vinylogous photocleavage systems. Although formyl hydrolysis to the \"expected\" amide products can and does occur under physiological conditions, the rates of this hydrolysis are slow for the simple models in this study. Within more complex peptides or proteins, selectivity in photocleavage pathways may differ significantly, depending on local chemical environment. It is also worth noting that N-formyl products are themselves acylating reagents, and thus could find use in photochemical generation of selective acyl donors.</p>\n\n\n<p>Experimental section and additional information.</p>",
"role": "user"
},
{
"content": "Photo-responsive modifications and photo-uncaging concepts are useful for spatiotemporal control of peptides structure and function. While side chain photo-responsive modifications are relatively common, access to photo-responsive modifications of backbone N–H bonds is quite limited. This letter describes a new photocleavage pathway, affording N-formyl amides from vinylogous nitroaryl precursors under physiologically relevant conditions via a formal oxidative C=C cleavage. The N-formyl amide products have unique properties and reactivity, but are difficult or impossible to access by traditional synthetic approaches.",
"role": "assistant"
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science.healthver_entailment | science.healthver_entailment.806 | [
{
"content": "Evaluate the given public health statement using the provided research abstract. Your goal is to determine the relationship between the claim and the abstract content.\n\n- \"decision\": Indicate whether the abstract \"SUPPORTS\", \"CONTRADICTS\", or provides \"INSUFFICIENT\" information regarding the claim.\n- \"justification\": List sentences from the abstract that back your decision. If the decision is \"INSUFFICIENT\", leave this list empty.\n\nStatement: Can hydroxychloroquine treat COVID-19? No\n\nResearch Abstract:\nHydroxychloroquine (HCQ) garnered scientific attention in early February following publication of reports showing in vitro activity of chloroquine (CQ) against COVID‐19.\nWhile studies are mixed on this topic, the therapeutic effect of HCQ or CQ still need more valid clinical evidence.\nIn this descriptive observational study, we aimed to discuss the treatment response of HCQ in COVID‐19 infected patients and 30 cases were included.\nThe demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and interleukin‐6 (IL‐6) before and after HCQ therapy and clinical outcome in the 30 COVID‐19 patients were assessed.\nIn order to evaluate the effect of mediation time point, we also divided these cases into two groups, patients began administrated with HCQ within 7 days hospital (defined as early delivery group) and 7 days after hospital (defined as later delivery group).\nWe found that, the elevated IL‐6, a risk factor in severe patients were reduced to normal level after HCQ treatment.\nMore importantly, patients treated with HCQ at the time of early hospital recovered faster than those who treated later or taken as second line choose for their obvious shorter hospitalization time.\nIn summary, early use of HCQ was better than later use and the effect of IL‐6 and CRP level can not be ruled out.\nThis article is protected by copyright.\nAll rights reserved.",
"role": "user"
},
{
"content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"More importantly, patients treated with HCQ at the time of early hospital recovered faster than those who treated later or taken as second line choose for their obvious shorter hospitalization time.\"]}",
"role": "assistant"
}
]
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science.craftchem_ner | science.craftchem_ner.2020 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nSterollevels,asdeterminedbygaschromatography(GC)analysis,inplasmaandtissuesoftheAbcg8-/-miceareshowninTable2.",
"role": "user"
},
{
"content": "[\"Sterol\"]",
"role": "assistant"
}
]
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science.chemsum_single_document_summarization | science.chemsum_single_document_summarization.6240 | [
{
"content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nUK-1 and Structural Analogs are Potent Inhibitors of Hepatitis C Virus Replication\n\nContent Extracts:\n\n<p>The hepatitis C virus (HCV), the causative agent of the hepatitis C infection, has been declared a worldwide health concern by the World Health Organization (WHO).1,2 Estimates predict that a minimum of 3% of the global population, approximately 170 million people, are currently infected.3 Of those diagnosed with the virus, 70–80% of cases are not suppressed by the body's immune system and chronic liver infection develops.4 This acute infection of the hepatocytes leads to liver cirrhosis, hepatocellular carcinoma, and eventually liver failure.5 Moreover, HCV infection is currently the leading cause of liver transplantation.6</p><p>Two direct-acting antiviral (DAA) drugs, Boceprevir and Telaprevir, were approved by the FDA for HCV treatment in 2011. Although these drugs represent the first DAAs approved for HCV therapy, during early phases of development it was found that monotherapy utilizing either of these drugs alone resulted in the rapid development of resistant strains.7,8 As a result, these drugs are only FDA approved when given in combination therapy with two previously approved broad spectrum antivirals, ribavirin and pegylated interferon (PEG-IFN).9,10 The new treatment regimes have increased overall response rates, but the severe side effects and extremely high cost associated with PEG-IFN remain problematic.11 While combination therapy is the most promising approach for future HCV treatment, replacement of broad spectrum antivirals with inhibitors specific for HCV will likely result in much more favorable treatment outcomes.</p><p>HCV is a positive sense RNA virus that, following entry into the host hepatocyte, encodes for a single polyprotein of approximately 3000 amino acids.12–14 The polyprotein is processed co- and post-translationally by both host and viral proteases to yield ten viral proteins. The amino terminal third of the peptide contains the four structural proteins core, E1, E2, and p7. The remaining two-thirds of the protein is composed of the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B.15 Although each NS protein possesses a unique function (or functions), as a whole they are responsible for the synthesis of viral RNA, and thus critical for viral replication.16 For this reason, the NS proteins are commonly pursued as drug targets in HCV research.</p><p>NS3 is a protein exhibiting multiple functions and is well characterized both structurally and functionally. NS3 and the adjacent NS4A function as a complex, with NS4A serving as both a cofactor for NS3 and as a membrane anchor.17 The amino terminal domain of NS3 and NS4A form a dimeric serine protease that is responsible for the intramolecular cleavage of NS3 from NS4A, as well as the intermolecular cleavage between all downstream non-structural proteins.18 In addition, the carboxy terminus of NS3 functions as an ATP dependent helicase, and this activity is facilitated by NS4A.19 The exact relevance of the helicase activity as it pertains to HCV viral replication is not known, but it has been shown that a functional helicase is required for in vivo HCV replication.16,20,21 Several functions for the helicase have been proposed, including aiding in the polymerase processivity, assisting with RNA folding, modulating host gene expression, and involvement in genome encapsidation.22,23 There are currently no HCV helicase inhibitors in clinical trials, but numerous strategies for helicase inhibition have been investigated. Since the NS3 helicase activity is dependent upon ATP hydrolysis, various nucleoside analogs have been developed to inhibit the NTPase activity of NS3.24 Other helicase inhibitors include compounds that bind directly to the nucleic acid binding site of the helicase or to unknown allosteric sites.25,26</p><p>UK-1 (Figure 1) is a Streptomyces metabolite that exhibits broad spectrum anti-cancer activity and has also been shown to chelate magnesium and zinc.27–29 It was hypothesized that UK-1 and structural analogs could potentially inhibit HIV-1 integrase via magnesium coordination in the enzyme active site. As such, a series of UK-1 analogs (1-6) were synthesized and screened against HIV-1, as well as a number of other viruses. Although no activity against HIV-1 was observed, all of the compounds screened did prove to be effective inhibitors of HCV viral replication in replicons, with IC50 values as low as 0.50μM. In an attempt to determine the mechanism of HCV inhibition, these compounds were also screened against the HCV NS3 helicase, NS3 NTPase, and NS5B polymerase.</p><p>The compounds evaluated are shown in Figure 1. UK-1 and analogs 1-3 were synthesized as previously reported.29,30. The synthesis of 5 is shown in Scheme 1 (for the synthesis of 6, the same methodology was used). This began with carboxylation of 1,5-dihydroxynaphthalene, using magnesium methyl carbonate as previously described.31 The resulting acid was reacted with benzyl chloride, which upon hydrolysis gave 7. The acid was then activated with 1,1′-carbonyldiimidazole (CDI) and coupled to methyl 3-hydroxyanthranilate, giving compound 8. Refluxing 8 in m-xylene with pyridinium p-toluenesulfonate (PPTS) resulted in cyclodehydration as well as monodebenzylation, to give target compound 5. Compound 4 was synthesized similarly, starting with 1-hydroxy-2-naphthoic acid. It should be noted that the position of the benzyl group in 5 (and 6) was not readily determined using 2D NMR techniques. However, fluorescence experiments confirmed the product structure (Supplemental Information: Scheme 2, Figure 3). Briefly, the desired product showed a large Stokes shift consistent with an excited state intramolecular proton transfer (ESIPT) only feasible in isomer 5 (and 6), as opposed to the other possible product of monodebenzylation.32</p><p>Potential inhibition of the helicases of Flaviviridae viruses HCV, Japanese encephalitis virus (JEV), and dengue virus (DENV) was investigated using previously described methods.33,34 None of the compounds inhibit JEV or DENV helicases (IC50>700μM), however several of the compounds did inhibit the activity of the HCV helicase (Table 1, Figure 2). UK-1 itself shows weak inhibition using a DNA substrate, but no inhibition with an RNA substrate. Importantly, naphthol derivatives 4-6 show helicase inhibition, with 5 and 6 exhibiting IC50 values in the low micromolar range. None of the compounds inhibit the ATPase activity of the HCV helicase (IC50>1200 μM), eliminating this as a possible mechanism of action. Compounds 5 and 6 do not affect the gel mobility of an EcoRI-digested pT7-7 plasmid, suggesting the inhibition results from direct helicase interaction, rather than simple nucleic acid binding.</p><p>To determine if the compounds are active against HCV replication in cells, they were screened in the replicon assay (Table 1). Quite interestingly, all seven compounds were active, with EC50 values in the low- to sub-micromolar range. While the mechanism of viral inhibition for compounds 5 and 6 may result from helicase inhibition, this is not the case for 1-3 and seems unlikely for weak helicase inhibitors UK-1 and 4. This suggests that within this group of compounds, there is a second, as yet undetermined mechanism of inhibition. The compounds were then screened against the HCV RNA-dependent RNA polymerase NS5B, and very little inhibition was observed (inhibition ≤ 30% at 100 μM). There was no significant difference in activities between analogs 1-3, despite expected differences in cell permeability and susceptibility to cellular esterases. Compounds 5 and 6 exhibit cell toxicity values greater than 20 μM, giving selectivity indices greater than 10 and 37, respectively. All other compounds showed measureable toxicity under the assay conditions, although the selectivity index for UK-1 is still greater than 20.</p><p>All noted compounds are significantly better inhibitors in replicons than in the helicase assay. This discrepancy could result from the fact that the helicase experiments were conducted with the helicase and NTPase domains of NS3 (NS3h). The helicase activity of full length NS3 is greater than that of NS3h alone.35–37 It has also been shown that adjacent NS4A acts as a cofactor for NS3 and increases helicase activity.38 It is therefore possible that the inhibitors are more active in the presence of full length NS3/NS4A than NS3h alone. This could explain the increased inhibitory activity of 5 and 6 in replicons versus in the helicase assay. Alternatively, based on the similar activities of all inhibitors in replicons, these compounds could potentially share the same target, which is not the NS3 helicase. To further explore this possibility, evidence for a direct interaction between 5 (and 6) with purified NS3 is being sought, as well as potential interactions with other HCV proteins.i</p><p>In summary, several novel inhibitors of HCV viral replication have been identified which exhibit minimal cytotoxicity. Two of these compounds (5 and 6) inhibit the NS3 helicase with micromolar IC50 values and are highly selective; no inhibition is observed with the closely related helicases of DENV and JEV. It has been speculated that viral inhibition may be a result of direct interaction with the helicase, as neither ATPase inhibition nor direct RNA binding is observed. A second group of compounds effectively inhibits HCV RNA replication in the replicon assay via an as yet to be determined mechanism. Experiments are currently underway to further investigate and verify the proteins target(s) for all inhibitors.</p>",
"role": "user"
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{
"content": "The bacterial natural product UK-1 and several structural analogs inhibit replication of the hepatitis C virus in the replicon assay, with IC50 values as low as 0.50 \\xce\\xbcM. The NS3 helicase has been identified as a possible target of inhibition for several of these compounds, while the remaining inhibitors act via an undetermined mechanism. Gel shift assays suggest that helicase inhibition is a direct result of inhibitor-enzyme binding as opposed to direct RNA binding, and the ATPase activity of NS3 is not affected. The syntheses and biological results are presented herein.",
"role": "assistant"
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science.mslr2022_cochrane_multidoc_summarization | science.mslr2022_cochrane_multidoc_summarization.2925 | [
{
"content": "Review the provided collection of medical RCT summaries. Your objective is to distill the essential insights into a brief conclusion. Focus solely on the synthesis of findings without additional commentary. The RCT summaries are as follows:\n\n\n\nReport Title 1:\nA randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.\nReport Abstract 1:\nOpen-label oral immunotherapy (OIT) protocols have been used to treat small numbers of patients with peanut allergy. Peanut OIT has not been evaluated in double-blind, placebo-controlled trials.\n To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind, placebo-controlled study.\n In this multicenter study, children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo. Initial escalation, build-up, and maintenance phases were followed by an oral food challenge (OFC) at approximately 1 year. Titrated skin prick tests (SPTs) and laboratory studies were performed at regular intervals.\n Twenty-eight subjects were enrolled in the study. Three peanut OIT subjects withdrew early in the study because of allergic side effects. During the double-blind, placebo-controlled food challenge, all remaining peanut OIT subjects (n = 16) ingested the maximum cumulative dose of 5000 mg (approximately 20 peanuts), whereas placebo subjects (n = 9) ingested a median cumulative dose of 280 mg (range, 0-1900 mg; P < .001). In contrast with the placebo group, the peanut OIT group showed reductions in SPT size (P < .001), IL-5 (P = .01), and IL-13 (P = .02) and increases in peanut-specific IgG(4) (P < .001). Peanut OIT subjects had initial increases in peanut-specific IgE (P < .01) but did not show significant change from baseline by the time of OFC. The ratio of forkhead box protein 3 (FoxP3)(hi): FoxP3(intermediate) CD4+ CD25+ T cells increased at the time of OFC (P = .04) in peanut OIT subjects.\n These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation. The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance.\n Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.",
"role": "user"
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{
"content": "The one small RCT we found showed that allergen-specific peanut OIT can result in desensitisation in children, and that this is associated with evidence of underlying immune-modulation. However, this treatment approach was associated with a substantial risk of adverse events, although the majority of these were mild. In view of the risk of adverse events and the lack of evidence of long-term benefits, allergen-specific peanut OIT cannot currently be recommended as a treatment for the management of patients with IgE-mediated peanut allergy. Larger RCTs are needed to investigate the acceptability, long-term effectiveness and cost-effectiveness of safer treatment regimens, particularly in relation to the induction of clinical and immunological tolerance.",
"role": "assistant"
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science.scientific_lay_summarisation_plos_single_doc_summ | science.scientific_lay_summarisation_plos_single_doc_summ.7417 | [
{
"content": "Transform the following sections from a biomedical study into a simple summary for the general public. Focus on making the information accessible and easy to understand.\n\nResearch Heading: Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer\nContent:\nAbstract:\nHereditary factors are presumed to play a role in one third of colorectal cancer( CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost( P = 0. 0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.\nIntroduction:\nColorectal cancer( CRC)( MIM 114500) is a major cancer type, with over one million new cases diagnosed worldwide each year. It is the third most common malignancy[1], and the second most common cause of cancer mortality[2]. Inherited factors are estimated to play a crucial role in at least one third of all CRC cases[3]. However, high-penetrance mutations in known CRC predisposing genes, such as the mismatch repair( MMR) genes, APC, MUTYH( MYH), SMAD4, BMPR1A, STK11/LKB1, PTEN, AXIN2, POLE, and POLD1 explain only around 5% of these cases[4]–[6]. There are a few examples of rare variants in CRC predisposing genes conferring moderate or low carrier risk, such as APC( I1307K)[7], BLM[8] and GALNT12[9]. Of these, the APC I1307K variant has been most extensively studied and occurs almost exclusively in the Ashkenazi Jewish population[7]. In addition to these, genome-wide association( GWA) studies have identified common low-penetrance variants at approximately 20 genomic loci associated with CRC susceptibility. However, the identified common variants at these loci exert only a modest effect on CRC risk[10]–[12]. Unknown variants of moderate or low penetrance are likely to explain at least part of the missing heritability in CRC. CRC families with few affected individuals are an attractive patient group to search for such genetic factors, but tools for such work have been poor. These families are relatively common but too small for linkage analyses, and the culprit variants are likely to be too diverse and rare to be detected in GWA studies. One approach has been to study the additive contribution of low-penetrance variants on familial risk. A previous study has estimated that ten known low-penetrance CRC variants collectively explain around 9% of the variance in familial risk[13]. Advances in sequencing technologies have made exome sequencing a feasible approach to search for rare coding variants of varying penetrance. In this study, we aimed at identifying variants predisposing to common familial CRC by performing exome sequencing on 96 independent familial CRC cases derived from a consecutive collection of unselected patients. Here, familial CRC is characterized as having at least one first-degree relative diagnosed with CRC; indeed the great majority of the 96 familial cases displayed only one first-degree relative with CRC. All patients were from Finland, known for its relatively homogenous population[14],[15]. This empowers the analysis since affected individuals are more likely to share ancestral predisposition mutations and haplotypes, stemming from a handful of founders. To our knowledge, this is the largest effort to date where exome sequencing has been applied to familial forms of cancer to identify novel predisposing genes.\nDiscussion:\nExome sequencing is a powerful tool for discovering novel genetic variants that predispose to disease[17]. To examine the genetic basis of common familial CRC we exome sequenced 96 independent cases( Table 1) derived from a previously described population-based collection of patients[4],[18] and from an additional unselected collection( unpublished). To our knowledge, this is the largest effort to date where familial CRC has been studied by exome sequencing to identify novel CRC predisposing genes. Several strategies were applied to improve the power of gene discovery. First, a large set of familial CRC cases( at least one first-degree relative diagnosed with CRC) was utilized, negative for any known high penetrance CRC mutation. Second, the cases were from Finland, known for its isolated population with reduced genetic heterogeneity. Such isolated populations are enriched for rare founder variants, facilitating identification of disease genes[15]. Third, tumor tissue availability for all the CRC cases allowed for the assessment of somatic allelic imbalance, which gave important additional information related to pathogenicity of the variants. Fourth, genotyping of selected variants was performed in a set of validation phase population matched samples, consisting of 954 cases and 586 controls. In total, we identified 11 novel candidate CRC susceptibility genes with rare truncating variants in two or three familial CRC cases; UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4( Table 2 and Table S2). They were absent or rare( MAF≤0. 001) in the general population. The results fit with the “rare variant hypothesis” that proposes that a significant proportion of the missing heritability of complex diseases is due to a series of rare variants, each conferring a moderate increase in risk. Typically, such risk alleles function dominantly and independently[19],[20]. The “rare variant hypothesis” is strongly supported by evolutionary theory, which argues that variants that promote disease are selected against and are therefore rare. Another argument for the hypothesis comes from recent empirical population genetic data which shows that rare variants are enriched for deleterious mutations[21]. The question remains whether the identified candidate genes act as classical tumor suppressors with second hits or show alternative characteristics, such as haploinsufficiency or dominant-negative effects. Of the genes identified, four out of 11 showed loss of the wild-type allele in at least one tumor. In total, seven LOH events were observed and none showed loss of the mutant allele( P = 0. 0078). This suggests that complete inactivation of these genes seems to be preferentially selected for in tumor evolution and that these germline variants are prime candidates for CRC susceptibility. Perhaps the strongest candidate predisposition gene, in view of the LOH data and case frequency, was the apoptosis-associated gene UACA. Three of the 96 familial CRC cases were found to carry heterozygous truncating variants( p. Q1116X and p. R1292X) in UACA( Table 2). We performed genotyping to screen the variants in a set of validation phase samples. We identified three additional unrelated cases who were heterozygous for the variants encoding either p. Q1116X or p. R1292X. Second hits by LOH involving the germline wild-type allele were found in three of the six tumors( Figure 2). The average age of onset of CRC in the familial cases was 54 years( 58, 54 and 50)( Figure 3), younger than the mean age of onset of 71 in familial cases without the UACA truncating variants( Table S1). UACA has recently been identified as a novel regulator of apoptosis. It is known to reside within the Apaf-1/procaspase-9 complex and regulate apoptosis activating factor( APAF-1). It also regulates the apoptotic pathway by controlling the activation of nuclear factor( NF)-κB[22]. In addition, UACA gene expression has been shown to be down-regulated in non-small cell lung carcinoma( MIM 211980)[23]. Taken together, the loss of UACA in cancer cells might result in altered activation of apoptotic pathways, ultimately promoting genesis of CRC. Another gene of particular interest was TWSG1. The detected truncating germline variant( p. Q41X) was present in two familial CRC cases( 2/96 cases) and completely absent in 1, 039 Finnish population matched controls( Table 2). Loss of the remaining normal TWSG1 allele was observed in both tumors indicating that the gene might act as a classical tumor suppressor gene( Figure 2). The index case with Q41X in family 1 developed CRC at the age of 53 and segregation analysis showed that the variant was inherited from the affected mother( Figure 3). The mother had developed CRC at the age of 68 and lung cancer at the age of 77. The variant did not segregate with CRC in family 2. Rare risk alleles of moderate penetrance are usually over-represented in familial cases; however co-segregation of disease is not always observed[19]. Previous studies have shown TWSG1 to be a regulator of BMP-signaling[24]. It is known to act downstream of TGF-β, inducing SMAD2 phosphorylation and mediating DNA binding on Smad3/4 consensus sites[25]. TWSG1 functions in cellular pathways that are essential in genesis of CRC, however, its exact role in these pathways remains to be clarified. In summary, exome sequencing is a well-justified strategy for discovering cancer predisposing variants. The identification of predisposing variants has substantial implications for disease risk assessment and surveillance in family members. Here, we identified eleven candidate predisposing genes with truncating variations in familial CRC. A key challenge is how to identify predisposing variants in the background of non-pathogenic polymorphisms. Screening the eleven genes in familial CRC cases representing different populations will be important to gain robust evidence for pathogenicity, as well as to characterize the natural history of the respective phenotypes. This information, then, can be translated into tools for cancer prevention and early diagnosis in individuals carrying true predisposition alleles.",
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"content": "Many individuals with a family history of colorectal cancer have no detectable germline mutation in the known cancer predisposing genes . We aimed to identify novel susceptibility genes for this common phenotype by performing exome sequencing on 96 independent cases with familial colorectal cancer . Eighty-six patients had one affected first-degree relative , and ten patients had two or more . None of the patients had a previous diagnosis of a hereditary syndrome . We focused our search on genes with rare variants , predicted to truncate the protein product , since these are likely candidates for disease predisposition . Using this approach we identified truncating germline variants in eleven genes , present in two or three independent familial colorectal cancer cases . We analyzed the respective tumor DNAs and found loss of the wild-type allele in seven out of seven occasions , involving four genes . No tumor showed loss of the mutant allele which provides us with additional evidence for disease causality . Further studies are required to provide firm evidence for pathogenicity . Genetic knowledge on confirmed predisposing genes can ultimately be translated into tools for cancer prevention and early diagnosis in individuals carrying predisposition alleles .",
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science.scientific_papers_summarization_single_doc_pubmed | science.scientific_papers_summarization_single_doc_pubmed.10640 | [
{
"content": "Read the provided biomedical research paper and create a concise abstract. Ensure the abstract captures the main points of the paper.\n\nFull Paper:\ndictybase ( ) is the model organism database ( mod ) for the social amoeba dictyostelium discoideum . like other mods such as flybase ( 1 ) , wormbase ( 2,3 ) , mouse genome informatics ( 4 ) and the saccharomyces genome database ( sgd ) ( 5 ) ,\ndictybase ( 6 ) uses the organism 's genome sequence to organize the biological knowledge resulting from experimental studies using dictyostelium .\nan amoeba during most of its life , starvation induces a very interesting developmental program during which individual cells stream together by chemotaxis to form a multicellular tissue ( 7 ) .\na morphogenetic process involving cell migration and cellular morphogenesis transforms a simple mound of cells into a slug or pseudoplasmodium establishing a relatively simple developmental pattern .\nthis structure then develops into a fruiting body consisting of multiple cell types including spores and terminally differentiated stalk cells . these features together with the efficient genetic manipulation by gene targeting and replacement as well as insertional mutagenesis and suppressor screens have made dictyostelium a popular experimental system .\nresearch using dictyostelium has been critical in understanding fundamental processes such as cell migration ( 8) , cell signaling ( 9,10 ) , phagocytosis and morphogenesis .\nrecently dictyostelium has also been used to help establish the mechanisms of action of medically important drugs such as cisplatin ( 1114 ) , used to treat various cancers , and lithium and valproic acid ( 15 ) , used to treat depressive disorders .\nthe recently completed dictyostelium genome sequence is housed at dictybase and has been integrated with other experimental data to provide investigators with a rich new resource that will facilitate future studies using dictyostelium experimentally and for comparative genomics .\nin may 2005 the sequence of the complete genome of dictyostelium was reported ( 16 ) .\nthe a + t rich genome ( 77.6% ) consists of 34 million bases of dna sequence that are predicted to encode 13 573 genes a number of genes comparable with drosophila . dictybase houses and maintains the genome sequence produced by the international sequencing consortium . as the first free living protozoan to be completely sequenced\n, the predicted proteome supports the hypothesis that dictyostelium represents an early branch in the eukaryotic tree of life that diverged after the split between animals , plants and fungi , with dictyostelium and other amoebae more closely related to animals .\nmany dictyostelium proteins are more similar to human orthologs than are those of saccharomyces cerevisiae .\nthe abundance of short sequence repeats produces unusual runs of amino acids , such as polyasparagine and polyglutamine tracts of 20 residues or more .\nthe genome also contains a surprisingly large number of polyketide synthases , which may produce a previously unanticipated large complement of natural products .\nconsistent with this apparently large secondary metabolism , the genome contains many abc transporters that may be involved in export of these natural products .\nalso encoded are a large number of proteins containing multiple egf repeats that have been postulated to play roles in adhesion or cell recognition .\nthese fascinating genomic features together with the unique biology of dictyostelium and the rich body of dictyostelium literature ( nearly 8000 publications ) provide a valuable opportunity to annotate many of the genes with functional information that will widen the spectrum of characterized proteins in public databases .\nthis emphasizes the need for a well - curated database for dictyostelium a need .that dictybase strives to fulfill .\nas the mod for d.discoideum , dictybase provides highly curated information that facilitates research by providing a searchable , structured repository of dictyostelium experimental results .\nin addition to the complete genome sequence , groups performing high - throughput experiments such as large - scale mutagenesis and microarray - based gene expression studies are depositing their data in dictybase for integration and distribution to the research community . dictybase uses the genomic dna sequence as a scaffold on which to organize and display the biological knowledge and experimental evidence derived from dictyostelium research .\ndictybase is the most comprehensive source of information regarding dictyostelium , and the database presents the highest quality annotations of dictyostelium genes .\nnearly all of the data in dictybase is available for bulk download through our download center ( ) .\na gene page is available for each gene that has been shown or predicted to exist in the genome .\nthe gene page collects and organizes all of the available information related to that gene into several sections .\na general information section provides the official gene name together with any other names that have been used to refer to that gene .\nthis assures that a search of the database will allow retrieval of a gene using any name that has been used to refer to that gene .\nscientific curators verify published and proposed gene names to encourage use of the dictyostelium nomenclature guidelines ( ) and to ensure that names are not duplicated .\nalso in this section , gene product names and a brief description of the gene product are presented , as is the unique dictybaseid .\nnext , the chromosomal coordinates section presents a graphical view of the gene and associated sequences such as expressed sequence tags ( ests ) , cdnas and other genbank entries .\nan associated sequences section provides links to sequences corresponding to each of the sequence features known for that gene , including gene predictions as well as ests , cdnas and genomic sequences submitted by individual researchers to other public databases .\nthe protein information section contains the size , molecular weight and protein domains of the predicted protein .\nfunctional information is presented in sections for gene ontology ( go ) annotations and phenotypes whenever this information is available .\nphenotypic data is represented using a restricted vocabulary that describes the consequences of mutations reported for that gene .\nthe gene ontology section lists terms from each of the function , process and component ontologies associated with the gene ( 17,18 ) .\nfollowing links in each of these sections display additional details for these annotations . clicking on a go term or\nthe expression section leads to developmental profiles for the gene that have been generated by large - scale microarray based studies performed at the baylor college of medicine and the university of california , san diego .\nthe links section on the gene page provides links to genbank , uniprot , genedb at the sanger institute and , where appropriate , to signaling pathways at the signal transduction knowledge environment at science ( 19,20 ) .\nthis section also links to researchers in our colleague database who are investigating that gene or gene product .\na literature section lists the most recent publications referring to the gene and a link to a literature guide that contains a complete listing of papers relevant to that gene . as of the fall of 2005 ,\n> 500 gene pages had a summary paragraph written by a dictybase curator that contains the current knowledge regarding that gene .\ndictybase curators are in the process of manually reviewing all of the automated gene predictions in light of available data such as ests and cdnas .\ndictybase curators have reviewed nearly 2500 genes , which corresponds to 20% of the total number of genes .\ndictybase also serves as a clearinghouse for resource materials for students , researchers and educators using dictyostelium in a wide range of classroom and laboratory settings .\nwe maintain archives of the dictynews , a weekly electronic newsletter that presents abstracts of papers available upon acceptance for publication , as well as a growing collection of protocols for working with dictyostelium .\nthis resource provides access to dictyostelium strains , including natural isolates , targeted mutants and gfp labeled strains .\nthe collection also contains plasmids used to manipulate gene expression or create targeted gene disruptions .\ncurrently the dsc has > 700 strains and > 150 plasmids all available to researchers .\na shopping cart system allows stock center users to add strains and proceed to a checkout system familiar to any user of online ordering systems . for users who are also registered as colleagues in the dictybase colleagues database , addresses for delivery and contact information\ndictybase holds all of the stock center data and provides the informatics support for the dsc .\ndictybase was initially established as a clone of the software developed and generously provided by sgd .\nthese include the gbrowse tool for chromosome and map displays and , most recently , the chado database schema for storing sequence and sequence feature information .\nthis entailed porting of the chado schema to oracle since both dictybase and sgd are implemented in oracle .\ndictybase has developed new code that separates communication with the database from code that generates the html interfaces .\nthis object layer facilitated adoption of the chado schema without significant impact on the presentation interface and enables good software practices such as unit testing .\ndictybase strives to present a comprehensive , reliable , carefully curated dataset that integrates sequences , functional annotation , phenotypes , expression data and the research literature , while retaining the flexibility to integrate new data types as they become available .\nour goal is to assure that the information in dictybase is accessible in an effective and intuitive interface useful for biologists , while also maximizing its utility for the bioinformatics community to use computationally .\nour operating principles are to respond to users ' needs , to capitalize on the vast efforts of the dictyostelium research community , and to provide an important link in the network of mods .\nas additional amoebae genome sequences become available dictybase hopes to implement , and where necessary , develop interfaces and tools that facilitate comparative genomics of this diverse group of organisms .\nthis sample gene page shows the types of information that are displayed on a dictybase gene page .",
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"content": "dictybase ( ) is the model organism database ( mod ) for the social amoeba dictyostelium discoideum \n . the unique biology and phylogenetic position of dictyostelium offer a great opportunity to gain knowledge of processes not characterized in other organisms . \n the recent completion of the 34 mb genome sequence , together with the sizable scientific literature using dictyostelium as a research organism , provided the necessary tools to create a well - annotated genome . \n dictybase has leveraged software developed by the saccharomyces genome database and the generic model organism database project . \n this has reduced the time required to develop a full - featured mod and greatly facilitated our ability to focus on annotation and providing new functionality . \n we hope that manual curation of the dictyostelium genome will facilitate the annotation of other genomes .",
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science.chemsum_single_document_summarization | science.chemsum_single_document_summarization.27354 | [
{
"content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nSolar eclipse demonstrating the importance of photochemistry in new particle formation\n\nContent Extracts:\n\n<p>not known. In general, very little is known about the detailed connection between atmospheric photochemistry, production and composition of different low-volatility compounds, cluster formation and atmospheric NPF.</p><p>We measured aerosol precursor molecules, clusters and nanoparticles during a partial solar eclipse (81% of the sun blocked) on 20 March 2015 at SMEAR II-station, Finland 20 . Sudden changes in oxidant production during the eclipse gave us a unique opportunity to investigate the importance of photochemistry, especially OH-radical driven reactions, on the gas-to-particle conversion process. Similar boundary conditions are very difficult to find from any other kind of field measurement data. For example, daytime and night-time data differ from each other not only in terms of the strength of photochemistry, but also in terms of the chemical mixture of air pollutants and the presence of an additional oxidant (nitrate radical) during night time. Comparing data from clear-sky and cloudy days to each other would not allow isolating the effect of photochemistry either, as clear-sky and cloudy days tend to have different air mass properties. The closest analogy to a solar eclipse would be a transition between clear and cloudy skies. The problem with that data is that such transitions tend follow each other too rapidly to track the whole sequence of processes starting from atmospheric oxidation to the formation of growing nanoparticles.</p>\n\nResults\n<p>The eclipse day was a sunny, mostly clear-sky NPF event day with light winds (2− 3 m/s). During the eclipse, we observed a drop in the UV-B radiation intensity and ambient temperature (Fig. 1A), but no apparent change in either wind speed or direction. A drop similar to the UV-B radiation is collaterally expected in the OH-radical concentration (Fig. S1) 21 , for which we applied a proxy calculation in lack of direct measurements. Previous studies have shown a high correlation (> 85%) between the OH-radical concentration and its primary production from ozone photolysis 22,23 , supporting the validity of our proxy calculation. After a notable decrease in the NO x concentration prior to eclipse, concentrations of both NO and NO x were low during the eclipse (Fig. S2). Also, the measured SO 2 concentration remained low during the day (Fig. S2). The ozone concentration usually increases by about 10 ppb from morning to afternoon on springtime NPF event days at our measurement site 24 . The eclipse stalled this ozone increase momentarily, but did not cause any ozone decline as reported in earlier studies conducted in semi-polluted environments 22,25 . The lack of such decline in our measurements is probably related to the low NO x concentration, making the ozone concentration less susceptible to its local photochemical production than in more polluted sites. We also observed an instant decrease in photochemical energy conversion rates in the forest and, subsequently, reductions in transpiration and CO 2 exchange rates (Fig. S3). Monoterpene concentration decreased under detectable levels after the eclipse (Fig. S4).</p><p>The concentration of gaseous sulphuric acid (H 2 SO 4 ) and two nitrogen containing HOMs (C 10 H 15 O 9 N, 355 Th and C 10 H 15 O 8 N, 339 Th, referred here after as N-HOM, m/z contains charger ion mass) measured by a nitrate based chemical ionization mass spectrometer (CI-APi-TOF) 26 decreased considerably during the eclipse, indicating photochemical production pathways (Fig. 1B and S5). Local minima in sulphuric acid and concentrations of two major N-HOMs were observed 10-20 min after the minimum in UV-radiation (Fig. 1 and Figs S6-7), roughly consistent with the time scale over which any extremely low-volatile compound is expected to deplete from the gas phase due to its condensation onto pre-existing aerosol particles (the inverse of condensation sink, Fig. S8). The rest of measured HOMs and N-HOMs displayed highest concentrations well before the solar eclipse and did not decrease significantly during the eclipse (Fig. 1C and Fig. S9). The most plausible explanation for a HOM compound not to be affected by a solar eclipse is that its production in the gas phase is initiated, or maintained, by reactions involving ozone rather than photochemistry. Another possible explanation, at least for the HOMs that are not extremely low-volatile, is that they do not effectively condense onto pre-existing particles.</p><p>We measured ions and neutral particles using the particle size magnifier (PSM) 27 , neutral cluster and air ion spectrometer (NAIS) 28 and differential mobility particle sizer (DMPS) 29 . Concentrations of 1− 2 nm neutral particles and clusters dropped markedly during the eclipse (Fig. 2 and Fig. S10), confirming the strong association of the cluster formation with atmospheric photochemistry. Concentrations of < 2 nm ions (cluster ions) were not affected by the eclipse as their primary production depends on ionizing radiation. Concentrations of 2− 3 nm neutral particles and ions decreased by approximately the same factor, and their concentration minima were achieved a bit later than those of smaller particles. These features suggest that > 2 nm particles originated mainly from the growth of sub-2 nm neutral clusters, and that ions in that size range originated from the charging of the neutral particles by cluster ions, consistent with earlier studies made at SMEAR II 17,30 . The concentration of 3-6 nm particles changed little during the eclipse, indicating that their formation rate was suppressed compared to regular NPF days at SMEAR II when their concentration usually increases rapidly around noon 31,32 . We did not observe any systematic change in the submicron aerosol mass concentration, or its bulk chemical composition, during the eclipse (Fig. S11).</p><p>Long-term observations at the SMEAR II-station show, on average, higher concentrations of sulphuric acid, N-HOM and several other HOM monomers during NPF event days compared with non-event days (Fig. 3). During the eclipse, the formation rate of 1.5 nm particles, J 1.5 , was positively correlated with both sulphuric acid and N-HOM concentration, but not with the concentrations of other HOMs (Figs S12-15). Furthermore, J 1.5 was positively correlated with the product of the H 2 SO 4 concentration and concentration of any of the major HOMs.</p><p>Correlations with the formation rate of 2 nm particles, J 2 , were quantitatively similar but clearly weaker compared with J 1.5 (Figs S16-18). While these observations do not proof any causality between NPF and sulfuric acid or (N-)HOMs, they definitely support the idea that both sulfuric acid and some subset of (N-)HOMs at large enough concentrations are needed for active NPF at this site.</p><p>During the recovery from the solar eclipse, sulphuric acid concentration increased rapidly (Fig. 1B), consistent with its UV-driven production during daytime (Figs S19 and S20). Concentrations of N-HOMs increased at a slower rate (Fig. 1B), since their production route requires the initiation of NO 2 photolysis, VOC emissions and their oxidation to RO 2 radicals via either OH-radical reactions or ozonolysis (Fig. S21). Concentrations of sub-3 nm clusters and particles recovered somewhat later than sulphuric acid and N-HOM, as one would expect if these compounds were important precursors for small clusters. The observed growth rate of 2-3 nm particles was ~1 nm/h during the recovery from eclipse (Fig. S22). While our data do not reveal which compounds actually contributed to the particle growth, it is interesting to note that sulphuric acid together with the two major N-HOM compounds had high enough concentrations so that their concomitant, irreversible condensation onto sub-3 nm particles could explain the observed growth.</p><p>In summary, we have shown that the decrease in UV-radiation during the solar eclipse decreases the source rates of sulphuric acid and some (N-)HOMs, which further leads to a decrease in clustering and initial growth of aerosol particles. Since the condensation sink is hardly affected by the eclipse, low-volatile vapours continue condensing and small clusters coagulating onto existing aerosol particles. Thus, the gas-phase concentrations of the low-volatile vapour originating mainly from photochemistry and the number concentration of small clusters made of these vapours decrease notably. During the recovery phase of the eclipse, OH-radical, sulphuric acid, (N-)HOM and cluster concentrations recover and re-initialize NPF.</p><p>Our observations might explain why the frequently-observed night-time sub-3 nm clusters do not grow into larger aerosol particles. We conclude that when ozonolysis is the prominent formation route of condensing vapours (like HOMs at night-time, Fig. 3), the resulting ozonolysis products alone cannot grow these sub-3 nm clusters further into new aerosol particles in a boreal forest atmosphere at least in the observed concentration levels. Thus, extremely low-volatile reaction products from the OH-radical oxidation, especially sulphuric acid and a sub-set of (N-)HOMs, are the key compounds for cluster growth and observing NPF. Furthermore, the build-up of HOMs and their dimers in the morning, apparent prior to the eclipse (Figs 3 and S9) and during regular NPF event days compared with non-event days, may boost the particle growth.</p><p>We had a unique possibility to investigate atmospheric chemistry and clustering related to NPF during a partial solar eclipse at the SMEAR II-station using state-of-the-art instrumentation. Our results highlight the necessity of photochemistry in aerosol precursor formation and provide a plausible explanation of why NPF is observed almost solely during daytime in continental boundary layers. Our results confirm the crucial role of sulphuric acid in maintaining atmospheric NPF and show further that extremely low volatile organic compounds, potentially important to the initial steps of atmospheric NPF, are formed not only by ozone oxidation but also through photochemical reactions. Our results show that neutral pathways dominate the initial clustering and growth, at least at our measurement site. Such consistent observations, from the oxidation of precursor vapours to nanoparticles, have previously been achieved only in controlled laboratory experiments. Our results are an important step toward understanding the connections between atmospheric oxidation, NPF and secondary aerosol formation, which is needed for quantifying the complex interplay between future anthropogenic activities, air pollution and changing global climate.</p>\n\nMethods\n<p>All measurements were conducted at the SMEAR II-station, located in Hyytiälä (61°51′ N, 24°17′ E, 181 m a.s.l.), Southern Finland 20 . The main instrumentation was a mass spectrometer, a particle size magnifier and an ion mobility spectrometer. The mass spectrometric measurements were conducted with a CI-APi-TOF with nitrate based chemical ionization scheme in the negative ion mode 26 for the detection of aerosol precursor molecules and clusters such as sulphuric acid and highly oxidized organic compounds. Low volatile compounds were detected after a proton transfer or clustering with the charger ions. The number concentration of freshly formed 1-3 nm particles and clusters were measured by a PSM 27 that used diethylene glycol to activate and grow particles to 90 nm. After that, particles grow to detectable sizes by condensation of butanol inside a condensation particle counter. Neutral cluster and Air Ion Spectrometer (NAIS) 33,34 is an ion mobility spectrometer that was used to detect the size distributions of ions between 0.8 nm and 42 nm (mobility equivalent diameter) and total particles, i.e. neutral and charged, between ~2 nm and 42 nm. More detailed information of instrumentation and other used methods can be found in the Supplementary material.</p>",
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"content": "Solar eclipses provide unique possibilities to investigate atmospheric processes, such as new particle formation (NPF), important to the global aerosol load and radiative balance. The temporary absence of solar radiation gives particular insight into different oxidation and clustering processes leading to NPF. This is crucial because our mechanistic understanding on how NPF is related to photochemistry is still rather limited. During a partial solar eclipse over Finland in 2015, we found that this phenomenon had prominent effects on atmospheric on-going NPF. During the eclipse, the sources of aerosol precursor gases, such as sulphuric acid and nitrogen-containing highly oxidised organic compounds, decreased considerably, which was followed by a reduced formation of small clusters and nanoparticles and thus termination of NPF. After the eclipse, aerosol precursor molecule concentrations recovered and reinitiated NPF. Our results provide direct evidence on the key role of the photochemical production of sulphuric acid and highly oxidized organic compounds in maintaining atmospheric NPF. Our results also explain the rare occurrence of this phenomenon under dark conditions, as well as its seemingly weak connection with atmospheric ions.Solar eclipses have provided fundamental opportunities for scientific research, the most profound outcomes of which include the verification of Einstein's general theory of relativity 1 and characterization of the Sun's atmosphere 2 . Sun-induced photochemical reactions sustain life on Earth and play essential roles in atmospheric chemistry. Quantifying the chain of atmospheric processes initiated by photochemical reactions is crucial for our understanding on aerosol and cloud formation and climate change.New particle formation (NPF) produces around half of atmospheric cloud condensation nuclei, being important to the radiative balance and climate 3 . In most locations, observed NPF and subsequent particle growth take place during daytime only 4 . Simultaneously, photochemical cycles control the concentrations of reactive oxidants such as OH-radical and ozone. Clustering seems to be taking place also in the dark but these clusters are rarely growing [5][6][7] . Sulphuric acid, the principal driver of atmospheric NPF, is formed mainly by reaction of sulphur dioxide with OH-radicals, and to some extent also by its reaction with Criegee intermediates 8-10 . The newly formed particles are suggested to grow bigger in size mainly by condensation of low-volatile, highly-oxidized multifunctional compounds (HOMs) from terpene oxidation [11][12][13][14] . Some HOMs have extremely low volatilities (ELVOC) and they are able to condense onto sub-2 to 3 nm clusters, thus being responsible for the initial growth of fresh-formed particles and also a large part of secondary organic aerosol (SOA) 11,14,15 . Despite very high O:C ratios, not all HOMs are ELVOCs 16 , although the terms have been used interchangeably in previous studies (see SI for more details) 11 .In the presence of NOx, also nitrogen containing HOMs (N-HOMs) are formed, and they have been observed during NPF events [17][18][19] , but the exact contribution of N-HOMs vs. HOMs that do not contain nitrogen on NPF is",
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science.scientific_lay_summarisation_plos_single_doc_summ | science.scientific_lay_summarisation_plos_single_doc_summ.3874 | [
{
"content": "Transform the following sections from a biomedical study into a simple summary for the general public. Focus on making the information accessible and easy to understand.\n\nResearch Heading: The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome\nContent:\nAbstract:\nSequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene’s tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16, 260 autosomal protein coding genes in 11, 546 individuals. We observed 39, 893 truncating variants affecting 12, 062 genes, which significantly differed from an expectation of 12, 916 genes under a model of neutral de novo mutation( p<10−4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10. 8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.\nIntroduction:\nRecent population expansion and limited purifying selection have led to an abundance of rare human genetic variation[1–3] including stop-gain and frameshift mutations. Thus, there is increasing interest in the identification of natural human knockouts[3–8] through the cataloguing of homozygous truncations. However, heterozygous truncation can also lead to deleterious functional consequences through haploinsufficiency due to decreased gene dosage, or through a dominant-negative effect[9, 10]. In order to quantify the importance of heterozygous protein truncating variation, we characterized genes showing fewer de novo truncations in the general population than expected under a neutral model. We hypothesized that there is a set of genes that cannot tolerate heterozygous protein truncating variants( PTVs) because of early life lethality.\nDiscussion:\nThis work identifies a substantial proportion of genes that do not tolerate loss of one of the two gene copies, and by the evidence for a gradient of haploinsufficiency across a large proportion of the coding genome. Heterozygous PTVs are rarely compensated at the gene expression level, as shown in our previous work[13] and in recent analyses[7]. Despite the absence of dosage compensation, Rivas et al. suggest that homeostatic mechanisms at the cellular level maintain biological function[7]. However, we show clear evidence that over 10% of the genes cannot be compensated, while an additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The importance of these variants has also been observed in model organisms. Studies in mice show that when homozygous knockout mutants are not viable, up to 71. 7% of heterozygous PTVs have phenotypic consequences[24]. The systematic phenotyping of knockout mice also demonstrates that haploinsufficiency might be more common than generally suspected[25]. However, a practical limitation of the above approaches, in particular in animal studies, is that observation of phenotypes resulting from damaging mutations may require exposure to specific triggers or environmental interactions[6, 25]. In contrast, in humans, life-long exposures may eventually reveal a phenotypic trait or disease associated with heterozygous gene truncations[8]. Here, clinical symptoms could be observed later in life, and present sporadically–not necessarily within a pedigree. This is illustrated by a recent report on the consequences of haploinsufficiency of cytotoxic T-lymphocyte-associated protein 4 gene( CTLA-4) presenting as undiagnosed or misdiagnosed sporadic autoimmune disorder in the second to fifth decades of life[26]. Despite the prevalence of rare heterozygous PTVs, there has been more attention to the occurrence of homozygous truncations( human knockouts). However, the genes that are observed with biallelic PTVs have, as a set, characteristics of dispensability: less conservation, greater redundancy, less biological and cellular centrality, and limited essentiality in mice and cellular models. Thus, we argue that homozygous truncations result from high allele frequency variants that are less likely to carry functional consequences( the exception being recessive disorders in a population). There are a number of possible limitations to the present study. In the modeling work, we analyzed rare variants( less than <1% allele frequency) to focus on de novo events and for consistency with the de novo mutation rates estimated by Samocha et al.[12]. Nevertheless, our estimates held true when the whole analysis was repeated with the smaller subset of singleton variants—singletons possibly reflect false positive sequencing and alignment calls. It was also repeated with all variants irrespective of allele frequency( instead of analyzing variants of less than 1% allele frequency)( S3 Fig). Initially we omitted splice-site variants because of less predictability of the functional consequences. Extending the analysis to include splice-site variants did not change the results and conclusions( S3 Fig and S5 Table). This demonstrates that the results do not originate from a specific subset of variants. We did not have primary control on sequencing coverage for some of the exome sequence datasets that could result in ascertainment errors. To correct for this potential bias, we discarded genes where the observed number of synonymous mutations deviated from expectation. The intolerance of genes to de novo truncation was assessed across combined human populations. Therefore, estimations of the haploinsufficient genome account for the fraction of haploinsufficient genes common to all humans. Intolerance to heterozygous PTVs should be regarded as a different concept than gene sequence conservation. PTVs in a conserved gene might have a recessive mode of inheritance and are thus potentially observable in a viable individual. On the other extreme, positively selected genes could be haploinsufficient upon heterozygous truncation. These considerations notwithstanding, we consistently identified a quantifiable fraction of the human genome that is intolerant to heterozygous PTVs, with an estimated lower bound of 9. 5%. The prevalent nature of rare heterozygous PTVs suggests that a map of “essentiality” on the basis of dominant loss of function is within reach. The concept of the essential genome has been explored in analyses of minimal bacterial genomes[27], mouse knockout studies[28], studies of transposon or chemical mutagenesis[29], and in studies that used CRISPR-Cas9 genome-editing technology[14, 30]. Here, we propose that mapping the haploinsufficient genome will improve the understanding of the genetic architecture of diseases. In agreement with the recent work of Li et al.,[6] we argue that the burden of rare human heterozygous variation is an unexplored source of diversity of phenotypic traits and diseases.",
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"content": "Genome sequencing provides evidence for large numbers of putative protein truncating variants in humans . Most truncating variants are only observed in few individuals but are collectively prevalent and widely distributed across the coding genome . Most of the truncating variants are so rare that they are only observed in heterozygosis . The current study identifies 10% of genes where heterozygous truncations are not observed and describes their biological characteristics . In addition , for genes where rare truncations are observed , we argue that these are an unexplored source of diversity of phenotypic traits and diseases .",
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science.anat_em_ner | science.anat_em_ner.34 | [
{
"content": "Analyze the provided text from a biomedical study. Your task is to detect and list entities based on predefined categories.\n\nPresent your results in a JSON format: {\"AnatomicalEntity\": [\"entity1\", \"entity2\", ...]}. Each category should have a corresponding list of identified entities. \n\nText:\n\nIdentification of the putative transforming protein of the human T-cell leukemia viruses HTLV-I and HTLV-II. \nThe human T-cell leukemia viruses HTLV-I and HTLV-II are unique among the transforming retroviruses of vertebrates in their ability to transform human T cells in vitro and in their close association with human malignancies (T-cell lymphomas and leukemia). Their genomes are relatively simple, containing the genes gag, pol, env, and a 3' region termed \"X.\" This 3' region may be responsible for the transforming potential of the viruses. The existence of proteins encoded by the 3' region has been postulated on the basis of multiple open reading frames. In the present study this region is shown to contain a gene encoding a protein of 40 kilodaltons in HTLV-I and 37 kilodaltons in HTLV-II. It is proposed that these proteins be called, respectively, p40xI and p37xII.",
"role": "user"
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{
"content": "{\"AnatomicalEntity\": [\"malignancies\", \"leukemia\", \"X\", \"T cells\", \"3\\u0027 region\", \"T-cell leukemia\", \"T-cell lymphomas\"]}",
"role": "assistant"
}
]
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science.genia_ner | science.genia_ner.1154 | [
{
"content": "Analyze the provided text excerpt from a scientific document. Identify and extract distinct entities based on predefined categories.\n\nDeliver the results as a JSON structure where each key represents an entity category, and the associated value is a list of identified entities. If no entities are found for a category, return an empty list.\n\nText Excerpt:\n\nCyclosporin A interferes with the inducible degradation of NF-kappa B inhibitors, but not with the processing of p105 / NF-kappa B1 in T cells. The transcription factor NF-kappa B controls the induction of numerous cytokine promoters during the activation of T lymphocytes. Inhibition of T cell activation by the immunosuppressants cyclosporin A (CsA) and FK506 exerts a suppressive effect on the induction of these NF-kappa B-controlled cytokine promoters. We show for human Jurkat T leukemia cells, as well as human and mouse primary T lymphocytes, that this inhibitory effect is accompanied by an impaired nuclear translocation of the Rel proteins c-Rel, RelA / p65 and NF-kappa B1 / p50, whereas the nuclear appearance of RelB remains unaffected. CsA does not interfere with the synthesis of Rel proteins, but prevents the inducible degradation of cytosolic NF-kappa B inhibitors I kappa B alpha and I kappa B beta upon T cell activation. CsA neither inhibits the processing of the NF-kappa B1 precursor p105 to p50, nor does it \" stabilize \" the C-terminal portion of p105, I kappa B gamma, which is degraded during p105 processing to mature p50. These results indicate that CsA interferes with a specific event in the signal-induced degradation of I kappa B alpha and I kappa B beta, but does not affect the processing of NF-kappa B1 / p105 to p50.",
"role": "user"
},
{
"content": "{\"CellLine\": [\"human Jurkat T leukemia cells\"], \"CellType\": [\"human and mouse primary T lymphocytes\", \"T cells\", \"T lymphocytes\"], \"DNA\": [\"cytokine promoters\", \"NF - kappa B - controlled cytokine promoters\"], \"Protein\": [\"NF - kappa B1 precursor\", \"mature p50\", \"cytosolic NF - kappa B inhibitors\", \"NF - kappa B1 / p105\", \"I kappa B gamma\", \"c - Rel\", \"I kappa B alpha\", \"RelB\", \"NF - kappa B1 / p50\", \"transcription factor\", \"Rel proteins\", \"NF - kappa B\", \"p50\", \"I kappa B beta\", \"NF - kappa B1\", \"p105\", \"RelA / p65\"], \"RNA\": []}",
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}
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science.scientific_lay_summarisation_plos_single_doc_summ | science.scientific_lay_summarisation_plos_single_doc_summ.3405 | [
{
"content": "Transform the following sections from a biomedical study into a simple summary for the general public. Focus on making the information accessible and easy to understand.\n\nResearch Heading: Defining Immune Engagement Thresholds for In Vivo Control of Virus-Driven Lymphoproliferation\nContent:\nAbstract:\nPersistent infections are subject to constant surveillance by CD8+ cytotoxic T cells( CTL). Their control should therefore depend on MHC class I-restricted epitope presentation. Many epitopes are described for γ-herpesviruses and form a basis for prospective immunotherapies and vaccines. However the quantitative requirements of in vivo immune control for epitope presentation and recognition remain poorly defined. We used Murid Herpesvirus-4( MuHV-4) to determine for a latently expressed viral epitope how MHC class-I binding and CTL functional avidity impact on host colonization. Tracking MuHV-4 recombinants that differed only in epitope presentation, we found little latitude for sub-optimal MHC class I binding before immune control failed. By contrast, control remained effective across a wide range of T cell functional avidities. Thus, we could define critical engagement thresholds for the in vivo immune control of virus-driven B cell proliferation.\nIntroduction:\nThe gamma-herpesviruses( γHVs) infect >90% of humans and cause diseases including nasopharyngeal carcinoma, African Burkitt's lymphoma and Kaposi's Sarcoma. Their colonization of circulating memory B cells is crucial to persistence and hence to disease ontogeny. Viral latency gene expression in B cells provides an immune target[1] that has been exploited to prevent lymphoproliferative disease in acutely immunodeficient patients by T cell transfer[2]. However, extending this approach to established cancers and developing related vaccines have proved difficult. A significant problem is that the narrow species tropisms of human γHVs severely restrict in vivo analysis, and hence an understanding of how empirical therapies such as adoptive T cell transfer work. Immune recognition can be assayed in vitro; but while Epstein-Barr virus( EBV) latency gene products drive autonomous B cell proliferation in vitro, most in vivo infected cells are resting memory B cells that have passed though lymphoid germinal centers( GCs)[3]. This makes difficult in vitro analysis of in vivo immune control. One way to make progress is to study related viruses that are experimentally more accessible. Probably the best characterized is Murid Herpesvirus-4( MuHV-4, archetypal strain MHV-68)[4]–[6]. MuHV-4 is more closely related to the Kaposi's Sarcoma-associated Herpesvirus( KSHV) than to EBV[7]. However it shares many features of host colonization with EBV, for example it exploits lymphoid GCs to establish persistence in circulating memory B cells[8]–[10]. Therefore it can be used to reveal fundamental mechanisms of γHV/host interaction. MuHV-4 studies have shown that γHV-driven lymphoproliferation occurs in complex lesions incorporating T cell evasion and infected cells with distinct patterns of viral gene expression[10]. In addition to cis-acting T cell evasion during episome maintenance[11],[12], EBV inhibits the transporter associated with antigen processing( TAP) via BNLF2a[13]–[15] and MHC class I export to the cell surface via BILF1[16],[17]; KSHV degrades MHC class I and other immune receptors via K3 and K5[18]; and MuHV-4 degrades MHC class I and TAP via MK3[19]–[21]. Disrupting MK3 impairs virus-driven lymphoproliferation[22]. The γHVs also evade immune recognition during latency by expressing few CTL targets. However a gene that modulates signaling through the B cell receptor- M2 in MuHV-4[23]–[26], LMP-2A in EBV[27] and K1 in KSHV[28]- is expressed more widely than growth program genes[3], and shows protein sequence diversity[29]–[33] consistent with immune selection. More directly, the presence of an H2Kd binding epitope in M2[34],[35] significantly reduces long-term MuHV-4 latent loads in BALB/c mice[29]. Therefore despite viral evasion, CTL help to regulate long-term infection[36],[37], and CTL recognition of M2/K1/LMP-2A, which in EBV may extend also to EBNA3A/B/C[38],[39], provides a potential point of attack. LMP-2A is also a candidate vaccine target for nasopharyngeal carcinoma[40]. Thus, how M2/K1/LMP-2A recognition works in vivo is important to understand. CTL effector capacity broadly correlates with functional avidity, as determined by the capacity of T cell receptor( TcR) engagement to trigger CTL proliferation, cytokine production and target cell lysis at limiting antigen dose[41]. Therefore with limited γHV protein expression during latency, peptide affinity for MHC class I and TcR functional avidity are likely to be crucial for immune control. The diversity of LMP-2A, K1 and M2 prompted us to analyze in vivo the consequences of varying MHC class I binding and TcR functional avidity for a single epitope derived from M2. These parameters affected dramatically the control of virus-driven lymphoproliferation, even in the context of immune evasion. The capacity of MuHV-4 to correlate biochemical interactions with in vivo immune function allowed us to establish quantitative guidelines for infection control.\nDiscussion:\nGamma-herpesvirus epitope recognition by CTL has been studied extensively[1],[54], but ours is the first quantitative assessment of how epitope/MHC class I/TcR complex formation affects host colonization. Where no latency epitope expression existed, introducing one led to a profound, CTL-dependent suppression of virus-driven lymphoproliferation. This was consistent with the impact of endogenous epitope presentation in H2d mice[29]. The latter affected only long-term viral loads; OVA expression in H2b mice also conferred susceptibility to CTL during acute lymphoproliferation, when trans-acting immune evasion operates[1]. This greater effect of epitope presentation possibly reflected differences in host susceptibility to immune evasion: the MuHV-4 K3 degrades H2Kb relatively poorly[19] and degrades TAP better in H2d than H2b cells[20]. The precise cellular targets for CD8+ T cell recognition of M2-linked epitopes remain unknown. One possibility is proliferating germinal centre B cells, as B cells are a major site of M2 expression[10],[34]. Infected B cells could also be recognized before the onset of proliferation; and as myeloid cells transfer infection to B cells[56], CD8+ T cells could also suppress lymphoproliferation indirectly, by targeting infected myeloid cells[1]. A key point for physiologically relevant epitope presentation is that it conforms to normal latent gene expression. Exogenous promoters such as HCMV IE1 show activity independent of endogenous viral gene expression[57] and this can lead to attenuation[58]. Previous analysis of endogenous M2 epitope[29] established its importance for determining the different long-term latent loads of H2d and H2b mice. Here, to identify presentation thresholds, we made use of the well-characterized SIINFEKL epitope, attaching it to a neutral region of M2( its C-terminus). This allowed the generation of a very well-defined model epitope with the kinetics and copy number of a known endogenous epitope. Epitope presentation varies with MHC class I genotype. C57BL/6 mice have only 2 MHC class I molecules and appear not to recognize an endogenous M2 epitope. In this context, M2-SIINFEKL illustrated the impact of strong epitope presentation, and wild-type M2( or M2-vA8) that of poor epitope presentation. The SIINFEKL variants covered the range between, and so allowed us to identify functional recognition thresholds. Small differences( <1. 6-fold) in H2Kb epitope binding had no obvious impact on in vivo CTL efficacy, but a 60-fold reduction abolished protection and a 6-fold reduction showed a partial phenotype. Thus, M2-linked epitope presentation left little room for sub-optimal MHC class I binding. By contrast when H2Kb binding was maintained, reducing TcR functional avidity 14-fold had little effect, reducing it 200, 000-fold abolished control, and reducing it 4, 000-fold gave an intermediate phenotype. Therefore this aspect of recognition was more flexible even for monoclonal, Rag-1−/− CTL, and a polyclonal population could attack any epitope so long as its MHC class I binding was strong. In complex viral infections, larger CTL responses are not necessarily more effective responses. These parameters can correlate: MuHV-4 lacking its K3 evasion gene elicits more CTL and achieves lower titers[22]; and our reconstituted mice showed a correlation between more CTL and less virus. But as with latent epitope presentation downstream of ORF73[11], OVA-specific CTL responses that completely suppressed lymphoproliferation were small compared to lytic epitope responses[51]; and mice infected with vE1 made large epitope-specific responses yet showed poor virus control. We hypothesize that CTL can be stimulated by the key, self-renewing population of infected B cells, when infection is suppressed, but also by infected cells less important to host colonization, when large responses may achieve little. Crucially, viral evasion may make the self-renewing population harder to target. Thus, vE1 showed a strong acute reduction in total viral DNA+ cell frequencies, but relative sparing of GC B cells and consequently high long-term virus loads. A position 1 mutation also impairs the control by Rag-1−/−OT-I mice of MuHV-4 expressing OVA from an HCMV IE1 promoter[59]. However such mice lack B cells or CD4+ T cells, and without CD4+ T cells MuHV-4 causes a lethal, chronic lytic infection even with a strong, polyclonal CTL response[60],[61]. Our reconstituted mice maintained both virus-driven lymphoproliferation and infection control without outgrowth of CTL escape mutants. Thus we could relate directly quantitative changes in epitope recognition to the control of lymphoproliferation. An important task with EBV is to predict in vivo CTL efficacy. Extrapolating from CTL numbers and in vitro assays alone is clearly problematic. For example, large responses to lytic epitopes in infectious mononucleosis[54] could be interpreted as important, or simply as poor latency epitope recognition when better recognition might preclude large lytic responses and avoid symptoms. The precise relatedness of EBV memory B cell colonization via GCs to MuHV-4 memory B cell colonization via GCs is unknown. But all γHVs have evolved to colonize lymphocytes with maximal efficiency, within limits set ultimately by the immune system, so similar quantitative thresholds would not be surprising. Our data therefore have important general implications for γHV-specific CTL function, and for predicting in vivo CTL efficacy from biochemical measures.",
"role": "user"
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{
"content": "Chronic viral infections cause huge morbidity and mortality worldwide . γ-herpesviruses provide an example relevant to all human demographics , causing , inter alia , Hodgkin's disease , Burkitt's lymphoma , Kaposi's Sarcoma , and nasopharyngeal carcinoma . The proliferation of latently infected B cells and their control by CD8+ T cells are central to pathogenesis . Although many viral T cell targets have been identified in vitro , the functional impact of their engagement in vivo remains ill-defined . With the well-established Murid Herpesvirus-4 infection model , we used a range of recombinant viruses to define functional thresholds for the engagement of a latently expressed viral epitope . These data advance significantly our understanding of how the immune system must function to control γ-herpesvirus infection , with implications for vaccination and anti-cancer immunotherapy .",
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science.ncbi_ner | science.ncbi_ner.488 | [
{
"content": "Examine the text below and extract disease-related entities. Present your findings in a structured JSON format.\n\nYour response should be a JSON object with keys as entity types and values as lists of entities. If no entities are found, return an empty list for that type.\n\nContent:\n\nDuchenne muscular dystrophy gene expression in normal and diseased human muscle. A probe for the 5 end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers..",
"role": "user"
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{
"content": "{\"Disease\": [\"Duchenne muscular dystrophy\", \"DMD\"]}",
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science.pico_ner | science.pico_ner.1072 | [
{
"content": "Examine the following abstract and identify distinct entities. Focus on extracting entities related to participants, interventions, and outcomes.\n\nPresent your findings in a JSON format like: {\"Participant\": [\"example entity\", ...], \"Intervention\": [\"example entity\", ...], \"Outcome\": [\"example entity\", ...]}. If no entities are found for a category, use an empty list.\n\nAbstract Content:\n\n[ Usage of titanoreine after procedure for prolapse and hemorrhoids ] . OBJECTIVE To evaluate the effect of titanoreine on early postoperative symptoms after procedure for prolapse and hemorrhoids ( PPH ) . METHODS From November 2002 to July 2003 , 80 patients who received PPH were randomly divided in to titanoreine group ( n=42 ) and control group without titanoreine ( n=38 ) . Symptom relief was recorded 24 hours , 6 days and 12 days after PPH , urine retention 24h after PPH , first stool time , wound healing time , mean hospital stay were also recorded . RESULTS The score of symptom was lower in titanoreine group ( 4.4 ) than that in the control group ( 6.1 ) 24 hours after PPH ( P < 0.05 ) , but no significant difference in symptom grade was found between the two groups 6 days and 12 days after PPH ( P > 0.05 ) . Decrements of symptom grade were lower in titanoreine group than those of control group at any point after PPH ( P < 0.05 ) . There was no significant difference in urine retention rate and mean hospital stay between two groups ( P > 0.05 ) . CONCLUSIONS Titanoreine can effectively relieve the early postoperative symptoms after PPH .",
"role": "user"
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{
"content": "{\"Intervention\": [\"titanoreine\", \"control group without titanoreine\", \"Titanoreine\"], \"Outcome\": [\"wound healing time\", \"relieve\", \"symptom grade\", \"Symptom relief\", \"urine retention rate\", \"score of symptom\", \"urine retention\", \"first stool time\", \"Decrements of symptom grade\", \"mean hospital stay\"], \"Participant\": [\"PPH\", \"prolapse and hemorrhoids\", \"80\"]}",
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science.craftchem_ner | science.craftchem_ner.993 | [
{
"content": "Analyze the following sentence to identify chemical entities of interest. List these entities in a JSON array format. If no entities are found, return an empty array.\n\nText to Analyze:\nThisprocessisthoughttorepresentaprotectivemethodoftheredbloodcellagainstanattackbyforexamplecomplementcomponents.",
"role": "user"
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{
"content": "[]",
"role": "assistant"
}
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science.scireviewgen_multidoc_summarization | science.scireviewgen_multidoc_summarization.1141 | [
{
"content": "Craft a cohesive chapter for a literature review using the abstracts provided. Focus on the chapter's theme, weaving together insights and findings from the abstracts. Highlight key points and note any research gaps.\nLiterature Review Title: A Survey on Subgraph Counting: Concepts, Algorithms and Applications to Network Motifs and Graphlets \nChapter Title: Vertices. \n1. Abstract of Cited Paper (BIB001): Motifs in a network are small connected subnetworks that occur in significantly higher frequencies than in random networks. They have recently gathered much attention as a useful concept to uncover structural design principles of complex networks. Kashtan et al. [Bioinformatics, 2004] proposed a sampling algorithm for efficiently performing the computationally challenging task of detecting network motifs. However, among other drawbacks, this algorithm suffers from sampling bias and is only efficient when the motifs are small (3 or 4 nodes). Based on a detailed analysis of the previous algorithm, we present a new algorithm for network motif detection which overcomes these drawbacks. Experiments on a testbed of biological networks show our algorithm to be orders of magnitude faster than previous approaches. This allows for the detection of larger motifs in bigger networks than was previously possible, facilitating deeper insight into the field. \n2. Abstract of Cited Paper (BIB002): BackgroundComplex networks are studied across many fields of science and are particularly important to understand biological processes. Motifs in networks are small connected sub-graphs that occur significantly in higher frequencies than in random networks. They have recently gathered much attention as a useful concept to uncover structural design principles of complex networks. Existing algorithms for finding network motifs are extremely costly in CPU time and memory consumption and have practically restrictions on the size of motifs.ResultsWe present a new algorithm (Kavosh), for finding k-size network motifs with less memory and CPU time in comparison to other existing algorithms. Our algorithm is based on counting all k-size sub-graphs of a given graph (directed or undirected). We evaluated our algorithm on biological networks of E. coli and S. cereviciae, and also on non-biological networks: a social and an electronic network.ConclusionThe efficiency of our algorithm is demonstrated by comparing the obtained results with three well-known motif finding tools. For comparison, the CPU time, memory usage and the similarities of obtained motifs are considered. Besides, Kavosh can be employed for finding motifs of size greater than eight, while most of the other algorithms have restriction on motifs with size greater than eight. The Kavosh source code and help files are freely available at: http://Lbb.ut.ac.ir/Download/LBBsoft/Kavosh/. \n3. Abstract of Cited Paper (BIB003): Many natural and artificial structures can be represented as complex networks. Computing the frequency of all subgraphs of a certain size can give a very comprehensive structural characterization of these networks. This is known as the subgraph census problem, and it is also important as an intermediate step in the computation of other features of the network, such as network motifs. The subgraph census problem is computationally hard and most associated algorithms for it are sequential. Here we present several increasingly efficient parallel strategies for, culminating in a scalable and adaptive parallel algorithm. We applied our strategies to a representative set of biological networks and achieved almost linear speedups up to 128 processors, paving the way for making it possible to compute the census for bigger networks and larger subgraph sizes. \n4. Abstract of Cited Paper (BIB004): Many natural structures can be naturally represented by complex networks. Discovering network motifs, which are overrepresented patterns of inter-connections, is a computationally hard task related to graph isomorphism. Sequential methods are hindered by an exponential execution time growth when we increase the size of motifs and networks. In this article we study the opportunities for parallelism in existing methods and propose new parallel strategies that adapt and extend one of the most efficient serial methods known from the Fanmod tool. We propose both a master-worker strategy and one with distributed control, in which we employ a randomized receiver initiated methodology capable of providing dynamic load balancing during the whole computation process. Our strategies are capable of dealing both with exact and approximate network motif discovery. We implement and apply our algorithms to a set of representative networks and examine their scalability up to 128 processing cores. We obtain almost linear speedups, showcasing the efficiency of our proposed approach and are able to reach motif sizes that were not previously achievable using conventional serial algorithms. \n5. Abstract of Cited Paper (BIB005): The ability to find and count subgraphs of a given network is an important non trivial task with multidisciplinary applicability. Discovering network motifs or computing graphlet signatures are two examples of methodologies that at their core rely precisely on the subgraph counting problem. Here we present the g-trie, a data-structure specifically designed for discovering subgraph frequencies. We produce a tree that encapsulates the structure of the entire graph set, taking advantage of common topologies in the same way a prefix tree takes advantage of common prefixes. This avoids redundancy in the representation of the graphs, thus allowing for both memory and computation time savings. We introduce a specialized canonical labeling designed to highlight common substructures and annotate the g-trie with a set of conditional rules that break symmetries, avoiding repetitions in the computation. We introduce a novel algorithm that takes as input a set of small graphs and is able to efficiently find and count them as induced subgraphs of a larger network. We perform an extensive empirical evaluation of our algorithms, focusing on efficiency and scalability on a set of diversified complex networks. Results show that g-tries are able to clearly outperform previously existing algorithms by at least one order of magnitude. \n6. Abstract of Cited Paper (BIB006): Counting the occurrences of small subgraphs in large networks is a fundamental graph mining metric with several possible applications. Computing frequencies of those subgraphs is also known as the subgraph census problem, which is a computationally hard task. In this paper we provide a parallel multicore algorithm for this purpose. At its core we use FaSE, an efficient network-centric sequential subgraph census algorithm, which is able to substantially decrease the number of isomorphism tests needed when compared to past approaches. We use one thread per core and employ a dynamic load balancing scheme capable of dealing with the highly unbalanced search tree induced by FaSE and effectively redistributing work during execution. We assessed the scalability of our algorithm on a varied set of representative networks and achieved near linear speedup up to 32 cores while obtaining a high efficiency for the total 64 cores of our machine. \n7. Abstract of Cited Paper (BIB007): Computing the frequency of small subgraphs on a large network is a computationally hard task. This is, however, an important graph mining primitive, with several applications, and here we present a novel multicore parallel algorithm for this task. At the core of our methodology lies a state-of-the-art data structure, the g-trie, which represents a collection of subgraphs and allows for a very efficient sequential search. Our implementation was done using Pthreads and can run on any multicore personal computer. We employ a diagonal work sharing strategy to dynamically and effectively divide work among threads during the execution. We assess the performance of our Pthreads implementation on a set of representative networks from various domains and with diverse topological features. For most networks, we obtain a speedup of over 50 for 64 cores and an almost linear speedup up to 32 cores, showcasing the flexibility and scalability of our algorithm. This paves the way for the usage of such counting algorithms on larger subgraph and network sizes without the obligatory access to a cluster.\n\nReview Chapter:",
"role": "user"
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{
"content": "One possibility is to consider each vertex v ∈ V (G) as a work-unit and split them among workers. A worker p then computes all size-k subgraph occurrences that contain vertex v. Naive approaches have different workers finding repeated occurrences that need to be removed BIB001 , but efficient sequential algorithms have canonical representations that eliminate this problem BIB003 BIB006 BIB002 , making each work-unit independent. Using vertices as work-units has the drawback of creating very coarse work-units: different vertices induce search spaces with very different computational costs. For instance, counting all the subgraph occurrences that start (or eventually reach) a hub-like node is much more time-consuming than counting occurrences of a nearly isolated node. For algorithms with vertices as work-units to be efficient they can either try to find a good initial division BIB001 or enable work sharing between workers BIB007 BIB008 BIB004 BIB005 . Each of these work division strategies is discussed in Section 5.5.",
"role": "assistant"
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science.qasper_extractive_qa | science.qasper_extractive_qa.657.0 | [
{
"content": "Analyze the given research paper excerpts and address the question provided. Extract the necessary information directly from the text. Your answer should be formatted as a JSON object with the following structure:\n\n\"answer\": A list of text segments from the paper that directly respond to the question.\n\"evidence\": A list of text segments from the paper where the answer can be found.\n\nIf the question cannot be answered with the given text, return \"null\".\n\nDocument: Self-Attentional Models Application in Task-Oriented Dialogue Generation Systems\n\nSelf-attentional models are a new paradigm for sequence modelling tasks which differ from common sequence modelling methods, such as recurrence-based and convolution-based sequence learning, in the way that their architecture is only based on the attention mechanism. Self-attentional models have been used in the creation of the state-of-the-art models in many NLP tasks such as neural machine translation, but their usage has not been explored for the task of training end-to-end task-oriented dialogue generation systems yet. In this study, we apply these models on the three different datasets for training task-oriented chatbots. Our finding shows that self-attentional models can be exploited to create end-to-end task-oriented chatbots which not only achieve higher evaluation scores compared to recurrence-based models, but also do so more efficiently.\n\nModels ::: Transformer\nAs discussed before, Transformer is the first model that entirely relies on the self-attention mechanism for both the encoder and the decoder. The Transformer uses the self-attention mechanism to learn a representation of a sentence by relating different positions of that sentence. Like many of the sequence modelling methods, Transformer follows the encoder-decoder architecture in which the input is given to the encoder and the results of the encoder is passed to the decoder to create the output sequence. The difference between Transformer (which is a self-attentional model) and other sequence models (such as recurrence-based and convolution-based) is that the encoder and decoder architecture is only based on the self-attention mechanism. The Transformer also uses multi-head attention which intends to give the model the ability to look at different representations of the different positions of both the input (encoder self-attention), output (decoder self-attention) and also between input and output (encoder-decoder attention) BIBREF6. It has been used in a variety of NLP tasks such as mathematical language understanding [110], language modeling BIBREF23, machine translation BIBREF6, question answering BIBREF24, and text summarization BIBREF25.\n\nModels ::: Universal Transformer\nThe Universal Transformer model is an encoder-decoder-based sequence-to-sequence model which applies recurrence to the representation of each of the positions of the input and output sequences. The main difference between the RNN recurrence and the Universal Transformer recurrence is that the recurrence used in the Universal Transformer is applied on consecutive representation vectors of each token in the sequence (i.e., over depth) whereas in the RNN models this recurrence is applied on positions of the tokens in the sequence. A variation of the Universal Transformer, called Adaptive Universal Transformer, applies the Adaptive Computation Time (ACT) BIBREF26 technique on the Universal Transformer model which makes the model train faster since it saves computation time and also in some cases can increase the model accuracy. The ACT allows the Universal Transformer model to use different recurrence time steps for different tokens.\nWe know, based on reported evidence that transformers are potent in NLP tasks like translation and question answering. Our aim is to assess the applicability and effectiveness of transformers and universal-transformers in the domain of task-oriented conversational agents. In the next section, we report on experiments to investigate the usage of self-attentional models performance against the aforementioned models for the task of training end-to-end task-oriented chatbots.\n\nExperiments\nWe run our experiments on Tesla 960M Graphical Processing Unit (GPU). We evaluated the models using the aforementioned metrics and also applied early stopping (with delta set to 0.1 for 600 training steps).\n\nExperiments ::: Datasets\nWe use three different datasets for training the models. We use the Dialogue State Tracking Competition 2 (DSTC2) dataset BIBREF27 which is the most widely used dataset for research on task-oriented chatbots. We also used two other datasets recently open-sourced by Google Research BIBREF28 which are M2M-sim-M (dataset in movie domain) and M2M-sim-R (dataset in restaurant domain). M2M stands for Machines Talking to Machines which refers to the framework with which these two datasets were created. In this framework, dialogues are created via dialogue self-play and later augmented via crowdsourcing. We trained on our models on different datasets in order to make sure the results are not corpus-biased. Table TABREF12 shows the statistics of these three datasets which we will use to train and evaluate the models.\nThe M2M dataset has more diversity in both language and dialogue flow compared to the the commonly used DSTC2 dataset which makes it appealing for the task of creating task-oriented chatbots. This is also the reason that we decided to use M2M dataset in our experiments to see how well models can handle a more diversed dataset.\n\nExperiments ::: Training\nWe used the tensor2tensor library BIBREF29 in our experiments for training and evaluation of sequence modeling methods. We use Adam optimizer BIBREF30 for training the models. We set $\\beta _1=0.9$, $\\beta _2=0.997$, and $\\epsilon =1e-9$ for the Adam optimizer and started with learning rate of 0.2 with noam learning rate decay schema BIBREF6. In order to avoid overfitting, we use dropout BIBREF31 with dropout chosen from [0.7-0.9] range. We also conducted early stopping BIBREF14 to avoid overfitting in our experiments as the regularization methods. We set the batch size to 4096, hidden size to 128, and the embedding size to 128 for all the models. We also used grid search for hyperparameter tuning for all of the trained models. Details of our training and hyperparameter tuning and the code for reproducing the results can be found in the chatbot-exp github repository.\n\nExperiments ::: Inference\nIn the inference time, there are mainly two methods for decoding which are greedy and beam search BIBREF32. Beam search has been proved to be an essential part in generative NLP task such as neural machine translation BIBREF33. In the case of dialogue generation systems, beam search could help alleviate the problem of having many possible valid outputs which do not match with the target but are valid and sensible outputs. Consider the case in which a task-oriented chatbot, trained for a restaurant reservation task, in response to the user utterance “Persian food”, generates the response “what time and day would you like the reservation for?” but the target defined for the system is “would you like a fancy restaurant?”. The response generated by the chatbot is a valid response which asks the user about other possible entities but does not match with the defined target.\nWe try to alleviate this problem in inference time by applying the beam search technique with a different beam size $\\alpha \\in \\lbrace 1, 2, 4\\rbrace $ and pick the best result based on the BLEU score. Note that when $\\alpha = 1$, we are using the original greedy search method for the generation task.\n\nExperiments ::: Evaluation Measures\nBLEU: We use the Bilingual Evaluation Understudy (BLEU) BIBREF34 metric which is commonly used in machine translation tasks. The BLEU metric can be used to evaluate dialogue generation models as in BIBREF5, BIBREF35. The BLEU metric is a word-overlap metric which computes the co-occurrence of N-grams in the reference and the generated response and also applies the brevity penalty which tries to penalize far too short responses which are usually not desired in task-oriented chatbots. We compute the BLEU score using all generated responses of our systems.\nPer-turn Accuracy: Per-turn accuracy measures the similarity of the system generated response versus the target response. Eric and Manning eric2017copy used this metric to evaluate their systems in which they considered their response to be correct if all tokens in the system generated response matched the corresponding token in the target response. This metric is a little bit harsh, and the results may be low since all the tokens in the generated response have to be exactly in the same position as in the target response.\nPer-Dialogue Accuracy: We calculate per-dialogue accuracy as used in BIBREF8, BIBREF5. For this metric, we consider all the system generated responses and compare them to the target responses. A dialogue is considered to be true if all the turns in the system generated responses match the corresponding turns in the target responses. Note that this is a very strict metric in which all the utterances in the dialogue should be the same as the target and in the right order.\nF1-Entity Score: Datasets used in task-oriented chores have a set of entities which represent user preferences. For example, in the restaurant domain chatbots common entities are meal, restaurant name, date, time and the number of people (these are usually the required entities which are crucial for making reservations, but there could be optional entities such as location or rating). Each target response has a set of entities which the system asks or informs the user about. Our models have to be able to discern these specific entities and inject them into the generated response. To evaluate our models we could use named-entity recognition evaluation metrics BIBREF36. The F1 score is the most commonly used metric used for the evaluation of named-entity recognition models which is the harmonic average of precision and recall of the model. We calculate this metric by micro-averaging over all the system generated responses.\n\nResults and Discussion ::: Comparison of Models\nThe results of running the experiments for the aforementioned models is shown in Table TABREF14 for the DSTC2 dataset and in Table TABREF18 for the M2M datasets. The bold numbers show the best performing model in each of the evaluation metrics. As discussed before, for each model we use different beam sizes (bs) in inference time and report the best one. Our findings in Table TABREF14 show that self-attentional models outperform common recurrence-based sequence modelling methods in the BLEU, Per-turn accuracy, and entity F1 score. The reduction in the evalution numbers for the M2M dataset and in our investigation of the trained model we found that this considerable reduction is due to the fact that the diversity of M2M dataset is considerably more compared to DSTC2 dataset while the traning corpus size is smaller.\n\nResults and Discussion ::: Time Performance Comparison\nTable TABREF22 shows the time performance of the models trained on DSTC2 dataset. Note that in order to get a fair time performance comparison, we trained the models with the same batch size (4096) and on the same GPU. These numbers are for the best performing model (in terms of evaluation loss and selected using the early stopping method) for each of the sequence modelling methods. Time to Convergence (T2C) shows the approximate time that the model was trained to converge. We also show the loss in the development set for that specific checkpoint.\n\nResults and Discussion ::: Effect of (Self-)Attention Mechanism\nAs discussed before in Section SECREF8, self-attentional models rely on the self-attention mechanism for sequence modelling. Recurrence-based models such as LSTM and Bi-LSTM can also be augmented in order to increase their performance, as evident in Table TABREF14 which shows the increase in the performance of both LSTM and Bi-LSTM when augmented with an attention mechanism. This leads to the question whether we can increase the performance of recurrence-based models by adding multiple attention heads, similar to the multi-head self-attention mechanism used in self-attentional models, and outperform the self-attentional models.\nTo investigate this question, we ran a number of experiments in which we added multiple attention heads on top of Bi-LSTM model and also tried a different number of self-attention heads in self-attentional models in order to compare their performance for this specific task. Table TABREF25 shows the results of these experiments. Note that the models in Table TABREF25 are actually the best models that we found in our experiments on DSTC2 dataset and we only changed one parameter for each of them, i.e. the number of attention heads in the recurrence-based models and the number of self-attention heads in the self-attentional models, keeping all other parameters unchanged. We also report the results of models with beam size of 2 in inference time. We increased the number of attention heads in the Bi-LSTM model up to 64 heads to see its performance change. Note that increasing the number of attention heads makes the training time intractable and time consuming while the model size would increase significantly as shown in Table TABREF24. Furthermore, by observing the results of the Bi-LSTM+Att model in Table TABREF25 (both test and development set) we can see that Bi-LSTM performance decreases and thus there is no need to increase the attention heads further.\nOur findings in Table TABREF25 show that the self-attention mechanism can outperform recurrence-based models even if the recurrence-based models have multiple attention heads. The Bi-LSTM model with 64 attention heads cannot beat the best Trasnformer model with NH=4 and also its results are very close to the Transformer model with NH=1. This observation clearly depicts the power of self-attentional based models and demonstrates that the attention mechanism used in self-attentional models as the backbone for learning, outperforms recurrence-based models even if they are augmented with multiple attention heads.\n\nConclusion and Future Work\nWe have determined that Transformers and Universal-Transformers are indeed effective at generating appropriate responses in task-oriented chatbot systems. In actuality, their performance is even better than the typically used deep learning architectures. Our findings in Table TABREF14 show that self-attentional models outperform common recurrence-based sequence modelling methods in the BLEU, Per-turn accuracy, and entity F1 score. The results of the Transformer model beats all other models in all of the evaluation metrics. Also, comparing the result of LSTM and LSTM with attention mechanism as well as the Bi-LSTM with Bi-LSTM with attention mechanism, it can be observed in the results that adding the attention mechanism can increase the performance of the models. Comparing the results of self-attentional models shows that the Transformer model outperforms the other self-attentional models, while the Universal Transformer model gives reasonably good results.\nIn future work, it would be interesting to compare the performance of self-attentional models (specifically the winning Transformer model) against other end-to-end architectures such as the Memory Augmented Networks.\n\nTable 6: Evaluation of effect of self-attention mechanism using DSTC2 dataset (Att: Attetnion mechanism; UT: Universal Transformers; ACT: Adaptive Computation Time; NH: Number of attention heads)\n\nInquiry: What are the three datasets used?",
"role": "user"
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{
"content": "{\"answer\": [\"DSTC2\", \"M2M-sim-M\", \"M2M-sim-R\"], \"evidence\": [\"We use three different datasets for training the models. We use the Dialogue State Tracking Competition 2 (DSTC2) dataset BIBREF27 which is the most widely used dataset for research on task-oriented chatbots. We also used two other datasets recently open-sourced by Google Research BIBREF28 which are M2M-sim-M (dataset in movie domain) and M2M-sim-R (dataset in restaurant domain). M2M stands for Machines Talking to Machines which refers to the framework with which these two datasets were created. In this framework, dialogues are created via dialogue self-play and later augmented via crowdsourcing. We trained on our models on different datasets in order to make sure the results are not corpus-biased. Table TABREF12 shows the statistics of these three datasets which we will use to train and evaluate the models.\"]}",
"role": "assistant"
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.631 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nAbstract The prevalence of e-learning systems and on-line courses has made educational material widely accessible to students of varying abilities and backgrounds. There is thus a growing need to accommodate for individual differences in e-learning systems. This paper presents an algorithm called EduRank for personalizing educational content to students that combines a collaborative filtering algorithm with voting methods. EduRank constructs a difficulty ranking for each student by aggregating the rankings of similar students using different aspects of their performance on common questions. These aspects include grades, number of retries, and time spent solving questions. It infers a difficulty ranking directly over the questions for each student, rather than ordering them according to the student’s predicted score. The EduRank algorithm was tested on two data sets containing thousands of students and a million records. It was able to outperform the state-of-the-art ranking approaches as well as a domain expert. EduRank was used by students in a classroom activity, where a prior model was incorporated to predict the difficulty rankings of students with no prior history in the system. It was shown to lead students to solve more difficult questions than an ordering by a domain expert, without reducing their performance.\n\nCited Works Summary:\n[1]: Researchers who make tutoring systems would like to know which sequences of educational content lead to the most effective learning by their students. The majority of data collected in many ITS systems consist of answers to a group of questions of a given skill often presented in a random sequence. Following work that identifies which items produce the most learning we propose a Bayesian method using similar permutation analysis techniques to determine if item learning is context sensitive and if so which orderings of questions produce the most learning. We confine our analysis to random sequences with three questions. The method identifies question ordering rules such as, question A should go before B, which are statistically reliably beneficial to learning. Real tutor data from five random sequence problem sets were analyzed. Statistically reliable orderings of questions were found in two of the five real data problem sets. A simulation consisting of 140 experiments was run to validate the method's accuracy and test its reliability. The method succeeded in finding 43 of the underlying item order effects with a 6 false positive rate using a p value threshold of <= 0.05. Using this method, ITS researchers can gain valuable knowledge about their problem sets and feasibly let the ITS automatically identify item order effects and optimize student learning by restricting assigned sequences to those prescribed as most beneficial to learning.",
"role": "user"
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"content": "Our work relates to several areas of research in student modeling. Several approaches within the educational data mining community have used computational methods for sequencing students' learning items. Pardos and Heffernan [1] infer order over questions by predicting students' skill levels over action pairs using Bayesian knowledge tracing. They show the efficacy of this approach on a test-set comprising random sequences of three questions as well as simulated data. This approach explicitly considers each possible order sequence and does not scale to handling a large number of sequences, as in the student ranking problem we consider in this paper.",
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science.medmentions_ner | science.medmentions_ner.371 | [
{
"content": "Analyze the provided paragraph from a scientific document. Your goal is to identify and extract relevant entities.\n\nFormat your findings as a JSON object, where each key represents a category of entities, and the corresponding value is a list of entities identified in that category. If no entities are found for a category, return an empty list.\n\nFocus on precision and ensure that the output is strictly in JSON format.\n\nDocument:\n\nDetailed Morphology of All Life Stages of the Agave Red Worm, Comadia redtenbacheri (Hammerschmidt) (Lepidoptera: Cossidae) The agave red worm, Comadia redtenbacheri (Hammerschmidt), is an important source of food and income in Mexico. Despite its importance, several aspects of its biology, morphology, and behavior remain poorly studied. In this work, we describe and illustrate the morphology of all the life stages that may aid in understanding certain aspects of its biology. To obtain all life stages, last instar larvae were collected from agave plants and allowed to pupate; after the adults emerged, they were allowed to mate and oviposit. The frenulum is longer in males; epiphysis I is longer in females than in males; the abdomen bears two types of tubercles of unknown function. Eggs present a reticulate chorion; primary rosette cells are highly variable in shape; the micropylar formula is (10-14): (12-13). First instar larvae are white, becoming red as they develop; L3 in the prothorax is subprimary; the SV setal group in A1 is comprised of only SV1 on first instar larvae; last instars have several secondary setae. Pupae are adecticous and obtect; there are rows of spines on the dorsum of the abdomen. The biological significance of some of the findings is discussed.",
"role": "user"
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"content": "{\"AnatomicalStructure\": [\"tubercles\", \"Eggs\", \"SV setal\", \"rosette cells\", \"setae\", \"spines\", \"epiphysis I\", \"reticulate chorion\"], \"Bacterium\": [], \"BiologicFunction\": [\"develop\", \"oviposit\", \"mate\"], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [], \"ClinicalAttribute\": [], \"Eukaryote\": [\"agave plants\", \"Pupae\", \"Agave Red Worm\", \"Comadia redtenbacheri\", \"Lepidoptera\", \"pupate\", \"adults\", \"agave red worm\", \"instar larvae\", \"instars\", \"Cossidae\"], \"Finding\": [\"adecticous\", \"subprimary\", \"findings\", \"obtect\"], \"Food\": [\"food\"], \"HealthCareActivity\": [], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"frenulum\", \"micropylar formula\"], \"MedicalDevice\": [], \"Organization\": [], \"PopulationGroup\": [], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [], \"SpatialConcept\": [\"dorsum of the abdomen\", \"Mexico\", \"A1\", \"prothorax\", \"L3\", \"SV1\", \"abdomen\"], \"Virus\": []}",
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science.scicite_classification | science.scicite_classification.1209 | [
{
"content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nLess work has been done on assessing the value of FLAIR signal in the postoperative cavity [13–16].",
"role": "user"
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{
"content": "Background",
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science.bc7_litcovid_topic_classification | science.bc7_litcovid_topic_classification.2834 | [
{
"content": "Analyze the given paragraph from COVID-19 research. Determine the relevant topics discussed in the text. Your response should be a JSON array containing the identified topics. Ensure the output is a valid JSON array with no additional commentary.\n\nText:\n\nCommunity acquired co-infection in COVID-19 is not well defined. Current literature describes co-infection in 0-40% of COVID-19 patients. In this retrospective report, co-infection was identified in 3.7% of patients and 41% of patients admitted to intensive care (p<0.005). Despite infrequent co-infection, antibiotics were used in 69% of patients.",
"role": "user"
},
{
"content": "[\"Treatment\", \"Diagnosis\"]",
"role": "assistant"
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science.scireviewgen_multidoc_summarization | science.scireviewgen_multidoc_summarization.4911 | [
{
"content": "Craft a cohesive chapter for a literature review using the abstracts provided. Focus on the chapter's theme, weaving together insights and findings from the abstracts. Highlight key points and note any research gaps.\nLiterature Review Title: Network Coding Meets Multimedia: a Review \nChapter Title: A. In-network error control \n1. Abstract of Cited Paper (BIB001): Forward error correction (FEC) schemes have been proposed and used successfully for multicasting realtime video content to groups of users. Under traditional IP multicast, application-level FEC can only be implemented on an end-to-end basis between the sender and the clients. Emerging overlay and peer-to-peer (p2p) networks open the door for new paradigms of network FEC. The deployment of FEC within these emerging networks has received very little attention (if any). In this paper, we analyze and optimize the impact of network-embedded FEC (NEF) in overlay and p2p multimedia multicast networks. Under NEF, we place FEC codecs in selected intermediate nodes of a multicast tree. The NEF codecs detect and recover lost packets within FEC blocks at earlier stages before these blocks arrive at deeper intermediate nodes or at the final leaf nodes. This approach significantly reduces the probability of receiving undecodable FEC blocks. In essence, the proposed NEF codecs work as signal regenerators in a communication system and can reconstruct most of the lost data packets without requiring retransmission. We develop an optimization algorithm for the placement of NEF codecs within random multicast trees. Based on extensive H.264 video simulations, we show that this approach provides significant improvements in video quality, both visually and in terms of PSNR values. \n2. Abstract of Cited Paper (BIB002): This paper exhibits a class of universal Raptor codes: for a given integer k, and any real /spl epsiv/>0, Raptor codes in this class produce a potentially infinite stream of symbols such that any subset of symbols of size k(1 + /spl epsiv/) is sufficient to recover the original k symbols, with high probability. Each output symbol is generated using O(log(1//spl epsiv/)) operations, and the original symbols are recovered from the collected ones with O(klog(1//spl epsiv/)) operations. \n3. Abstract of Cited Paper (BIB003): In Part I of this paper, we introduced the paradigm of network error correction as a generalization of classical link-by-link error correction. We also obtained the network generalizations of the Hamming bound and the Singleton bound in classical algebraic coding theory. In Part II, we prove the network generalization of the Gilbert-Varshamov bound and its enhancement. With the latter, we show that the tightness of the Singleton bound is preserved in the network setting. We also discuss the implication of the results in this paper. Definition 2. An etwork code ist-error-correcting if it can correct all τ -errors for τ ≤ t, i.e., if the total number of errors in the network is at most t, then the source message can be recovered by all the sink nodes u ∈U.A network code is Y-error-correcting if it can correct E-errors for all E ∈ Y. In Part I, we have proved the network generalizations of the Hamming bound and the Singleton bound. In this part, we will prove a network generalization of the Gilbert-Varshamov bound and its enhancement. With the latter, we will show that the tightness of the Singleton bound is preserved in the network setting. The rest of Part II is organized as follows. In Section 2, we prove the Gilbert bound and the Varshamov bound for network error-correcting codes. In Section 3, we sharpen the Varshamov bound obtained in Section 2 to the strengthened Varshamov bound. By means of the latter, we prove the tightness of the Singleton bound for \n4. Abstract of Cited Paper (BIB004): The problem of error control in random linear network coding is addressed from a matrix perspective that is closely related to the subspace perspective of Rotter and Kschischang. A large class of constant-dimension subspace codes is investigated. It is shown that codes in this class can be easily constructed from rank-metric codes, while preserving their distance properties. Moreover, it is shown that minimum distance decoding of such subspace codes can be reformulated as a generalized decoding problem for rank-metric codes where partial information about the error is available. This partial information may be in the form of erasures (knowledge of an error location but not its value) and deviations (knowledge of an error value but not its location). Taking erasures and deviations into account (when they occur) strictly increases the error correction capability of a code: if mu erasures and delta deviations occur, then errors of rank t can always be corrected provided that 2t les d - 1 + mu + delta, where d is the minimum rank distance of the code. For Gabidulin codes, an important family of maximum rank distance codes, an efficient decoding algorithm is proposed that can properly exploit erasures and deviations. In a network coding application, where n packets of length M over F(q) are transmitted, the complexity of the decoding algorithm is given by O(dM) operations in an extension field F(qn). \n5. Abstract of Cited Paper (BIB005): In this paper, we consider the problem of streaming video information on lossy packet networks with path and source diversity, such as wireless mesh networks or more generally overlay architectures. We propose to distribute the video information between several streaming servers and to implement network coding in the forwarding peers in order to increase the quality of the video decoded by the streaming client. A network coding algorithm based on Raptor codes permits to combine video packets in the network nodes and to increase the symbol diversity in the network. Coupled with the path diversity in the overlay network, this solution is shown to offer a significant gain in video quality compared to baseline streaming solutions when loss rate becomes important or the network diversity is reduced. \n6. Abstract of Cited Paper (BIB006): We present a system for collaborative video streaming in wired overlay networks. We propose a scheme that builds on both rateless codes and network coding in order to improve the system throughput and the video quality at clients. Our hybrid coding algorithm permits to efficiently exploit the available source and path diversity without the need for expensive routing nor scheduling algorithms. We consider specifically an architecture where multiple streaming servers simultaneously deliver video information to a set of clients. The servers apply Raptor coding on the video packets for error resiliency, and the overlay nodes selectively combine the Raptor coded video packets in order to increase the packet diversity in the system. We analyze the performance of selective network coding and describe its application to practical video streaming systems. We further compute an effective source and channel rate allocation in our collaborative streaming system. We estimate the expected symbol diversity at clients with respect to the coding choices. Then we cast a minmax quality optimization problem that is solved by a low-cost bisection based method. The experimental evaluation demonstrates that our system typically outperforms Raptor video streaming systems that do not use network coding as well as systems that perform decoding and encoding in the network nodes. Finally, our solution has a low complexity and only requires small buffers in the network coding nodes, which are certainly two important advantages toward deployment in practical streaming systems. \n7. Abstract of Cited Paper (BIB007): The theory of network coding promises significant benefits in network performance, especially in lossy networks and in multicast and multipath scenarios. To realize these benefits in practice, we need to understand how coding across packets interacts with the acknowledgment (ACK)-based flow control mechanism that forms a central part of today's Internet protocols such as transmission control protocol (TCP). Current approaches such as rateless codes and batch-based coding are not compatible with TCP's retransmission and sliding-window mechanisms. In this paper, we propose a new mechanism called TCP/NC that incorporates network coding into TCP with only minor changes to the protocol stack, thereby allowing incremental deployment. In our scheme, the source transmits random linear combinations of packets currently in the congestion window. At the heart of our scheme is a new interpretation of ACKs-the sink acknowledges every degree of freedom (i.e., a linear combination that reveals one unit of new information) even if it does not reveal an original packet immediately. Thus, our new TCP ACK rule takes into account the network coding operations in the lower layer and enables a TCP-compatible sliding-window approach to network coding. Coding essentially masks losses from the congestion control algorithm and allows TCP/NC to react smoothly to losses, resulting in a novel and effective approach for congestion control over lossy networks such as wireless networks. An important feature of our solution is that it allows intermediate nodes to perform re-encoding of packets, which is known to provide significant throughput gains in lossy networks and multicast scenarios. Simulations show that our scheme, with or without re-encoding inside the network, achieves much higher throughput compared to TCP over lossy wireless links. We present a real-world implementation of this protocol that addresses the practical aspects of incorporating network coding and decoding with TCP's window management mechanism. We work with TCP-Reno, which is a widespread and practical variant of TCP. Our implementation significantly advances the goal of designing a deployable, general, TCP-compatible protocol that provides the benefits of network coding.\n\nReview Chapter:",
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"content": "If a node does not receive sufficiently many packets due to congestions or delays, decoding of the content is not possible; this leads to dramatic quality degradations. Applying Forward Error Correction (FEC) codes to the media amounts to adding redundancy symbols for loss recovery. Since most multimedia communications occur in packet network environments, losses typically occur in the form of packet erasures. Erasure correction codes are a nice and viable solution, e.g., Reed-Solomon codes, low-density parity-check codes, turbo codes, as well as the more recent digital fountain codes such as LT codes BIB001 or Raptor codes BIB003 . The latter are based on the cascade application of a FEC block code, followed by an LT code. This results in linear encoding and decoding complexity that is attractive for NC. These concepts can be extended to a distributed environment with multiple senders and receivers, particularly when the intermediate nodes are allowed to apply NC. This leads to the concept of \"network error correction\", which has become increasingly popular in the information theory community , BIB004 . Practical coding solutions have mostly employed rankmetric codes BIB005 . In these codes, codewords are matrices, as opposed to vectors, and the rank is employed as a distance metric between two codewords, i.e., the rank of the matrix difference. Rank-metric codes have become popular for storage applications, where information is stored in two-dimensional arrays but errors are typically confined to one or few rows or columns. Gabidulin codes are the rank-metric analog of Reed-Solomon codes, and are probably the most studied rank-metric codes , . These codes are interesting for NC, as they can be used to solve a distributed erasure correction problem of the form Y = AX + Z, where the received packets Y are modeled as combinations of the source packets X using a linear transformation matrix A, plus a matrix Z of error packets. It should be noted that, while there have been many recent theoretical advances in the area of network error correction, practical coding solutions have yet to be proposed. In BIB002 , the concept of \"network-embedded forward error correction\" has been proposed. Conventional multicast systems apply FEC codes in an end-to-end fashion, that is, only the source nodes and the destination nodes are involved in the coding and decoding processes. These are delivered to the receivers, which attempt to perform FEC decoding in order to recover the original data. The idea behind network-embedded FEC is to have a few enhanced \"supernodes\" that perform FEC decoding and re-encoding, instead of simply relaying packets. These nodes act as signal regenerators: they are able to locally recover from information losses and thereby to significantly improve the overall performance, at the price of added complexity. In BIB002 , a greedy algorithm is proposed to select the near-optimal locations of the enhanced nodes. The main conceptual difference between network-embedded FEC and NC lies in the decoding-recoding approach. In network-embedded FEC, every enhanced node has to wait until enough packets are received in order to be able to decode and then re-encode a data segment. Therefore, it is not possible for an enhanced node to immediately forward re-encoded packets on its outgoing links, which may induce delays in the system. While network-embedded FEC can be seen as a very simple form of NC, it is not as good as a true NC solution, which would immediately re-encode and transmit packets without additional delay. Channel coding techniques have also been employed in BIB006 , BIB007 to perform NC on multimedia sessions in overlay networks. Rateless codes are used to construct an NC scheme in which the source packets are initially encoded by the server using a non-systematic Raptor code and then disseminated in the overlay. Each node schedules packet transmissions according to the amount of available bandwidth. If the number of received packets for a given media segment exceeds the available outgoing bandwidth, then only a part of the received packets are forwarded. Alternatively, if the available bandwidth is larger than the number of received packets, a node forwards the received packets, and then creates and forwards new linear combinations, leading to full exploitation of the available resources. In generating linear combinations of received symbols, one has to make sure that the new symbols are linearly independent to the original ones in order to avoid unnecessary redundancy. In BIB007 , this has been taken care of by using combinations of only two symbols, and making sure that the same symbol is not used in multiple combinations. In general, this scheme is very effective computation-wise, but symbols cannot be recombined repeatedly, as this would generate linear dependencies in the new symbols. The scheme might thus present limitations for very large-scale networks. Finally, another class of error control solutions is based on employing NC in the context of packet retransmission. In particular, it has been shown that existing transport protocols such as TCP can be augmented by NC, leading to significantly improved performance BIB008 . Similarly, NC has been employed in wireless networks in order to recover from packet losses. These aspects are discussed in more detail in Section V.",
"role": "assistant"
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.1091 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nThe success of deep learning in medical imaging is mostly achieved at the cost of a large labeled data set. Semi-supervised learning (SSL) provides a promising solution by leveraging the structure of unlabeled data to improve learning from a small set of labeled data. Self-ensembling is a simple approach used in SSL to encourage consensus among ensemble predictions of unknown labels, improving generalization of the model by making it more insensitive to the latent space. Currently, such an ensemble is obtained by randomization such as dropout regularization and random data augmentation. In this work, we hypothesize -- from the generalization perspective -- that self-ensembling can be improved by exploiting the stochasticity of a disentangled latent space. To this end, we present a stacked SSL model that utilizes unsupervised disentangled representation learning as the stochastic embedding for self-ensembling. We evaluate the presented model for multi-label classification using chest X-ray images, demonstrating its improved performance over related SSL models as well as the interpretability of its disentangled representations.\n\nCited Works Summary:\n[1]: This paper introduces a novel measure-theoretic learning theory to analyze generalization behaviors of practical interest. The proposed learning theory has the following abilities: 1) to utilize the qualities of each learned representation on the path from raw inputs to outputs in representation learning, 2) to guarantee good generalization errors possibly with arbitrarily rich hypothesis spaces (e.g., arbitrarily large capacity and Rademacher complexity) and non-stable non-robust learning algorithms, and 3) to clearly distinguish each individual problem instance from each other. Our generalization bounds are relative to a representation of the data, and hold true even if the representation is learned. We discuss several consequences of our results on deep learning, one-shot learning and curriculum learning. Unlike statistical learning theory, the proposed learning theory analyzes each problem instance individually via measure theory, rather than a set of problem instances via statistics. Because of the differences in the assumptions and the objectives, the proposed learning theory is meant to be complementary to previous learning theory and is not designed to compete with it.\n\n[2]: Deep learning networks have shown state-of-the-art performance in many image reconstruction problems. However, it is not well understood what properties of representation and learning may improve the generalization ability of the network. In this paper, we propose that the generalization ability of an encoder-decoder network for inverse reconstruction can be improved in two means. First, drawing from analytical learning theory, we theoretically show that a stochastic latent space will improve the ability of a network to generalize to test data outside the training distribution. Second, following the information bottleneck principle, we show that a latent representation minimally informative of the input data will help a network generalize to unseen input variations that are irrelevant to the output reconstruction. Therefore, we present a sequence image reconstruction network optimized by a variational approximation of the information bottleneck principle with stochastic latent space. In the application setting of reconstructing the sequence of cardiac transmembrane potential from body-surface potential, we assess the two types of generalization abilities of the presented network against its deterministic counterpart. The results demonstrate that the generalization ability of an inverse reconstruction network can be improved by stochasticity as well as the information bottleneck.\n\n[3]: In this paper, we present a simple and efficient method for training deep neural networks in a semi-supervised setting where only a small portion of training data is labeled. We introduce self-ensembling, where we form a consensus prediction of the unknown labels using the outputs of the network-in-training on different epochs, and most importantly, under different regularization and input augmentation conditions. This ensemble prediction can be expected to be a better predictor for the unknown labels than the output of the network at the most recent training epoch, and can thus be used as a target for training. Using our method, we set new records for two standard semi-supervised learning benchmarks, reducing the (non-augmented) classification error rate from 18.44 to 7.05 in SVHN with 500 labels and from 18.63 to 16.55 in CIFAR-10 with 4000 labels, and further to 5.12 and 12.16 by enabling the standard augmentations. We additionally obtain a clear improvement in CIFAR-100 classification accuracy by using random images from the Tiny Images dataset as unlabeled extra inputs during training. Finally, we demonstrate good tolerance to incorrect labels.",
"role": "user"
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"content": "This work is mostly related to two lines of research: 1) SSL based on regularization with random transformations, and 2) disentangled representation learning and its use in SSL. In the former, consistency-based regularization is applied on ensemble predictions obtained by randomization techniques such as random data augmentation, dropout, and random max-pooling [3] . This randomization was empirically shown to improve the generalization and stability of the SSL model, while its theoretical basis was recently shown to be related to the reduction of model sensitivity to the latent space [1] [2] . Motivated by this theory, in this work, we attempt to utilize the knowledge about the stochastic latent space -- obtained in unsupervised learning -- in this randomization process.",
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science.scicite_classification | science.scicite_classification.3183 | [
{
"content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nTwo methods (based on Local Binary Patterns), which were previously reported as competitive in automated diagnosis of CD [11] were utilized in addition to state-of-the-art global mid-level image representations which are obtained by pooling local image descriptors.",
"role": "user"
},
{
"content": "Method",
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}
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science.chemdner_ner | science.chemdner_ner.1441 | [
{
"content": "Analyze the given text to identify specific entities. Focus on extracting relevant data.\n\nProvide your findings in JSON format. Each category should list the entities found.\n\nText:\n\nTargeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways. Mutations in REarranged during Transfection (RET) receptor tyrosine, followed by the oncogenic activation of RET kinase is responsible for the development of medullary thyroid carcinoma (MTC) that responds poorly to conventional chemotherapy. Targeting RET, therefore, might be useful in tailoring surveillance of MTC patients. Here we showed that theaflavins, the bioactive components of black tea, successfully induced apoptosis in human MTC cell line, TT, by inversely modulating two molecular pathways: (i) stalling PI3K/Akt/Bad pathway that resulted in mitochondrial transmembrane potential (MTP) loss, cytochrome-c release and activation of the executioner caspases-9 and -3, and (ii) upholding p38MAPK/caspase-8/caspase-3 pathway via inhibition of Ras/Raf/ERK. Over-expression of either constitutively active myristoylated-Akt-cDNA (Myr-Akt-cDNA) or dominant-negative-caspase-8-cDNA (Dn-caspase-8-cDNA) partially blocked theaflavin-induced apoptosis, while co-transfection of Myr-Akt-cDNA and Dn-caspase-8-cDNA completely eradicated the effect of theaflavins thereby negating the possibility of existence of other pathways. A search for the upstream signaling revealed that theaflavin-induced disruption of lipid raft caused interference in anchorage of RET in lipid raft that in turn stalled phosphorylation of Ras and PI3Kinase. In such anti-survival cellular micro-environment, pro-apoptotic signals were triggered to culminate into programmed death of MTC cell. These findings not only unveil a hitherto unexplained mechanism underlying theaflavin-induced MTC death, but also validate RET as a promising and potential target for MTC therapy.",
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"content": "{\"Chemical\": [\"theaflavin\", \"theaflavins\", \"tyrosine\"]}",
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science.genia_ner | science.genia_ner.571 | [
{
"content": "Analyze the provided text excerpt from a scientific document. Identify and extract distinct entities based on predefined categories.\n\nDeliver the results as a JSON structure where each key represents an entity category, and the associated value is a list of identified entities. If no entities are found for a category, return an empty list.\n\nText Excerpt:\n\nA cell type-specific enhancer in the human B7. 1 gene regulated by NF-kappaB. The costimulatory molecule B7. 1 provides a second signal critical for T cell activation. The distribution of this integral membrane protein is restricted to certain tissues where its level of expression is modulated by multiple exogenous stimuli. To identify the molecular basis for specificity and inducibility, the chromatin configuration of the human B7. 1 gene was examined in intact nuclei from various cell types. The identification of a tissue-specific deoxyribonuclease I hypersensitive site approximately 3kb upstream of the transcription start site led to the characterization of a cell type-specific enhancer region. This 183-bp region was both cell type specific and responsive to two distinct stimuli, lipopolysaccharide and dibutyryl cAMP, known to regulate B7. 1 expression. Deletional and site-directed mutagenesis revealed the presence of multiple functionally critical cis elements within this region, one of which was a nuclear factor (NF) -kappaB consensus sequence. In B7. 1-positive B cells, this element bound several members of the NF-kappaB family, transcription factors already implicated in signal transduction pathways relevant to B7. 1 expression. This is the first description, to our knowledge, of regulatory elements that control expression of a gene encoding a B7 costimulatory molecule.",
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"content": "{\"CellLine\": [], \"CellType\": [\"B7 . 1 - positive B cells\"], \"DNA\": [\"cell type - specific enhancer\", \"3kb upstream\", \"human B7 . 1 gene\", \"cell type - specific enhancer region\", \"nuclear factor (NF) - kappaB consensus sequence\", \"regulatory elements\", \"cis elements\", \"transcription start site\", \"183 - bp region\", \"chromatin\", \"deoxyribonuclease I hypersensitive site\"], \"Protein\": [\"B7 costimulatory molecule\", \"integral membrane protein\", \"NF - kappaB family\", \"B7 . 1\", \"deoxyribonuclease I\", \"transcription factors\", \"NF - kappaB\", \"costimulatory molecule B7 . 1\"], \"RNA\": []}",
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science.chemdner_ner | science.chemdner_ner.3277 | [
{
"content": "Analyze the given text to identify specific entities. Focus on extracting relevant data.\n\nProvide your findings in JSON format. Each category should list the entities found.\n\nText:\n\nResistance to aerobic exercise training causes metabolic dysfunction and reveals novel exercise-regulated signaling networks. Low aerobic exercise capacity is a risk factor for diabetes and strong predictor of mortality; yet some individuals are \"exercise resistant\", and unable to improve exercise capacity through exercise training. To test the hypothesis that resistance to aerobic exercise training underlies metabolic disease-risk, we used selective breeding for 15 generation to develop rat models of low- and high-aerobic response to training. Before exercise training, rats selected as low- and high-responders had similar exercise capacities. However, after 8-wks of treadmill training low-responders failed to improve their exercise capacity, while high-responders improved by 54%. Remarkably, low-responders to aerobic training exhibited pronounced metabolic dysfunction characterized by insulin resistance and increased adiposity, demonstrating that the \"exercise resistant\" phenotype segregates with disease risk. Low-responders had impaired exercise-induced angiogenes0is in muscle; however, mitochondrial capacity was intact and increased normally with exercise training, demonstrating that mitochondria are not limiting for aerobic adaptation or responsible for metabolic dysfunction in low-responders. Low-responders had increased stress/inflammatory signaling and altered TGFβ signaling, characterized by hyperphosphorylation of a novel exercise-regulated phosphorylation site on SMAD2. Using this powerful biological model system we have discovered key pathways for low exercise training response that may represent novel targets for the treatment of metabolic disease.",
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{
"content": "{\"Chemical\": []}",
"role": "assistant"
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science.chemprot_ner | science.chemprot_ner.686 | [
{
"content": "Analyze the following text to identify specific entities. Focus on the categories provided: [\"Chemical\", \"Protein\"].\n\nDeliver your findings as a JSON structure: {\"Chemical\": [\"ExampleChemical\", ...], \"Protein\": [\"ExampleProtein\", ...]}. Each key represents an entity type, and the associated list contains the entities found. \n\nEnsure the response is strictly the JSON format without any extra text.\n\nSource:\n\nTransport by OATP1B1 and OATP1B3 enhances the cytotoxicity of epigallocatechin 3-O-gallate and several quercetin derivatives.\nOrganic anion transporting polypeptides (OATPs) 1B1 and 1B3 are transporters that are expressed selectively in human hepatocytes under normal conditions. OATP1B3 is also expressed in certain cancers. Flavonoids such as green tea catechins and quercetin glycosides have been shown to modulate the function of some OATPs. In the present study, the extent to which six substituted quercetin derivatives (1-6) affected the function of OATP1B1 and OATP1B3 was investigated. Uptake of the radiolabeled model substrates estradiol 17β-glucuronide, estrone 3-sulfate, and dehydroepiandrosterone sulfate (DHEAS) was determined in the absence and presence of compounds 1-6 using Chinese hamster ovary (CHO) cells stably expressing either OATP1B1 or OATP1B3. Several of compounds 1-6 inhibited OATP-mediated uptake of all three model substrates, suggesting that they could also be potential substrates. Compound 6 stimulated OATP1B3-mediated estradiol 17β-glucuronide uptake by increasing the apparent affinity of OATP1B3 for its substrate. Cytotoxicity assays demonstrated that epigallocatechin 3-O-gallate (EGCG) and most of compounds 1-6 killed preferentially OATP-expressing CHO cells. EGCG, 1, and 3 were the most potent cytotoxic compounds, with EGCG and 3 selectively killing OATP1B3-expressing cells. Given that OATP1B3 is expressed in several cancers, EGCG and some of the quercetin derivatives studied might be promising lead compounds for the development of novel anticancer drugs.",
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"content": "{\"Chemical\": [\"DHEAS\", \"estrone 3-sulfate\", \"Flavonoids\", \"estradiol 17\\u03b2-glucuronide\", \"quercetin\", \"quercetin glycosides\", \"catechins\", \"dehydroepiandrosterone sulfate\", \"epigallocatechin 3-O-gallate\", \"EGCG\"], \"Protein\": [\"OATP1B3\", \"OATP1B1\", \"OATP\", \"Organic anion transporting polypeptides (OATPs) 1B1 and 1B3\", \"OATPs\"]}",
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.3180 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nThe task of image generation started to receive some attention from artists and designers to inspire them in new creations. However, exploiting the results of deep generative models such as Generative Adversarial Networks can be long and tedious given the lack of existing tools. In this work, we propose a simple strategy to inspire creators with new generations learned from a dataset of their choice, while providing some control on them. We design a simple optimization method to find the optimal latent parameters corresponding to the closest generation to any input inspirational image. Specifically, we allow the generation given an inspirational image of the user choice by performing several optimization steps to recover optimal parameters from the model's latent space. We tested several exploration methods starting with classic gradient descents to gradient-free optimizers. Many gradient-free optimizers just need comparisons (better worse than another image), so that they can even be used without numerical criterion, without inspirational image, but with only with human preference. Thus, by iterating on one's preferences we could make robust Facial Composite or Fashion Generation algorithms. High resolution of the produced design generations are obtained using progressive growing of GANs. Our results on four datasets of faces, fashion images, and textures show that satisfactory images are effectively retrieved in most cases.\n\nCited Works Summary:\n[1]: How can we explain the predictions of a black-box model? In this paper, we use influence functions -- a classic technique from robust statistics -- to trace a model's prediction through the learning algorithm and back to its training data, thereby identifying training points most responsible for a given prediction. To scale up influence functions to modern machine learning settings, we develop a simple, efficient implementation that requires only oracle access to gradients and Hessian-vector products. We show that even on non-convex and non-differentiable models where the theory breaks down, approximations to influence functions can still provide valuable information. On linear models and convolutional neural networks, we demonstrate that influence functions are useful for multiple purposes: understanding model behavior, debugging models, detecting dataset errors, and even creating visually-indistinguishable training-set attacks.\n\n[2]: We introduce a method to stabilize Generative Adversarial Networks (GANs) by defining the generator objective with respect to an unrolled optimization of the discriminator. This allows training to be adjusted between using the optimal discriminator in the generator's objective, which is ideal but infeasible in practice, and using the current value of the discriminator, which is often unstable and leads to poor solutions. We show how this technique solves the common problem of mode collapse, stabilizes training of GANs with complex recurrent generators, and increases diversity and coverage of the data distribution by the generator.\n\n[3]: Large Convolutional Network models have recently demonstrated impressive classification performance on the ImageNet benchmark. However there is no clear understanding of why they perform so well, or how they might be improved. In this paper we address both issues. We introduce a novel visualization technique that gives insight into the function of intermediate feature layers and the operation of the classifier. We also perform an ablation study to discover the performance contribution from different model layers. This enables us to find model architectures that outperform Krizhevsky al on the ImageNet classification benchmark. We show our ImageNet model generalizes well to other datasets: when the softmax classifier is retrained, it convincingly beats the current state-of-the-art results on Caltech-101 and Caltech-256 datasets.\n\n[4]: Rendering the semantic content of an image in different styles is a difficult image processing task. Arguably, a major limiting factor for previous approaches has been the lack of image representations that explicitly represent semantic information and, thus, allow to separate image content from style. Here we use image representations derived from Convolutional Neural Networks optimised for object recognition, which make high level image information explicit. We introduce A Neural Algorithm of Artistic Style that can separate and recombine the image content and style of natural images. The algorithm allows us to produce new images of high perceptual quality that combine the content of an arbitrary photograph with the appearance of numerous wellknown artworks. Our results provide new insights into the deep image representations learned by Convolutional Neural Networks and demonstrate their potential for high level image synthesis and manipulation.\n\n[5]: Convolutional neural networks memorize part of their training data, which is why strategies such as data augmentation and drop-out are employed to mitigate overfitting. This paper considers the related question of \"membership inference\", where the goal is to determine if an image was used during training. We consider it under three complementary angles. We show how to detect which dataset was used to train a model, and in particular whether some validation images were used at train time. We then analyze explicit memorization and extend classical random label experiments to the problem of learning a model that predicts if an image belongs to an arbitrary set. Finally, we propose a new approach to infer membership when a few of the top layers are not available or have been fine-tuned, and show that lower layers still carry information about the training samples. To support our findings, we conduct large-scale experiments on Imagenet and subsets of YFCC-100M with modern architectures such as VGG and Resnet.\n\n[6]: Generative Adversarial Networks (GANs) have achieved remarkable results in the task of generating realistic natural images. In most applications, GAN models share two aspects in common. On the one hand, GANs training involves solving a challenging saddle point optimization problem, interpreted as an adversarial game between a generator and a discriminator functions. On the other hand, the generator and the discriminator are parametrized in terms of deep convolutional neural networks. The goal of this paper is to disentangle the contribution of these two factors to the success of GANs. In particular, we introduce Generative Latent Optimization (GLO), a framework to train deep convolutional generators without using discriminators, thus avoiding the instability of adversarial optimization problems. Throughout a variety of experiments, we show that GLO enjoys many of the desirable properties of GANs: learning from large data, synthesizing visually-appealing samples, interpolating meaningfully between samples, and performing linear arithmetic with noise vectors.\n\n[7]: Deep neural networks (DNNs) have demonstrated state-of-the-art results on many pattern recognition tasks, especially vision classification problems. Understanding the inner workings of such computational brains is both fascinating basic science that is interesting in its own right---similar to why we study the human brain---and will enable researchers to further improve DNNs. One path to understanding how a neural network functions internally is to study what each of its neurons has learned to detect. One such method is called activation maximization, which synthesizes an input (e.g. an image) that highly activates a neuron. Here we dramatically improve the qualitative state of the art of activation maximization by harnessing a powerful, learned prior: a deep generator network. The algorithm (1) generates qualitatively state-of-the-art synthetic images that look almost real, (2) reveals the features learned by each neuron in an interpretable way, (3) generalizes well to new datasets and somewhat well to different network architectures without requiring the prior to be relearned, and (4) can be considered as a high-quality generative method (in this case, by generating novel, creative, interesting, recognizable images).\n\n[8]: We propose a class of loss functions, which we call deep perceptual similarity metrics (DeePSiM), allowing to generate sharp high resolution images from compressed abstract representations. Instead of computing distances in the image space, we compute distances between image features extracted by deep neural networks. This metric reflects perceptual similarity of images much better and, thus, leads to better results. We demonstrate two examples of use cases of the proposed loss: (1) networks that invert the AlexNet convolutional network; (2) a modified version of a variational autoencoder that generates realistic high-resolution random images.\n\n[9]: While it is nearly effortless for humans to quickly assess the perceptual similarity between two images, the underlying processes are thought to be quite complex. Despite this, the most widely used perceptual metrics today, such as PSNR and SSIM, are simple, shallow functions, and fail to account for many nuances of human perception. Recently, the deep learning community has found that features of the VGG network trained on the ImageNet classification task has been remarkably useful as a training loss for image synthesis. But how perceptual are these so-called \"perceptual losses\"? What elements are critical for their success? To answer these questions, we introduce a new Full Reference Image Quality Assessment (FR-IQA) dataset of perceptual human judgments, orders of magnitude larger than previous datasets. We systematically evaluate deep features across different architectures and tasks and compare them with classic metrics. We find that deep features outperform all previous metrics by huge margins. More surprisingly, this result is not restricted to ImageNet-trained VGG features, but holds across different deep architectures and levels of supervision (supervised, self-supervised, or even unsupervised). Our results suggest that perceptual similarity is an emergent property shared across deep visual representations.",
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"content": "A number of works focus on neural visualization of trained networks for image classification [3] [8] [7] . A somehow related task lies in membership inference, where the goal is to determine if an image has been seen for training [5] [1] . The notion of feature similarity in image generation is widely employed, for instance in style transfer [4] , and generation quality assessment [9] . The most similar work in spirit to our image inspiration strategy is the Inference-via-optimization approach defined to evaluate the severity of mode collapse in Unrolled GANs [2] . We can also cite the approach of [6] that also matches vectors in the latent space of GANs with precise pictures at training time using a Nesterov gradient.",
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science.scicite_classification | science.scicite_classification.4419 | [
{
"content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nHowever and in contrast to our results, other works demonstrated that the repeated subcutaneous administration of morphine did not induce antihyperalgesic and antiallodynic tolerance after the partial sciatic nerve injury-induced neuropathic pain (Narita et al., 2011; Sounvoravong et al., 2004).",
"role": "user"
},
{
"content": "Result",
"role": "assistant"
}
]
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.671 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nDeep reinforcement learning has achieved great successes in recent years, however, one main challenge is the sample inefficiency. In this paper, we focus on how to use action guidance by means of a non-expert demonstrator to improve sample efficiency in a domain with sparse, delayed, and possibly deceptive rewards: the recently-proposed multi-agent benchmark of Pommerman. We propose a new framework where even a non-expert simulated demonstrator, e.g., planning algorithms such as Monte Carlo tree search with a small number rollouts, can be integrated within asynchronous distributed deep reinforcement learning methods. Compared to a vanilla deep RL algorithm, our proposed methods both learn faster and converge to better policies on a two-player mini version of the Pommerman game.\n\nCited Works Summary:\n[1]: Safe Reinforcement Learning can be defined as the process of learning policies that maximize the expectation of the return in problems in which it is important to ensure reasonable system performance and or respect safety constraints during the learning and or deployment processes. We categorize and analyze two approaches of Safe Reinforcement Learning. The first is based on the modification of the optimality criterion, the classic discounted finite infinite horizon, with a safety factor. The second is based on the modification of the exploration process through the incorporation of external knowledge or the guidance of a risk metric. We use the proposed classification to survey the existing literature, as well as suggesting future directions for Safe Reinforcement Learning.",
"role": "user"
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"content": "Safe Reinforcement Learning tries to ensure reasonable system performance and or respect safety constraints during the learning and or deployment processes [1] . Roughly, there are two ways of doing safe RL: some methods adapt the optimality criterion, while others adapt the exploration mechanism. Our work uses continuous action guidance of lookahead search with MCTS for better exploration.",
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science.scientific_papers_summarization_single_doc_arxiv | science.scientific_papers_summarization_single_doc_arxiv.201860 | [
{
"content": "Write an abstract for the research paper below. Your response should only include the abstract and no additional text.\n\nArticle text:\nquasar absorption line systems with strong lyman-@xmath0 lines are often divided into two classes : damped lyman-@xmath0 ( dlas , log n@xmath3@xmath8 20.3 ) and sub - damped lyman-@xmath0 ( sub - dla 19 @xmath9 log n@xmath3@xmath10 20.3 , @xcite ) which contain a major fraction of the neutral gas in the universe , while the majority of the baryons are thought to lie in the highly ionized and diffuse lyman-@xmath0 forest clouds with log n@xmath3@xmath9 15 in intergalactic space @xcite .\nthe lower threshold of log n@xmath3=20.3 for classification of dlas stems from previous 21 cm emission studies of nearby spirals , where the sensitivity limited column density of log n@[email protected] was seen to lie near the holmberg radius ( r@xmath11 ) of the galaxy @xcite .\nnonetheless , the damping wings which can be used to accurately measure n@xmath3 in these systems do begin the sub - dla regime of log n@[email protected] . with their high gas content , the dla and sub - dla systems\nare believed to be associated directly with galaxies at all redshifts in which they are seen . among the many elements often detected in qso absorber systems including c , n , o , mg , si , s , ca , ti , cr , mn , fe , ni , and zn , zn is the preferred tracer of the gas - phase metallicity as it is relatively undepleted in the galactic ism , especially when the fraction of h in molecular form is low , as is the case in most dlas .\nzn also tracks the fe abundance in galactic stars ( e.g. , @xcite ) , and the lines of zn ii @xmath132026,2062 are relatively weak and typically unsaturated . these lines can be covered with ground based spectroscopy over a wide range of redshifts , 0.65 @xmath9 z @xmath9 3.5 , which covers a large portion ( @xmath14 ) of the history of the universe .\nabundances of refractory elements such as cr and fe relative to zn also give a measure of the amount of dust depletion @xcite .\nabundance ratios such as [ si / fe ] , [ o / fe ] and [ mn / fe ] shed light on the enrichment from the different types of supernovae , as the @xmath0-capture elements si and o for example are produces mainly in type ii explosions while the iron peak elements are produced mainly by type ia supernovae . in previous studies ,\ndla systems have been the preferred systems for chemical abundance investigation owing to their high gas content @xcite .\nmost dlas however have been found to be metal poor , typically far below the solar level and below where models predict the mean metallicity should be at the corresponding redshifts at which they are seen ( e.g. , @xcite and references therein ) .\nthe sub - dla systems have until recently been largely ignored , with their contribution to the overall metal budget unknown .\nevidence for the possibility of a non - negligible contribution from sub - dlas to the metal budget came from @xcite , who noted that based on fe ii lines the sub - dla systems have faster evolution of the fe abundance and higher abundances on average than dla systems .\nthis has also been validated by @xcite .\ngalactic chemical evolution is a slow process , and long timescales must be examined to search for the signs of the gradual chemical enrichment that models predict @xcite . although redshifts @xmath15 span 70@xmath16 of the age of the universe ( using a concordance cosmology of @xmath17 , h@xmath18=70 km s@xmath19mpc@xmath19 ) , few observations have been made of @xmath15 sub - dlas due to the lack of spectrographs with enough sensitivity in short wavelengths and the paucity of known sub - dlas in this redshift range .\nwith such a large fraction of the age of the universe covered in the redshift regime , it is clearly important for understanding the nature of sub - dla systems and galactic chemical evolution as well .\nwe have greatly increased the sample of sub - dlas in past several years with our vlt uves and magellan - ii mike spectra . in this paper\n, we report on ten new systems observed with the mike spectrograph on the magellan - ii clay telescope .\nthe structure of this paper is as follows : in @xmath20 [ sec : obs ] , we discuss details of our observations and data reduction techniques . @xmath20\n[ sec : objects ] gives details on the individual objects in these new observations .\n@xmath20 [ sec : mnfe ] investigates the ratio of [ mn / fe ] in qso absorbers . in @xmath20\n[ sec : abund ] we discuss the abundances of these absorbers and we give a brief discussion .\nwe also provide an appendix at the end of this paper , showing plots of the uv spectra with the fits to the lyman-@xmath0 lines , and tables containing the fit parameters for the individual systems .\nthe observations presented here were made with the 6.5 m magellan - ii clay telescope and the magellan inamori kyocera echelle ( mike ) spectrograph @xcite in 2007 sep .\nthis is a double sided spectrograph with both a blue and a red camera , providing for simultaneous wavelength coverage from @xmath73340 to @xmath79400 .\ntargets were observed in multiple exposures of 1800 to 2700 sec each to minimize cosmic ray defects .\nthe seeing was typically @xmath10 1@xmath21 , averaging @xmath7 0.7@xmath21 .\nall of the target qsos were observed with the 1@xmath21x5@xmath21 slit and the spectra were binned 2x3 ( spatial by spectral ) during readout .\nthe resolving power of the mike spectrograph is @xmath719,000 and @xmath725,000 on the red and blue sides respectively with a 1@xmath21 slit .\ntable 1 gives a summary of the observations .\nthese spectra were reduced using the mike pipeline reduction code in idl developed by s. burles , j. x. prochaska , and r. bernstein .\nwavelengths were calibrated using a th - ar comparison lamp taken after each exposure .\nthe data were first bias subtracted from the overscan region and flat - fielded .\nthe data were then sky - subtracted and the spectral orders were extracted using the traces from flat field images .\nthese extracted spectra were then corrected for heliocentric velocities and converted to vacuum wavelengths .\neach individual order was then combined in iraf using rejection parameters to reduce the effects of cosmic rays .\nthese combined spectra were then normalized using a polynomial , typically of order five or less , or spline function to fit the continuum .\nour new observations consists of 10 absorbers , nine sub - dlas and one dla z@xmath22@xmath9 1.5 .\nsee @xcite for a discussion of our selection criteria . throughout this paper\nthe qso names are given in j2000 coordinates , except in table 1 where the original name , based on j1950 coordinates is also given if applicable @xcite .",
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},
{
"content": "the damped and sub - damped lyman-@xmath0(dla and sub - dla ) systems seen in the spectra of qsos offer a unique way to study the interstellar medium of high redshift galaxies . in this paper \n we report on new abundance determinations in a sample of 10 new systems , nine of the lesser studied sub - dlas and one dla , along the line of sight to seven qsos from spectra taken with the mike spectrograph . \n lines of mg i , mg ii , al ii , al iii , ca ii , mn ii , fe ii , and zn ii were detected . here , we give the column densities and equivalent widths of the observed absorption lines , as well as the abundances determined for these systems . \n zn , a relatively undepleted element in the local interstellar medium ( ism ) is detected in one system with a high metallicity of [ zn / h][email protected] . \n in one other system , a high abundance based on the more depleted element fe is seen with [ fe / h]=@xmath2 , although zn is not detected . \n the n@xmath3-weighted mean metallicity of these sub - dla systems based on fe is @xmath4[fe / h]@xmath5=@xmath6 , nearly @xmath70.7 dex higher ( a factor of 5 ) than what is seen in dlas in this redshift range . \n the relative abundance of [ mn / fe ] is also investigated . \n a clear trend is visible for these systems as well as systems from the literature , with [ mn / fe ] increasing with increasing metallicity in good agreement with with milky way stellar abundances . \n [ firstpage ] quasars : absorption lines - ism : abundances",
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science.covidfact_entailment | science.covidfact_entailment.919 | [
{
"content": "Evaluate the following claim concerning COVID-19 using the provided research abstract. Your goal is to determine the relationship between the claim and the abstract content.\n\n- \"verdict\": Decide if the abstract supports or contradicts the claim.\n- \"evidence\": List sentences from the abstract that justify your decision.\n\nClaim: Genome-wide crispr screen reveals two genes that regulate sars-cov-2 infection\n\nResearch Abstract:\nIdentification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis.\nHere we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway.\nSmall molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death.\nWe also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication.\nIn contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death.\nTogether this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.",
"role": "user"
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"content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-\\u03b2 signaling pathway.\"]}",
"role": "assistant"
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science.data_reco_mcq_sc | science.data_reco_mcq_sc.8929 | [
{
"content": "Explore the following research question and associated terms. Identify the most suitable dataset from the list provided. Use the dataset descriptions to guide your choice.\n\nInquiry: I want to train a fully supervised model for multi-label classification.\n\nKeywords: multi-label classification images\n\nDataset Information:\nMelinda: Introduces a new dataset, MELINDA, for Multimodal biomEdicaL experImeNt methoD clAssification. The dataset is collected in a fully automated distant supervision manner, where the labels are obtained from an existing curated database, and the actual contents are extracted from papers associated with each of the records in the database.\nCOCO: The MS COCO (Microsoft Common Objects in Context) dataset is a large-scale object detection, segmentation, key-point detection, and captioning dataset. The dataset consists of 328K images.\nConvAI2: The ConvAI2 NeurIPS competition aimed at finding approaches to creating high-quality dialogue agents capable of meaningful open domain conversation. The ConvAI2 dataset for training models is based on the PERSONA-CHAT dataset.\nNYU-VP: NYU-VP is a new dataset for multi-model fitting, vanishing point (VP) estimation in this case. Each image is annotated with up to eight vanishing points, and pre-extracted line segments are provided which act as data points for a robust estimator.\n\nAvailable Datasets: A: Melinda B: COCO C: ConvAI2 D: NYU-VP",
"role": "user"
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{
"content": "COCO",
"role": "assistant"
}
]
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science.pico_ner | science.pico_ner.2715 | [
{
"content": "Examine the following abstract and identify distinct entities. Focus on extracting entities related to participants, interventions, and outcomes.\n\nPresent your findings in a JSON format like: {\"Participant\": [\"example entity\", ...], \"Intervention\": [\"example entity\", ...], \"Outcome\": [\"example entity\", ...]}. If no entities are found for a category, use an empty list.\n\nAbstract Content:\n\nManuka honey-impregnated dressings in the treatment of neuropathic diabetic foot ulcers . In this study , we investigate the effect of manuka honey-impregnated dressings ( MHID ) on the healing of neuropathic diabetic foot ulcers ( NDFU ) . A total of 63 Caucasians , type 2 diabetic patients followed up in the diabetic foot outpatient clinic comprised the study population . Patients were randomised in two groups as follows : group I patients were treated with MHID and group II patients were treated with conventional dressings ( CD ) . The patients were followed up on a weekly basis for 16 weeks . Mean healing time was 31 ± 4 days in group I versus 43 ± 3 days in group II ( P < 0·05 ) . In group I patients 78·13 % of ulcers became sterile during the first week versus 35·5 % in group II patients ; the corresponding percentages for weeks 2 , 4 and 6 were 15·62 % versus 38·7 % , 6·25 % versus 12·9 % and 0 % versus 12·9 % respectively . The percent of ulcers healed did not differ significantly between groups ( 97 % for MHID and 90 % for CD ) . MHID represent an effective treatment for NDFU leading to a significant reduction in the time of healing and rapid disinfection of ulcers .",
"role": "user"
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"content": "{\"Intervention\": [\"conventional dressings ( CD )\", \"Manuka honey-impregnated dressings\", \"MHID\", \"manuka honey-impregnated dressings ( MHID )\", \".\"], \"Outcome\": [], \"Participant\": [\"neuropathic diabetic foot ulcers .\", \"type 2 diabetic patients\", \"63 Caucasians\", \"healing of neuropathic diabetic foot ulcers ( NDFU )\"]}",
"role": "assistant"
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science.genia_ner | science.genia_ner.1171 | [
{
"content": "Analyze the provided text excerpt from a scientific document. Identify and extract distinct entities based on predefined categories.\n\nDeliver the results as a JSON structure where each key represents an entity category, and the associated value is a list of identified entities. If no entities are found for a category, return an empty list.\n\nText Excerpt:\n\nHuman neutrophil elastase proteolytically activates the platelet integrin alphaIIbbeta3 through cleavage of the carboxyl terminus of the alphaIIb subunit heavy chain. Involvement in the potentiation of platelet aggregation. Neutrophil elastase (NE) and cathepsin G are two serine proteinases released concomitantly by stimulated polymorphonuclear neutrophils. We previously demonstrated that while NE by itself does not activate human platelets, it strongly enhances the weak aggregation induced by a threshold concentration of cathepsin G (threshold of cathepsin G) (Renesto, P., and Chignard, M. (1993) Blood 82, 139-144). The aim of this study was to delineate the molecular mechanisms involved in this potentiation process. Two main pieces of data prompted us to focus on the activation of the platelet fibrinogen receptor, the alphaIIbbeta3 integrin. First, previous studies have shown this integrin to be particularly prone to proteolytic regulation of its function. Second, we found that the potentiating activity of NE on the threshold of cathepsin G-induced platelet aggregation was strictly dependent on the presence of exogenous fibrinogen. Using flow cytometry analysis, NE was shown to trigger a time-dependent binding of PAC-1 and AP-5, two monoclonal antibodies specific for the activated and ligand-occupied conformers of alphaIIbbeta3. Furthermore, the potentiated aggregation was shown to result from an increased capacity of platelets to bind fibrinogen. Indeed, the combination of NE and threshold of cathepsin G increased the binding of PAC-1 approximately 5. 5-fold over basal values measured on nontreated platelets, whereas this binding raised only by approximately 3-fold in threshold of cathepsin G-stimulated platelets (p < 0. 05). By contrast, phosphatidic acid accumulation, pleckstrin phosphorylation, and calcium mobilization produced by the combination of NE and threshold of cathepsin G were not significantly different from those measured with threshold of cathepsin G alone (p > 0. 05), indicating that the phospholipase C / protein kinase C pathway is not involved in the potentiation of aggregation. The foregoing data, as well as the requirement of catalytically active NE to trigger alphaIIbbeta3 activation and potentiate threshold of cathepsin G-initiated platelet aggregation, led us to examine whether the structure of this integrin was affected by NE. Immunoblot and flow cytometry analysis revealed a limited proteolysis of the carboxyl terminus of the alphaIIb subunit heavy chain (alphaIIbH), as judged by the disappearance of the epitope for the monoclonal antibody PMI-1. Mass spectrometry studies performed on a synthetic peptide mapping over the cleavage domain of alphaIIbH predicted the site of proteolysis as located between Val837 and Asp838. Treatment by NE of ATP-depleted platelets or Chinese hamster ovary cells expressing human recombinant alphaIIbbeta3 clearly established that activation of the integrin was independent of signal transduction events and was concomitant with the proteolysis of alphaIIbH.",
"role": "user"
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"content": "{\"CellLine\": [\"Chinese hamster ovary cells\"], \"CellType\": [\"polymorphonuclear neutrophils\", \"human platelets\", \"ATP - depleted platelets\", \"nontreated platelets\", \"cathepsin G - stimulated platelets\"], \"DNA\": [], \"Protein\": [\"/ protein kinase C\", \"alphaIIbbeta3\", \"Human neutrophil elastase\", \"cathepsin G -\", \"serine proteinases\", \"exogenous fibrinogen\", \"monoclonal antibodies\", \"platelet integrin\", \"phospholipase C\", \"alphaIIbbeta3 integrin\", \"monoclonal antibody PMI - 1\", \"cathepsin G\", \"carboxyl terminus\", \"Neutrophil elastase\", \"PAC - 1\", \"alphaIIbH\", \"platelet fibrinogen receptor\", \"cleavage domain\", \"integrin\", \"human recombinant alphaIIbbeta3\", \"NE\", \"AP - 5\", \"alphaIIb subunit heavy chain\"], \"RNA\": []}",
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science.scitldr_aic | science.scitldr_aic.1058 | [
{
"content": "Review the provided sections from a computer science paper and distill the primary contribution into a single sentence. Provide only the summary sentence.\n\nSections:\n\nWe propose a new method for training neural networks online in a bandit setting.\nSimilar to prior work, we model the uncertainty only in the last layer of the network, treating the rest of the network as a feature extractor.\nThis allows us to successfully balance between exploration and exploitation due to the efficient, closed-form uncertainty estimates available for linear models.\nTo train the rest of the network, we take advantage of the posterior we have over the last layer, optimizing over all values in the last layer distribution weighted by probability.\nWe derive a closed form, differential approximation to this objective and show empirically over various models and datasets that training the rest of the network in this fashion leads to both better online and offline performance when compared to other methods.\nApplying machine learning models to real world applications almost always involves deploying systems in dynamic, non-stationary environments.\nThis dilemma requires models to be constantly re-updated with new data in order to maintain a similar model performance across time.\nOf course, doing this usually requires the new data to be relabeled, which can be expensive or in some cases, impossible.\nIn many situations, this new labeled data can be cheaply acquired by utilizing feedback from the user, where the feedback/reward indicates the quality of the action taken by the model for the given input.\nSince the inputs are assumed independent, this task can be framed in the contextual bandit setting.\nLearning in this setting requires a balance between exploring uncertain actions (where we risk performing sub optimal actions) and exploiting actions the model is confident will lead to high reward (where we risk missing out on discovering better actions).Methods\nbased on Thompson sampling (TS) or Upper Confidence Bounds (UCB) provide theoretically BID1 BID0 and empirically established ways BID12 BID3 for balancing exploration/exploitation in this setting. Unfortunately\n, both methods require estimation of model uncertainty. While this can\nbe done easily for most linear models, it is a difficult and open problem for large neural network models underlying many modern machine learning systems. An empirical study\nby BID17 shows that having good uncertainty estimates is vital for neural networks learning in a bandit setting. Closed formed uncertainty\nestimations (and online update formulas) are available for many linear models. Since the last layer of many\nneural networks are usually (generalized) linear models, a straightforward way for learning neural networks in a bandit setting is to estimate the uncertainty (as a distribution over weights) on the last layer only, holding the previous layers fixed as feature functions which provide inputs to the linear model. This method (and variants thereof\n) has been proposed in bandit settings BID17 BID13 as well as other related settings (Snoek et al., 2015; BID16 BID11 and has been shown to work surprisingly well considering its simplicity. This style of methods, which we\nrefer to as Bayesian last layer or BLL methods, also has the advantage of being both relatively model-agnostic and scalable to large models. Of course, BLL methods come with\nthe tacit assumption that the feature functions defined by the rest of the network output good (linearly separable) representations of our inputs. This means that, unless the input\ndata distribution is relatively static, the rest of the network will need to be updated in regular intervals to maintain low regret.In order to maintain low regret, the retraining objective must: 1) allow new data to be incorporated\nquickly into the learned model, and 2) prevent previously learned information\nfrom being quickly forgotten. Previous papers retrain BLL methods simply\nby sampling minibatches from the entire pool of previously seen data and maximizing log-likelihood over these minibatches, which fails to meet the first criteria above.In this paper we present a new retraining objective for BLL methods meeting both requirements. We avoid retraining the last layer with the\nentire network (throwing out the uncertainty information we learned about the last layer) or retraining with the last layer fixed (fixing the last layer to the mean of its distribution). Instead, we utilize the uncertainty information\ngathered about the last layer, and optimize the expected log-likelihood of both new and old data, marginalizing 1 over the entire distribution we have on the last layer. This gives a more robust model that performs relatively\nwell over all likely values of the last layer. While this objective cannot be exactly computed, we derive\na closed form, differentiable, approximation. We show that this approximation meets both criteria above,\nwith a likelihood term to maximize that depends only on the new data (meeting the first point), and a quadratic regularization term that is computed only with previously seen data (meeting the second point). We show empirically that this method improves regret on the\nmost difficult bandit tasks studied in BID17 . We additionally test the method on a large state-of-the-art\nrecurrent model, creating a bandit task out of a paraphrasing dataset. Finally, we test the method on convolutional models, constructing\na bandit task from a benchmark image classification dataset. We show that our method is fast to adapt to new data without quickly\nforgetting previous information.\nAs previously done in BID17 , we use a two layer MLP as the underlying model, using the same configuration across all methods.\nFor Marginalize and Sample New, we perform the retraining after 1000 rounds.\nFor Sample All we update after 100 rounds just like BID17 .\nIn Table 1 we report the average cumulative regret as well as the cumulative regret relative to a policy that selects arms uniformly at random.\nWe report the results for both Thompson Sampling (TS) and for UCB policies.\nResults are similar for either UCB and TS which shows that policies does not influence performance of the training mechanisms.On most of the tasks both Marginalize (our method) and Sample New outperforms Sample All (method used in BID17 ) in terms of cumulative regret.\nBoth Marginalize and Sample New techniques are very similar in performance for the three datasets.\nAll the three datasets used in this experiment are low dimensional, static, and relatively easy to learn, hence there is not much history to retain for Sample New technique.\nIn the next section we will present results on larger datasets and also evaluate where we will show that our method performs better than Sample New.\nIn TAB2 we show that our method Marginalize outperforms both Sample All and Sample New techniques for both multiclass and pool based tasks.\nSample All and Sample New have comparable cumulative regret.\nSample New has worse offline accuracy on Quora dataset (because it forgets old information), while it has better offline accuracy on MSR (because it is able to adapt quicker).\nFor Batch train, both multiclass and pool based tasks are same-a binary classification problem.\nBatch train performs only slightly better than our method in terms of offline accuracy, where Batch train gets full feedback, while our method only gets partial (bandit) feedback.\nFIG1 further shows that when the data distribution changes (switching form Quora to MSR in the pool based task) Marginalize and Sample New are able to adapt much faster than Sample All.\nOverall Marginalize achieved a lower regret as well as higher offline accuracy for both the bandit settings.\nIn Table 3 we present results for the image classification bandit task, using average cumulative regret and offline accuracy as evaluation metrics.\nAgain, Sample New performs better than Sample All for cumulative regret but under-performs in the offline setting.\nAs expected, our method performs well for both cumulative regret and offline setting.\nFor the multiclass task, our method performs significantly lower than batch train.\nThis is not too surprising, for two reasons:\ni) Training a CNN architecture takes many more epochs over the data to converge (∼ 20 in our case) which is not achieved in a bandit setting;\nii) CIFAR-10 has 10 classes, each defining an arm and in our setting; the bandit algorithms only gets feedback for one class in each round, compared to the full feedback received in batch train.\nEffectively, the number of labels per class in cut by a factor of 10.\nThis is not as much an issue in the pool task, where we can see the results between batch train and the bandit algorithms are comparable.\nIn this paper we proposed a new method for training neural networks in a bandit setting.\nWe tackle the problem of exploration-exploitation by estimating uncertainty only in the last layer, allowing the method to scale to large state-of-the-art models.\nWe take advantage of having a posterior over the last layer weights by optimizing the rest of the network over all values of the last layer.\nWe show that method outperforms other methods across a diverse set of underlying models, especially in online tasks where the distribution shifts rapidly.\nWe leave it as future work to investigate more sophisticated methods for determining when to retrain the network, how to set the weight (β) of the regularization term in a more automatic way, and its possible connections to methods used for continual learning.",
"role": "user"
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"content": "This paper proposes a new method for neural network learning in online bandit settings by marginalizing over the last layer",
"role": "assistant"
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science.data_reco_mcq_sc | science.data_reco_mcq_sc.11673 | [
{
"content": "Explore the following research question and associated terms. Identify the most suitable dataset from the list provided. Use the dataset descriptions to guide your choice.\n\nInquiry: A new approach for video captioning by incorporating temporal contextual knowledge.\n\nKeywords: video captioning\n\nDataset Information:\nKnowIT VQA: KnowIT VQA is a video dataset with 24,282 human-generated question-answer pairs about The Big Bang Theory. The dataset combines visual, textual and temporal coherence reasoning together with knowledge-based questions, which need of the experience obtained from the viewing of the series to be answered.\nDPC-Captions: This is an open-source image captions dataset for the aesthetic evaluation of images. The dataset is called DPC-Captions, which contains comments of up to five aesthetic attributes of one image through knowledge transfer from a full-annotated small-scale dataset.\nCOCO: The MS COCO (Microsoft Common Objects in Context) dataset is a large-scale object detection, segmentation, key-point detection, and captioning dataset. The dataset consists of 328K images.\nDuoRC: DuoRC contains 186,089 unique question-answer pairs created from a collection of 7680 pairs of movie plots where each pair in the collection reflects two versions of the same movie. Why another RC dataset?\n\nAvailable Datasets: A: KnowIT VQA B: DPC-Captions C: COCO D: DuoRC",
"role": "user"
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{
"content": "COCO",
"role": "assistant"
}
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science.mslr2022_ms2_multidoc_summarization | science.mslr2022_ms2_multidoc_summarization.13519 | [
{
"content": "Analyze the following collection of medical RCT summaries. Your goal is to craft a concise synthesis of the findings. Focus on the core insights and present them succinctly. Only include the synthesis in your response. Below are the RCT summaries:\n\n\n\nReport 1:\nTitle: Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation.\nSummary: INTRODUCTION This 7-year , prospect i ve , matched-cohort , clinical study evaluated the effects of intramuscular depot medroxyprogesterone acetate ( DMPA ) ( 150 mg/mL ) on bone mineral density ( BMD ) in women aged 25 - 35 years . METHODS Bone mineral density changes in new DMPA-IM users ( n=248 ) were compared with those in women using nonhormonal contraception ( n=360 ) for up to 240 weeks of treatment and 96 weeks of posttreatment follow-up ( in subjects receiving > or=1 dose ) . RESULTS At week 240 of treatment , mean percentage changes from baseline in DMPA-IM vs. nonhormonal subjects were : -5.16 % ( n=21 ) vs. + 0.19 % ( n=65 ) , total hip ( p<.001 ) ; -5.38 % ( n=33 ) vs. + 0.43 % ( n=105 ) , lumbar spine ( p<.001 ) . At week 96 posttreatment , these values were : -0.20 % ( n=25 ) vs. + 0.84 % ( n=43 ) , total hip ( p=.047 ) ; -1.19 % ( n=41 ) vs. + 0.47 % ( n=66 ) , lumbar spine ( p=.017 ) . CONCLUSIONS These results show BMD declines during DMPA-IM use ; following discontinuation , significant increases in BMD occur through 96 weeks posttreatment\n\n\nReport 2:\nTitle: A randomized, single blind comparative trial of norethindrone enanthate and depo-medroxyprogesterone acetate in Bangladesh.\nSummary: A r and omized , single blind comparative trial of norethindrone enanthate ( NET-ENT ) and depo-medroxyprogesterone acetate ( DMPA ) was conducted in the Model Clinic , Decca , Bangladesh , to determine if there were differences in reported side effects , reasons for discontinuation and discontinuation rates of these two injectables . On all follow-up visits the proportion of women reporting no bleeding ( amenorrhea ) was higher for the DMPA clients compared to the NET-ENT clients . Concurrent with these findings , the proportion of women reporting irregular bleeding was consistently higher for the NET-ENT clients . Concurrent with these findings , the proportion of women reporting irregular bleeding was consistently higher for the NET-ENT clients compared to those receiving DMPA . By the fourth injection , less than 15 % of the clients in both drug groups still reported having regular cyclic bleeding ( 4 of the 26 DMPA clients and 4 of the 28 NET-ENT clients ) . Five of the 133 women on DMPA and 6 of the 106 women on NET-ENT became pregnant while using the injectables . At the end of one year of follow-up , 14 of the 133 DMPA and 14 of the 106 NET-ENT clients were still continuing ( came back for a fifth injection )\n\n\nReport 3:\nTitle: Multinational comparative clinical trial of long-acting injectable contraceptives: norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report.\nSummary: Final results are presented from a two-year WHO multinational comparative trial of three regimens : depot-medroxyprogesterone acetate ( DMPA ) given at 90-day intervals , norethisterone enanthate ( NET-EN ) given at 60-day intervals for the entire study period ( NET-EN ( 60-day ) ) , and NET-EN given at 60-day intervals for six months and thereafter at 84-day intervals ( NET-EN ( 84-day ) ) . 1587 DMPA subjects were observed for 20,550 woman-months , 789 NET-EN ( 60-day ) subjects were observed for 10,361 woman-months , and 796 NET-EN ( 84-day ) subjects were observed for 10,331 woman-months . This clinical trial represents the largest clinical trial undertaken on injectable contraceptives . After two years , the pregnancy rate with NET-EN ( 84-day ) was 1.4 ( + /- 0.6 S.E. ) per 100 women , as compared with the two-year rates of 0.4 ( + /- 0.3 S.E. ) per 100 women observed with DMPA and 0.4 ( + /- 0.2 S.E. ) with NET-EN ( 60-day ) . Both discontinuation rates for amenorrhea and the prevalence of amenorrhea lasting more than 90 days were significantly higher with DMPA than with either NET-EN regimen . Terminations for bleeding problems were similar with the three treatments , despite a better cyclic pattern for the first six months with the NET-EN regimens . The three treatments were comparable with respect to discontinuation rates for other medical or personal reasons , and for all reasons combined . For family planning programs , NET-EN ( 60-day ) has the advantage of low pregnancy rates compared to NET-EN ( 84-day ) , and a schedule of administration that does not change . Both NET-EN regimens produce less amenorrhea than DMPA . However , the NET-EN ( 60-day ) regimen has the logistic and economic disadvantage of requiring more frequent injections . All three injectable regimens compare favourably with oral contraceptives in terms of pregnancy and total continuation rates observed in clinical trial setting\n\n\nReport 4:\nTitle: Changes in bleeding patterns with depot medroxyprogesterone acetate subcutaneous injection 104 mg.\nSummary: OBJECTIVE This study aims to assess changes in bleeding patterns with the use of depot medroxyprogesterone acetate ( DMPA ) 104 mg/0.65 ml subcutaneous injection ( DMPA-SC 104 ) . STUDY DESIGN An analysis was conducted using data from two 1-year , noncomparative clinical trials ( N=1787 ) and a 2-year r and omized study comparing DMPA-SC 104 ( N=266 ) with DMPA intramuscular injection ( DMPA-IM ) . Bleeding was analyzed per 30-day interval by category and number of days . Analyses also were performed for age and body mass index ( BMI ) subgroups and for the percentages of women shifting from bleeding/spotting to amenorrhea after each injection . RESULTS Each study showed decreased incidence of irregular bleeding and increased amenorrhea with continued use of DMPA-SC 104 . Rates of amenorrhea at Month 12 ( 52 - 64 % across studies ) and Month 24 ( 71 % in the 2-year trial ) were comparable with those originally reported for DMPA-IM . Changes in bleeding patterns showed no consistent differences according to age or BMI . The percentages of subjects shifting from bleeding and /or spotting to amenorrhea increased with each subsequent injection . CONCLUSION Clinical data show that the incidence of amenorrhea increases over time with the use of DMPA-SC 104\n\n\nReport 5:\nTitle: Acceptability study of the two versus three monthly injectable contraceptives.\nSummary: The acceptability of 2 and 3 month injectable contraceptives was assessed and compared , and the acceptability of the injectables was further compared with that of oral contraceptives ( OCs ) and IUDs among a r and om sample of women , who attended a clinic in Alex and ria , Egypt . The study was conducted by the University of Alex and ria . The sample included 100 acceptors of the 2-month injectable , norethisterone oenanthate ( NET-O EN ) , 100 acceptors of the 3-month injectable , depo-medroxy pregesterone acetate ( DPMA ) , 60 OC acceptors , and 60 IUD acceptors . The women were interviewed prior to treatment and 2 or 3 times during the 6 months following their initial acceptance of the methods . Women who discontinued at any time during the 6-month period were interviewed concerning their reasons for discontinuing . The data was analyzed by calculating means and % distribution and by testing for significance . The percent lost to follow up was 12 % for the NET-O EN group , 12 % for DPMA users , and 0 % for IUD and OC acceptors . The mean age of the acceptors was 30.4 years for NET-O EN , 30.7 years for DMPA , 28.3 years for OCs , and 25.2 years for IUDs . For these acceptor groups , the respective mean number of years of schooling was 6.1 , 5.2 , 7.2 , and 7.5 , and the respective mean number of pregnancies was 5.6 , 5.4 , 3.8 , and 2.9 . All 320 of the women were married , and 319 were Muslim . 99.4 % lived in urban areas . 10 % had no living male children , and 23.7 % had no living female children . 2/3 of the injectable acceptors previously used 2 or more fertility control methods . A higher percent of IUD and OC acceptors , compared to injectable acceptors , reported using only 1 or no previous method . More than 1/2 of the injectable acceptors reported disruptions in their normal bleeding patterns . NET-O EN acceptors were more likely to experience heavy or prolonged bleeding while DPMA acceptors were more likely to report amenorrhea or a decreased flow . IUD acceptors were also bothered by bleeding problems . Almost all the women who reported changes in bleeding patterns were unhappy about the changes . Many of the women who reported amenorrhea worried that they might be pregnant . Women who experienced heavy or unpredictable bleeding worried about anemia and complained that bleeding interfered with their daily routines . 47.6 % of the women reported weight gains , but this was generally viewed as an advantage . Nausea was the major side effect associated with OC use . 32 % of the OC users , 28.0 % of the NET-E ON users , 30.0 % of the DMPA users , and none of the IUD users reported nausea . For all 4 groups , convenience and effectiveness were the major advantages the women attributed to their chosen method . Continuation rates were 68 % for NET-O EN , 70 % for DMPA , 75 % for OCs , and 75 % for IUDs . The major reason for discontinuation of injectables was bleeding problems . Among injectable users , a higher proportion of discontinuers ( 49 % ) than of continuers ( 20 % ) reported amenorrhea . The findings suggest that continuation for injectables could be improved if patients were given more detailed information about possible side effects and if they were advised to return to the clinic for treatment of any symptoms they experience\n\n\nReport 6:\nTitle: Acceptability of injectable contraceptives in Assiut, Egypt.\nSummary: The present work was a r and omized comparative study of two injectable progestogen-only contraceptives . The first group ( 200 subjects ) received 150 mg of depotmedroxyprogesterone acetate ( Depoprovera ) every 84 + /- 7 days and the second ( 200 subjects ) received 200 mg of norethisterone enanthate ( Noristerat ) every 56 + /- 7 days . Acceptors of injectable contraceptives in Assiut , Egypt , were mainly women looking for fertility termination . Menstrual disruption was the main side effect among both treatment groups . Amenorrhoea was the commonest menstrual complaint and was the main reason for discontinuation in both groups . Only one pregnancy occurred during NET-EN use ; two more pregnancies occurred , one in each of the two groups but there were indications that conception preceded the first injection . Menstrual irregularities were generally more frequent with DMPA users . However , DMPA had better one-year continuation rates than NET-EN ( 68.8 + /- 3.5 and 57.1 + /- 3.6 per 100 women , respectively )",
"role": "user"
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"content": "While the choice between DPMA and NET-EN as injectable progestogen contraceptives may vary between both health providers and patients , data from r and omized controlled trials indicate little difference between the effects of these methods , except that women on DMPA are more likely to develop amenorrhoea .\nThere is inadequate data to detect differences in some non-menstrual major and minor clinical effects",
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science.scientific_papers_summarization_single_doc_pubmed | science.scientific_papers_summarization_single_doc_pubmed.11026 | [
{
"content": "Read the provided biomedical research paper and create a concise abstract. Ensure the abstract captures the main points of the paper.\n\nFull Paper:\nmetastasis to the bone is a common complication of breast , lung , prostate , gastrointestinal , haematological , melanoma , and other tumours , , . in many patients with primary breast ,\nprostate and lung primary tumours , bone metastases ( bom ) are signs associated with the presence of disseminated disease .\nthese metastases to the bone will usually result in patients experiencing pain which is often palliated using single fraction radiotherapy ( sfrt ) or multiple fraction radiotherapy ( mfrt ) depending on the factors such as cancer type and presence of complication within the bone , , , .\nalthough the distribution of bom have been observed in many skeletal locations , bom that are distal to the elbow and knee joints are considered rare and therefore are infrequently reported .\ndepending on the primary tumour histopathology , the frequency of skeletal bone metastases ranges from 10% to close to 90% and bone lesions are found more commonly within the axial skeletal versus the appendicular skeleton . although any skeletal bone may be involved with metastatic disease , the vertebral body is most commonly associated with metastatic disease ; long bone involvement or metastases distal to the elbow and knee are rare , , .\nthis study sought to assess the incidence of distal bone metastases treated with radiotherapy in a provincial programme .\nall courses of rt for bone metastases from 2007 to 2011 for patients living in bc were identified in a provincial rt programme .\nthe bc cancer agency ( bcca ) information system ( cais ) was used to identify 8008 patients who received 16,277 palliative radiotherapy courses for bone metastases from 2007 to 2011 .\ninformation retrospectively collected on these patients included : patient age , gender , primary tumour histology , fractionation schedules , and location of bone metastases .\ntreated bom were categorized as distal if the bom was located within or distal to the elbow or knee .\npatients were grouped by primary tumour site as breast , lung , prostate gastrointestinal , haematological , melanoma , and other .\nmultivariable linear regression analysis was used to determine associations between primary tumour type and incidence of distal bone metastases .\np values were two - sided , and values less than.05 were considered statistically significant .\nwe used the spss statistical software package , version 19.0 ( chicago , il ) , for data entry and statistical analysis .\nfrom 2007 to 2011 , 8008 patients in bc were treated with 16 , 277 palliative radiotherapy courses ; 425 ( 3% ) of the courses prescribed were used to treat bones located within or distal to the elbow or knee .\nmale patients were treated more often than female patients ( 52% ) and sfrt was prescribed 49% of the time ( table 1 ) .\nbreast and lung malignancies were observed most commonly ( 23% ) , followed by prostate ( 19% ) , other ( 15% ) , lymphoma ( 11% ) , gastrointestinal ( 8% ) and melanoma ( 1% ) ( table 1 ) .\nwe demonstrated that melanoma malignancies resulted in the highest frequency ( 5% ) of distal bom ; followed by haematological ( 3% ) , lung ( 2% ) prostate ( 2% ) , other ( 2% ) , gastrointestinal ( 1% ) , and breast ( 1% ) .\ndistal bom where more commonly identified in the lower extremity ( 87% , p<0.001 ) .\ndistal bom were treated with sfrt significantly more often than non - distal bom ( p<0.001 ) ( fig .\n1 ) . table 2 presents the multi - variable analysis performed to determine the associations between distal bom and patient characteristics , which demonstrated that patients with melanoma have a significant higher odds of having distal bone metastases ( p=0.004 ) .\nthe regression analysis also showed significant correlation between having distal bone metastases treated at abbotsford centre ( odds ratio 2.37 , 95% confidence interval 1.543.64 , p<0.0001 ) ( table 2 ) .\nthis is the first large scale study to illustrate the incidence of distal bone metastases in patients being treated with palliative radiotherapy ( rt ) . from 2007 to 2011 , 16,277 courses of palliative rt was used to treat bone metastases in 8008 patients ; 425 ( 3% ) of which were rt courses for distal bom .\nin addition , distal bone metastases were significantly more likely to be treated with sfrt .\nthis population - based study demonstrates that patients with melanoma have the highest proportion of distal bom .\nthis differs from previous reports , which only present that prostate , breast , and lung cancer have the highest absolute number of distal bom , likely because these are the most common cancers with any type of bom , , , , .\nhere we showed that sfrt was used to treat distal bom more often than non - distal bom ( 66% versus 49% , respectively ) , likely because distal bom are located in regions that do not contain organs at risk such as the spinal cord .\na weakness of this study is that untreated bom are not captured , and therefore the incidence of distal bom may be under - represented .\nhowever , it is unlikely that the proportion of distal bom is markedly different than reported .\nin addition , the large population - based nature of this study provides adequate power to identify correlations between distal bom and primary tumour type , while being relatively free of selection bias .\nthis population based study identified an incidence of distal bom of 3% among patients treated with palliative rt .\nmb conceived of the study , participated in the data collection and statistical analysis , and designed and draughted the manuscript .\nxxx participated in the acquisition of data , analysis and interpretation of data and helped draughted the manuscript .",
"role": "user"
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"content": "purposethis study assesses the incidence of distal bone metastases in palliative radiotherapy ( rt ) patients.material and methodsall courses of rt for bone metastases from 20072011 for patient living in british columbia ( bc ) were identified in a provincial rt programme . treated bone metastases ( bom ) were categorized as distal if the bom was located within or distal to the elbow or knee . \n patients were grouped by primary tumour site as breast , lung , prostate gastrointestinal , haematological , melanoma , and other . \n the incidence of distal bone metastases and associations with primary tumour types were determined.resultsfrom 2007 to 2011 , 8008 patients were treated with 16,277 courses of rt , of which 425 ( 3% ) were courses of rt for distal bom . \n the incidence of distal bom in decreasing order by primary tumour type was melanoma ( 5% ) , haematological ( 3% ) , lung ( 2% ) , other ( 2% ) , prostate ( 2% ) , breast ( 1% ) and gastrointestinal ( 1% ) . \n distal bom where more commonly identified in the lower extremity ( 87% , p<0.001 ) . \n single fraction rt was used more commonly for distal vs non - distal bom ( 66% vs. 49% ; p<0.001).conclusionthe incidence of distal bom among patients treated with palliative rt was 3% and most commonly identified in patients with melanoma and haematological malignancies .",
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science.multixscience_multidoc_summarization | science.multixscience_multidoc_summarization.2336 | [
{
"content": "Examine the abstracts provided from a main scientific article and its cited works. Craft a narrative that synthesizes the key insights and contributions, emphasizing their interconnections. Employ numerical citations such as [1], [2], etc., to reference the cited works.\n\nMain Article Summary:\nThe 5G New Radio (NR) standard for wireless communications supports the millimetre-wave (mmWave) spectrum to yield unprecedented improvement of the access network capacity. However, intermittent blockages in the mmWave signal may degrade the system performance and lead to the under-utilisation of the allocated resources. To circumvent this problem, the transmission slot-time shall be adjusted according to the blockage condition, avoiding the resource under-utilisation. In this paper, we propose that the 5G NR flexible numerology should be applied to adapt the slot-time in order to mitigate the blockage effects. We validate this claim by analysing the expected data rate of a mmWave system, under a range of blockage scenarios. We show that different blockage scenarios may require different numerologies to produce best performance, and that the correct choice of numerology may improve this performance by as much as hundreds of Mbps. Our results carry insights important for the design of blockage-aware scheduling mechanisms for 5G.\n\nCited Works Summary:\n[1]: We explore the potential of optimizing resource allocation with flexible numerology in frequency domain and variable frame structure in time domain, with services of with different types of requirements. We prove the NP-hardness of the problem and propose a scalable optimization algorithm based on linear programming and Lagrangian duality. Numerical results show significant advantages of adopting flexibility in both time and frequency domains for capacity enhancement and meeting the requirements of mission critical services.\n\n[2]: The advent of 5G will enable further diverse types of services to be supported, some of which have different requirements from the radio access architecture such as extreme low latency, ultra-high reliability and massive connectivity. With the scarcity of the available bandwidth, careful design of radio frame structures is essential in order to efficiently support the challenging requirements of 5G. The flexible numerology design of the PHY layer frame structure is a key tool in achieving low latency and high reliability. In this paper, we present a methodology to compute the optimal numerology for a given set of requirements from the PHY layer. It is shown that during low mobility and high SNR regimes, the choice of the numerology becomes more critical than at high mobility and low SNR regimes.\n\n[3]: The 5G New Radio (NR) access technology defines multiple numerologies to support a wide range of carrier frequencies, deployment scenarios, and variety of use cases. In this paper, we consider a resource allocation problem to efficiently support multiple numerologies simultaneously. We assume frequency division multiplexing (FDM) of numerologies in a time division duplex (TDD) system with a self-contained slot format. We focus on optimizing the numerology subband (SB) configuration, as well as the duplexing ratio between downlink (DL) and uplink (UL) directions within each SB. The optimization problem minimizes the weighted sum of the normalized load (NL) for each SB in each direction. We prove that our optimization problem is convex and, furthermore, we derive the optimal closed-form expressions for the numerology SB configuration and the DL-UL duplexing ratio per SB. The effectiveness of the proposed resource allocation is validated through an end-to-end ns-3 based simulator, which shows how the optimization of the NLs is translated into an improved throughput and delay performance.\n\n[4]: In this paper, we use a New Radio (NR) simulator, based on ns-3, to assess the impact of 5G NR numerologies on the end-to-end (E2E) latencies in a realistic and complex scenario, including TCP and UDP flows. As expected, we found that TCP goodput increases with the numerology, since a larger numerology allows reducing the round-trip-time. However, although counter-intuitive, simulation results exhibit that the E2E latency of uplink (UL) UDP flows may not be reduced with the numerology. In fact, it depends on two key factors and their relationship: the processing delays (fixed or numerologydependent) and the inter-packet arrival time, which depends on the UDP flow rate and the packet size. We demonstrate how, in some cases, the latency is worsened by an increasing signaling exchange that grows with the numerology. In particular, this is due to a handshake mechanism in UL (scheduling request and UL grant) that is performed each time a data packet encounters empty RLC buffers. For some combination of flow rate, packet size, and processing delays that are not numerology dependent, increasing the numerology may not reduce the E2E delay. Therefore, we conclude that the selection of the numerology in an NR system should be carefully made by taking into account the traffic patterns and the processing delays.",
"role": "user"
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"content": "In state-of-the-art flexible numerology has been applied to improve the network latency where the TTI is optimised according to a latency deadline restriction [2] and according to the traffic pattern [4] . Also, it has been applied to improve the frame spectral efficiency when multiplexing different types of services, e.g., eMBB and URLLC [3] [1] .",
"role": "assistant"
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science.scicite_classification | science.scicite_classification.4803 | [
{
"content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nAmong the available alternatives, we have selected three well-known tools: cbmc [27], a tool based on Bounded Model Checking (BMC), CPAchecker [15], a tool based on lazy abstraction and interpolation-based refinement, and Clousot [40], a recent tool based on Abstract Interpretation.",
"role": "user"
},
{
"content": "Method",
"role": "assistant"
}
]
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