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SciRIFF-4096-0214-v2

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[ { "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 novel multi-task learning approach based on deep convolutional neural networks.\n\nKeywords: multi-task learning image video\n\nDataset Information:\nGoPro: The GoPro dataset for deblurring consists of 3,214 blurred images with the size of 1,280×720 that are divided into 2,103 training images and 1,111 test images. The dataset consists of pairs of a realistic blurry image and the corresponding ground truth shapr image that are obtained by a high-speed camera.\nCOVIDx: An open access benchmark dataset comprising of 13,975 CXR images across 13,870 patient cases, with the largest number of publicly available COVID-19 positive cases to the best of the authors' knowledge.\nWikiReading: WikiReading is a large-scale natural language understanding task and publicly-available dataset with 18 million instances. The task is to predict textual values from the structured knowledge base Wikidata by reading the text of the corresponding Wikipedia articles.\nCelebA: CelebFaces Attributes dataset contains 202,599 face images of the size 178×218 from 10,177 celebrities, each annotated with 40 binary labels indicating facial attributes like hair color, gender and age.\n\nAvailable Datasets: A: GoPro B: COVIDx C: WikiReading D: CelebA", "role": "user" }, { "content": "CelebA", "role": "assistant" } ]

[ { "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: We don't know yet whether BCG will reduce the severity of COVID-19\n\nResearch Abstract:\nThe impact of COVID-19 is changing with country wise and depend on universal immunization policies.\nCOVID-19 badly affects countries that did not have universal immunization policies or having them only for the selective population of countries (highly prominent population) like Italy, USA, UK, Netherland, etc.\nUniversal immunization of BCG can provide great protection against the COVID-19 infection because the BCG vaccine gives broad protection against respiratory infections.\nBCG vaccine induces expressions of the gene that are involved in the antiviral innate immune response against viral infections with long-term maintenance of BCG vaccine-induced cellular immunity.\nCOVID-19 cases are reported very much less in the countries with universal BCG vaccination policies such as India, Afghanistan, Nepal, Bhutan, Bangladesh, Israel, Japan, etc.\nas compared to without BCG implemented countries such as the USA, Italy, Spain, Canada, UK, etc.\nBCG vaccine provides protection for 50-60 years of immunization, so the elderly population needs to be revaccinated with BCG.\nSeveral countries started clinical trials of the BCG vaccine for health care workers and elderly people.\nBCG can be uses as a prophylactic treatment until the availability of the COVID-19 vaccine.", "role": "user" }, { "content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"Universal immunization of BCG can provide great protection against the COVID-19 infection because the BCG vaccine gives broad protection against respiratory infections.\", \"COVID-19 cases are reported very much less in the countries with universal BCG vaccination policies such as India, Afghanistan, Nepal, Bhutan, Bangladesh, Israel, Japan, etc.\", \"as compared to without BCG implemented countries such as the USA, Italy, Spain, Canada, UK, etc.\", \"BCG can be uses as a prophylactic treatment until the availability of the COVID-19 vaccine.\"]}", "role": "assistant" } ]

[ { "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 am trying to train a fully supervised model for multimodal video classification\n\nKeywords: multimodal video classification audio, visual, depth, sensor\n\nDataset Information:\nSpeakingFaces: SpeakingFaces is a publicly-available large-scale dataset developed to support multimodal machine learning research in contexts that utilize a combination of thermal, visual, and audio data streams; examples include human-computer interaction (HCI), biometric authentication, recognition systems, domain transfer, and speech recognition. SpeakingFaces is comprised of well-aligned high-resolution thermal and visual spectra image streams of fully-framed faces synchronized with audio recordings of each subject speaking approximately 100 imperative phrases.\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.\nViolin: Video-and-Language Inference is the task of joint multimodal understanding of video and text. Given a video clip with aligned subtitles as premise, paired with a natural language hypothesis based on the video content, a model needs to infer whether the hypothesis is entailed or contradicted by the given video clip.\nUCF101: UCF101 dataset is an extension of UCF50 and consists of 13,320 video clips, which are classified into 101 categories. These 101 categories can be classified into 5 types (Body motion, Human-human interactions, Human-object interactions, Playing musical instruments and Sports).\n\nAvailable Datasets: A: SpeakingFaces B: Melinda C: Violin D: UCF101", "role": "user" }, { "content": "UCF101", "role": "assistant" } ]

[ { "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\nGenetic risk factors for glucocorticoid-induced osteonecrosis: a meta-analysis. Glucocorticoid-induced osteonecrosis is a common and severe adverse event. We conducted a meta-analysis to investigate whether polymorphisms in target genes were associated with the risk of corticosteroid-induced osteonecrosis. Published literature from PubMed and EMBASE were searched for eligible publications. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model. There were 23 articles with 35 genes described the relationship between polymorphisms and glucocorticoid-induced osteonecrosis. Meta-analyses were carried out for those SNPs with three or more eligible studies, which included four SNPs located in three genes (PAI-1, MTHFR, ABCB1). The meta-analysis revealed that the PAI-1 4G allele was associated with an increased risk of osteonecrosis compared with the 5G allele (combined studies: OR=1.932, 95% CI=1.145-3.261). The OR for the 4G/4G vs. 5G/5G genotype of PAI-1 was 3.217 (95% CI 1.667-6.209 with combined studies), The relative risk of osteonecrosis was increased in the 4G allele vs. 5G/5G and 4G/4G genotype vs. 5G allele, with odds ratios of 2.304 (95% CI=1.235-4.299) and 2.307 (95% CI=1.527-3.485) in combined studies, respectively. The ABCB1 C3435T genotype distributions available confirmed that the C allele increased osteonecrosis risk compared with the T allele (OR 1.668, 95% CI=1.214-2.293) and TT genotype (OR 2.946, 95% CI=1.422-6.101). There was no evidence for significant association between MTHFR C677T and ABCB1 G2677T/A polymorphisms and risk of osteonecrosis. Results of this meta-analysis indicate that the PAI-1 4G/5G and ABCB1 C3435T polymorphisms may be risk factors for osteonecrosis.", "role": "user" }, { "content": "{\"Chemical\": []}", "role": "assistant" } ]

[ { "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: A Survey of Genomic Traces Reveals a Common Sequencing Error, RNA Editing, and DNA Editing\nContent:\nAbstract:\nWhile it is widely held that an organism's genomic information should remain constant, several protein families are known to modify it. Members of the AID/APOBEC protein family can deaminate DNA. Similarly, members of the ADAR family can deaminate RNA. Characterizing the scope of these events is challenging. Here we use large genomic data sets, such as the two billion sequences in the NCBI Trace Archive, to look for clusters of mismatches of the same type, which are a hallmark of editing events caused by APOBEC3 and ADAR. We align 603, 249, 815 traces from the NCBI trace archive to their reference genomes. In clusters of mismatches of increasing size, at least one systematic sequencing error dominates the results( G-to-A). It is still present in mismatches with 99% accuracy and only vanishes in mismatches at 99. 99% accuracy or higher. The error appears to have entered into about 1% of the HapMap, possibly affecting other users that rely on this resource. Further investigation, using stringent quality thresholds, uncovers thousands of mismatch clusters with no apparent defects in their chromatograms. These traces provide the first reported candidates of endogenous DNA editing in human, further elucidating RNA editing in human and mouse and also revealing, for the first time, extensive RNA editing in Xenopus tropicalis. We show that the NCBI Trace Archive provides a valuable resource for the investigation of the phenomena of DNA and RNA editing, as well as setting the stage for a comprehensive mapping of editing events in large-scale genomic datasets.\nIntroduction:\nWith the exception of infrequent random somatic mutations, it is widely believed that the same genomic content should be fixed in an organism throughout its lifetime. This information will also serve as a template for exact RNA copies. Proteins that can modify genomic content, nevertheless, have been identified in humans and in many other organisms. RNA editing involves alteration of particular RNA nucleotides by specifically changing Adenosine( A) into Inosine( I), which in turn is read as Guanosine( G)[1]. It is performed by the adenosine deaminase that acts on RNA( ADAR) family of deaminases[2]–[5] and this process has been implicated in several vital neurological functions[6]. A-to-I editing is known to target only RNA molecules[7] with numerous instances of editing events in the human transcriptome[8]–[12]. A different family of proteins, the AID/APOBEC family of deaminases, can edit both DNA and RNA nucleotides, specifically changing Cytosine( C) into Uracil( U)[13]. The first family member to be found and studied was the apolipoprotein B editing complex 1( APOBEC1). This protein edits the apolipoprotein B( ApoB) RNA, which is involved in lipid transport[14],[15] but APOBEC1 can also deaminate cytidine in DNA[16]. Additional members of the family were found to target DNA. Activation-induced deaminase( AID) was discovered to be vital for the antigen-driven diversification of immunoglobulin genes in the vertebrate adaptive immune system[17]–[19] and the APOBEC3s were shown to be involved in the restriction of retrovirus proliferation in primates[20],[21]. For many years, the only known human endogenous target of the APOBEC protein family was the apoB RNA transcript. In this case, editing in position 6, 666 by APOBEC1 leads to a stop codon and eventually results in two functionally distinct isoforms of apolipoprotein B( ApoB)[15],[22]. This editing reaction is mediated by the APOBEC complementation factor( ACF)[23],[24] which guides APOBEC1 to the target locus. Deamination of cytosines to uracils in DNA( DNA editing) by various APOBEC protein families is characterized, in many cases, by clusters of G-to-A mismatches between the reference genome and the edited sequence. These mismatches are the end product of deamination of “C” into “U” in the other DNA strand. Recently, it was found that APOBEC3G can serve as a potent inhibitor of a wide range of retroviruses, including endogenous retrotransposons. This protein introduces large numbers of C-to-U mutations in the minus-strand of the viral DNA, eventually leading to G-to-A mutations after plus-strand synthesis[25]–[29]. Also, it has been demonstrated that APOBEC3G is capable of editing the mouse IAP retrotransposon[30]. Little is known, however, about the frequency or localization of editing in vivo. Although editing of retrotransposons and their integration back into the genome is expected to be rare, very deep DNA sequencing can be used to identify these events. In this paper we report initial results of a novel bioinformatic approach for detection of endogenous RNA and DNA candidate sites in various organisms. We obtained 600 million sequence traces from the NCBI Trace archive. This data repository contains DNA sequence chromatograms( traces) from various large-scale capillary electrophoresis sequencing projects, base calls, and quality estimates. Next, we aligned these traces to their consensus reference genomes and searched for clusters of mismatches. Interestingly, we have found not only evidence of genuine RNA and DNA editing events but have also isolated a very common technical sequencing artifact that leads to such clusters.\nDiscussion:\nThe NCBI trace archive serves as a repository of raw data for the assembly of consensus genomes. Recently, it was utilized for a different purpose in the search for structural variation in the human genome[45]. Here, we show that it can also be used in the search for DNA and RNA editing. In the future, sequencing results deposited in the NCBI short-read archive might shed more light on these phenomena. Shorter reads, however, will pose a more challenging analysis problem. Recently, we did an initial analysis of Illumina's human resequencing reads and the SOLiD reads from the same individual. These reads are available at the NCBI short-read archive and are the basis for the first individual African consensus genome[46],[47]. Given the importance of read-length and quality scores on the outcome of our current work, the current SOLiD and Illumina reads represent interesting trade-offs for the detection of editing. While Illumina's current read lengths are generally longer than SOLiD, the latter has much higher per-base quality. Adapting the techniques presented here to this new data presents an interesting opportunity for future research. The availability of computational resources for carrying out our analyses was essential to this project, as large computational effort was needed, six terabytes of disk for intermediate data and more than five “node years” of CPU time. With further computational effort, combining existing data in the trace archive with next generation sequencing data sets from multiple sequencing platforms and chemistries, it should be possible to greatly improve genomic databases and eliminate the sequencing errors reported here. By using well-calibrated quality scores and selecting traces with clusters of consecutive mismatches, we are able to investigate the scope of RNA editing sites in human and other genomes. The application of this technique in the search for editing events will make many large EST datasets more accessible for other organisms where quality scores are available. Currently, only a very small number of organisms, with large sets of full length RNA sequences, have been the subject of large-scale editing studies. Using quality scores, many additional genomes can be surveyed for editing with the opportunity for new discoveries in this emerging field. As a demonstration of the value of using quality data for ESTs, we are able to find a large number of candidate RNA editing events in Xenopus tropicalis. This discovery makes X. tropicalis the non human organism with the largest number of known editing sites so far. Since Xenopus is already an important model organism for the research of RNA editing, this new data-set could help foster new discoveries in this field. Despite the identification of thousands of newly discovered RNA editing sites in the current work, it is reasonable to believe that the actual number of editing sites is still significantly under-estimated. Support for this assertion comes from the stringency of our parameters: including length of alignment, percentage of identity and exclusion of insertions or deletions. These choices most likely limited the subset of EST data that we analyzed. Refinement of these criteria could lead to more comprehensive detection of RNA editing levels and, due to the breadth of EST data, even permit the comparison of editing levels in different tissues and disease conditions. In this work we also found evidence for recent or active events of DNA editing. While the true scope of these phenomena must be explored in future work, our approach, including the use of strict alignment criteria and quality scores, has proved effective at finding many intriguing examples. Using different parameters, mainly lower cutoffs and relaxation of the requirement for unique alignments, more DNA editing sites could be detected in the trace archive. Careful investigation, most likely combined with next-generation sequencing experiments, will help unravel the mechanisms of retroelement defenses in a variety of organisms. Moreover, DNA editing is known not to be limited to retrotransposons and can take place in other genomic loci. The most recognized example is the AID protein, which is a member of the AID/APOBEC protein family, and targets single stranded DNA in the immunoglobulin locus in B-cells. Similar approaches to the ones used here provide an exciting opportunity to survey how leakage of DNA editing events, outside retroelements, or immunoglobulins could cause many simultaneous mutations in the genome, a process that can eventually lead to cancer.", "role": "user" }, { "content": "Most biomedical , genomic research begins with the painstaking assembly of a “reference genome” for the organism of interest . Implicit in this process is an assumption that genomic information is constant throughout an organism . There are enzymes , however , that can change , or “edit , ” genomic information so that variations from the reference can exist within a single organism . In this work , we analyze the raw data used to assemble the reference genomes of ten organisms to discover evidence for editing . We found candidates for DNA and RNA editing as well as a sequencing error that has become incorporated into commonly used genomic resources . Our analysis demonstrates the utility of raw genomic data for the discovery of some editing events and sets the stage for further analysis as sequencing costs continue to decrease exponentially .", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nOne nodal family member Xnr3 lacks mesodermal-inducing activity via activating Smad2/3, but promotes neural induction by antagonizing BMP4 (Hansen et al., 1997; Haramoto et al., 2004).", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nIntramolecular Csp³–H/C–C bond amination of alkyl azides for the selective synthesis of cyclic imines and tertiary amines\n\nContent Extracts:\nIntroduction\n<p>N-Heterocycles are undoubtedly important chemicals in organic synthesis, and have been considered as key functionality regulators in pharmaceuticals. 1 The intramolecular nitrogen insertion into Csp 3 -H and/or C-C bonds provides an efficient approach to N-heterocycles. [2][3][4][5] The pioneering groups of Aubé 4 and Pearson 5 developed the intramolecular Schmidt reactions 2 and made signicant achievements for various N-heterocycle synthesis. 3 The earliest intramolecular aliphatic C-N bond formation named the Hofmann-Loffler-Freytag reaction 5 always started from unstable halogenated amines to construct N-heterocycles. Over the past two decades, the aliphatic C-H amination has achieved great progress via the C-H activation strategy. 6 However, most of these reactions required electron withdrawing directing groups and delivered amide products (Scheme 1a). Beginning with Breslow's pioneering work, 7 a metal-nitrene strategy was successfully applied in intramolecular Csp 3 -H bond N insertion, providing elegant approaches to amides bearing N-H bonds (Scheme 1a). 8 Thus, the development of direct aliphatic C-H/C-C amination is still highly desirable.</p><p>Organic azides are synthetically useful in drug discovery, bioconjugation and materials science. 9 Although the intramolecular Csp 3 -H bond amination/amidation of aryl azides 10 and sulfonyl azides 11 has achieved great progress, the corresponding transformation of alkyl azides 12 was rarely developed until recent results. 13 In 2013, Betley and coworkers demonstrated the pioneering intramolecular aliphatic C-H amination of alkyl azides catalyzed by an iron catalyst (Scheme 1b). 13a The groups of van der Vlugt, 13c Lin, 13d,e de Bruin, 13c,f and Chi 13g independently developed the same elegant intramolecular cyclization of alkyl azides by iron, palladium or cobalt catalysis to deliver N-Boc heterocycles (Scheme 1b), in which the involved nitrene type intermediates required an equivalent of Boc 2 O reagent to liberate the active catalyst to complete the catalytic cycle (Scheme 1b). Despite the advances of the above strategies (Scheme 1a and b), these intramolecular aliphatic amination/ amidation processes always delivered N-carbonyl or sulfonyl heterocycles with the formation of one C-N single bond.</p><p>Inspired by these results, we speculated that the oxidative generation of carbocation A may trigger the formation of cyclic intermediate B (Scheme 1c), which may undergo other transformations in the absence of transition-metal catalysts and provide opportunities for new products. Herein, we described a novel intramolecular nitrogen insertion into a Csp 3 -H and/or C-C bond of alkyl azides to deliver cyclic imines and tertiary amines (Scheme 1c). The aliphatic C-H or C-C bond was selectively cleaved with the efficient formation of two C-N single bonds or a C]N double bond.</p>\n\nResults and discussion\n<p>According to our previous element incorporation reactions through the carbocation intermediates generated in situ with the DDQ oxidant, 14 we chose azide 1a as the model substrate to investigate our speculation. As expected, dihydropyrrole 2a was obtained in 75% yield in the presence of DDQ and TFA at 60 C (Table 1, entry 1). Two C-H bonds were cleaved and a C]N double bond was constructed along with the release of N 2 in this case. TEMPO or CAN as the oxidant gave inferior yields (entries 2-3), while PIDA or NHPI could not execute the conversion of 1a to 2a (entries 4-5). The chlorinated solvent afforded better yields than that of other solvents such as DMSO, toluene, or MeCN (entries 6-9), and the reaction delivered the highest yield in TCE (entry 9). The pK a of acids inuenced the reaction strongly (entries 10-12). 2a was obtained in only 10% yield in the presence of acetic acid (entry 10), while MsOH or TfOH failed to facilitate this transformation (entries 11-12). The treatment of 1a with 0.4 mL of TFA afforded 2a in a satisfactory 73% isolated yield (entry 13). Lowering the temperature hampered the reactivity (entry 14).</p><p>We explored the generality of this intramolecular Csp 3 -H nitrogen insertion for d-aryl alkyl azides under standard reaction conditions (Table 2). Substrates bearing electron-donating substituents (MeO, tBu, PhO) at the aryl ring worked smoothly to afford the corresponding cyclic imines 2c-e in good yields. The electron-withdrawing substituents (F, Cl) caused low reactivity, resulting in pyrrolines 2f-g in diminished yields (26-31%). Substituents at the meta or ortho position of the arene rings 1h-j slightly affected the efficiency. Besides arenes, the heteroaryl azide 2-(4-azidobutyl)thiophene 1k was transformed to 2k in 32% yield. The substituents on the alkyl chain inuenced this reaction slightly (2l-o). The cyclic imines 2 were easily converted to diversied heterocycles. 15 Compared to the well-established approaches to cyclic imines, the present intramolecular N-insertion protocol features mild conditions and high atom economy.</p><p>In order to synthesize a six-membered cyclic imine, we conducted the reaction of alkyl azide 3a under standard conditions. However, the target imine product 4a was not detected (eqn (1)). We conducted the capture experiment by the addition of benzoyl chloride to the reaction of 3a (eqn (2)). Aldehyde 5a and amide 6 were obtained in 77% and 66% yields, respectively (eqn (2)), which indicated that the azide 3a was converted to amine via an imine cation intermediate and a hydrolysis process (for the detailed mechanism, see Scheme 2 and 3). a Reaction conditions: 1a (0.3 mmol), oxidant (0.36 mmol) and acid (0.2 mL) in a solvent (0. (1)</p><p>(2)</p><p>On the basis of this result, we investigated the one-pot reaction of alkyl azide 3 with DDQ and TFA followed by in situ reduction. We were delighted to nd that the corresponding cyclic tertiary amine 7a was obtained in 55% yield (Table 3). The substituent on the arene slightly inuenced the yield and a series of N-Bn pyrrolidines were synthesized in moderate yields. The azide substrates bearing alkyl substituents also smoothly delivered benzyl-substituted 7h or pyrrolidine 7i in moderate yield. In addition, naphthalene, thiophene, dibenzofuran and dibenzothiophene were all well tolerated to afford cyclic tertiary amines 7j-m in 33-81% yields. It is noteworthy that the transformation of 3 to 7 with the release of nitrogen as the only by-product, is thus highly atom-economic. Moreover, the present strategy cleaves the Csp 3 -Csp 3 bond 16 without strained rings or assisted functional groups. Besides pyrrolidine, piperidine derivative 7n also could be synthesized by the intramolecular N-insertion of alkyl azide 3n. Unfortunately, the present strategy could not be applied in the construction of seven-or eight-membered N-heterocycles.</p><p>Based on the above experiments, we proposed the possible mechanism of the reaction (Scheme 2). The oxidation of alkyl azides 1 and 3 at the benzylic position by DDQ with TFA provides benzylic cation intermediate A, which is attacked by the azide group to generate cyclic intermediate B. In the most stable conformation of B, the aryl group should stand on the equatorial bond, which makes a small torsion angle with the azide moiety. As a result, the following Schmidt rearrangement of B with the concerted release of N 2 and the aryl shi is unfavorable through periplanar migration, while the hydrogen or alkyl shi is potentially feasible through antiperiplanar migration. The ve-membered ring species C undergoes deprotonation with the release of N 2 to afford cyclic imine 2, while the six-membered ring intermediate D undergoes 1,2alkyl migration to generate the imine cation E, which is sequentially reduced to deliver tertiary amine 7.</p><p>To further understand the mechanism, we performed preliminary DFT calculations on the model reaction of alkyl azides 1 and 3 with DDQ and TFA (Scheme 3). 17 We rst studied the oxidation of 1 at the benzylic position by DDQ with TFA through O-attack hydride transfer pathway, which is the most thermodynamically favorable pathway in some similar cases. 18 The hydride transfer from 1 to the complex of DDQ and TFA through TS1 requires a Gibbs free energy barrier of 28.0 kcal mol À1 to form the benzylic carbocation intermediate A1 and DDQH-TFA À anion, which could be stabilized by another TFA molecule to afford DDQ-2H and H(CF 3 CO 2 ) 2 À species. Subsequently, the azide moiety would attack the formed carbocation in A1 to generate ve-membered ring C, which is exothermic by 19.2 kcal mol À1 . In the most stable conformation of C, the phenyl group on the equatorial bond has a small torsion angle (À24.4 ) with the azide moiety, while the benzylic hydrogen and alkyl group have big dihedral angles (95.4 and À150.0 , respectively) with the azide moiety. Therefore, the following Schmidt rearrangement 2 of C with the concerted release of N 2 and the hydrogen or alkyl shi is potentially feasible through antiperiplanar migration. The Schmidt rearrangement with the 1,2-H shi through the antiperiplanar transition state TS2 with a free energy barrier of 16.8 kcal mol À1 gives 2-H. The barrier of the 1,2-alkyl shi to imine cation E1 through TS3 (DG ‡ ¼ 21.7 kcal mol À1 ) is much higher than that of the 1,2-H shi pathway. Alternatively, the hydride transfer from 3 to the complex of DDQ and TFA through TS4 requires a Gibbs free energy barrier of 26.6 kcal mol À1 to form the benzylic carbocation A3. The azide moiety is favorable to attack the intramolecular carbocation to generate six-membered ring D, which is exothermic by 16.6 kcal mol À1 . In the most stable conformation of D, the dihedral angle of the azide moiety with the alkyl group increases to À159.5 , while the one with hydrogen decreases to 84.2 . This is likely to provide an advantage for the 1,2-alkyl shi. The following Schmidt rearrangement of D including the 1,2-H shi through TS5 requires a free energy barrier of 15.3 kcal mol À1 to give 4-H. In contrast with C, D undergoes a 1,2-alkyl shi through TS6 with a free energy barrier of 14.4 kcal mol À1 , which is favorable compared to the 1,2-H shi pathway, indicating that the 1,2-alkyl shi pathway becomes predominant. Reviewing the whole energy prole, it is revealed that the oxidation with hydride transfer is the rate-determining step, while the chemoselectivity in the nitrogenation of alkyl azides is essentially controlled by the conformation of the cyclic intermediate and the ring-side in the Schmidt rearrangement process. The experimentally observed electronic effects on the Ar group are consistent with the rst oxidation step with hydride transfer as the rate-determining step (see the ESI † for details).</p>\n\nConclusions\n<p>In summary, we have demonstrated a novel metal-free intramolecular Csp 3 -H/C-C amination of alkyl azides for the synthesis of cyclic imines and tertiary amines. Two C-N single bonds or a C]N double bond are efficiently constructed in these transformations through the highly selective benzyl Csp 3 -H or C-C bond cleavage. The mechanistic studies and DFT calculation indicate a carbocation pathway for this novel protocol. The present chemistry not only provides a new approach to N-heterocycles, but also expands the transformation and application of C-H/C-C amination in organic synthesis.</p>\n\nConflicts of interest\n<p>There are no conicts to declare.</p>", "role": "user" }, { "content": "The intramolecular Csp 3 -H and/or C-C bond amination is very important in modern organic synthesis due to its efficiency in the construction of diversified N-heterocycles. Herein, we report a novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines through selective Csp 3 -H and/or C-C bond cleavage. Two C-N single bonds or a C]N double bond are efficiently constructed in these transformations. The carbocation mechanism differs from the reported metal nitrene intermediates and therefore enables metal-free and new transformation.Scheme 1 Intramolecular N-insertion of the Csp 3 -H bond.", "role": "assistant" } ]

[ { "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\nRetinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha. CD38 is a leukocyte differentiation antigen that has been thought to be a phenotypic marker of different subpopulations of T-and B-lymphocytes. In myeloid cells, CD38 is expressed during early stages of differentiation. Virtually no information is available on regulation and functions of CD38. Recently we reported that all-trans-retinoic acid (ATRA) is a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells. Here we report that ATRA-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid-alpha receptor (RAR alpha). ATRA failed to induce CD38 expression in a mutant subclone of the HL-60 myeloid leukemia cell line (designated HL-60R) that is relatively resistant to ATRA-induced granulocytic differentiation. Retroviral vector-mediated transduction of RA receptor (RAR alpha) into this HL-60R subclone completely restored the sensitivity of these cells to ATRA in terms of their ability to express CD38. In contrast, CD38 expression was not inducible by ATRA in HL-60R cells, transfected with a functional RAR beta, RAR gamma, or RXR alpha receptor. Induction of CD38 in acute promyelocytic and acute myeloblastic leukemia cells was independent of ATRA-induced cytodifferentiation. Following culture with ATRA, increased CD38 protein levels were also observed in normal CD34 + bone marrow cells, but not on normal circulating granulocytes. From these results, we conclude that CD38 is ATRA inducible in myeloid leukemia cells and normal CD34 + bone marrow cells. This effect is independent of differentiation and is mediated by RAR alpha in HL-60 cells, suggesting a similar role for RAR alpha in CD38 expression in other hematopoietic cells.", "role": "user" }, { "content": "{\"CellLine\": [\"HL - 60R subclone\", \"HL - 60R cells\", \"HL - 60R\", \"mutant subclone\", \"HL - 60 cells\", \"HL - 60 myeloid leukemia cell line\"], \"CellType\": [\"human promyelocytic leukemia cells\", \"T - and B - lymphocytes\", \"acute promyelocytic and acute myeloblastic leukemia cells\", \"hematopoietic cells\", \"myeloid leukemia cells\", \"normal CD34 + bone marrow cells\", \"myeloid cells\", \"normal circulating granulocytes\", \"HL - 60 cells\"], \"DNA\": [], \"Protein\": [\"retinoic acid - alpha receptor\", \"RAR gamma\", \"leukocyte differentiation antigen\", \"CD38\", \"retinoic acid receptor - alpha\", \"RXR alpha receptor\", \"RAR alpha\", \"CD38 antigen\", \"retinoic acid - alpha receptor (RAR alpha)\", \"RAR beta\", \"RA receptor (RAR alpha)\", \"a leukocyte differentiation antigen\", \"RA receptor\"], \"RNA\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with the full text of a scientific research paper. Write an abstract summarizing the key points. Your response should contain only the abstract without any other text.\n\nArticle text:\nblazars have been shown to exhibit a sequence of properties as a function of source power ( fossati et al .\n1998 ) . as the source power increases , the emission line luminosity and the ratio of compton to synchrotron luminosity increase , while the synchrotron peak frequency @xmath0 and the ic peak frequency decrease .\nrecent multiwavelength studies support this scheme ( e.g. kubo et al .\n1998 ) , although the result that the ratio of the compton to synchrotron luminosity increases with source luminosity suffers from limited statistics , and should be only considered tentative .\nthe initial division of blazars into flat spectrum radio quasars ( fsrqs ) and bl lacertae objects ( bls ) was based on the equivalent width ( ew ) of the broad emission lines .\nsources with ew @xmath1 5 @xmath2 were classified as fsrqs and sources with ew @xmath3 5 @xmath2 as bls .\nthis difference in the ew of the emission lines has been interpreted as absence of a substantial blr in bls , and has been used to advance the idea that in bls the gev - tev emission is due to ssc , while in fsrqs the gev emission is due to ec .\nhowever , the ew criterion does not correspond to a dichotomy ( scarpa & falomo 1997 ) , because a weak blr is present in bls as well .\nadditionally , it is not the blr luminosity @xmath4 that is relevant for the ec luminosity , but the blr photon energy density @xmath5 that is measured in the comoving frame of the non - thermal source .\none needs to know not only @xmath4 , but also the blr radius @xmath6 and the location of the non - thermal emitter relative to the blr in order to quantify the relative importance of ssc versus ec emission .\nthe size of the blr has been measured only for radio quiet agns through reverberation mapping ( kaspi et al .\n2000 ) , and it has been found to scale with the ionizing luminosity @xmath7 of the acrretion disk as @xmath8 . it was additionally found that , assuming keplerian motions for the blr clouds , the mass of the central object scales with the ionizing luminosity as @xmath9 .\nhere we assume the scalings apply also to radio loud agn and examine the implications for blazars .\nfollowing the formalism of internal shocks propagating in a conical jet ( rees 1978 ) , we scale the location @xmath10 and the radius @xmath11 of the non - thermal spherical emitter with the mass @xmath12 of the central object .\nwe assume that @xmath4 is a fraction of @xmath7 and scale the kinetic luminosity and the poynting flux of the blob with @xmath7 .\nunder this scheme , the radius of the blr scales as @xmath13 , and the distance of the blob from the center of the system scales as @xmath14 .\ntherefore , we assume that for powerful sources the blob radiates from inside the blr , @xmath15 .\nhowever , if we consider increasingly weaker sources , @xmath6 falls faster than @xmath10 and , below some critical luminosity , the blob radiates from outside the blr . for a blob inside the blr , @xmath16 , where @xmath17 is the bulk motion lorents factor of the blob . for a blob outside the blr , the solid angle subtended by the blr , as seen by the blob ,\nis reduced .\nthis affects @xmath5 in two ways .\nthe first is the usual geometric @xmath18 factor , and the second is a relativistic de - boosting that , for @xmath19 , gives @xmath20 ( dermer & schlickeiser 1994 ) . the second effect dominates if the blob is located less than a few @xmath6 away from the blr .\nfor example , for @xmath21 , @xmath22 at a distance of @xmath23 is smaller than @xmath22 inside the blr by a factor of @xmath24 due to the usual @xmath18 and by a factor of @xmath25 due to relativistic de - boosting .\nwe apply this scaling using a model ( georganopoulos & kirk 2000 ) for the blob which includes both particle acceleration and radiative losses with ic scattering losses treated in the thomson regime .\nparticles are accelerated in an acceleration zone and escape into a radiation zone , before they eventually escape out of the system .\nthis simplified picture is intended to represent particles which are accelerated by a shock front , escape it , and radiate downstream before the compressed plasma re - expands .\nwhilst undergoing acceleration , particles simultaneously suffer synchrotron losses and losses by compton scattering of both photons of external origin ( ec ) and synchrotron photons ( ssc ) from the radiation zone . in the radiation zone ,\nec , ssc and synchrotron losses occur until the particle finally escapes after a time @xmath26 . the electron energy distribution ( eed ) is computed self - consistently , taking account of these processes . our assumption about the scaling of the poynting flux implies a constant magnetic field , which we take to be @xmath27 g. the blob\nis assumed to move with a lorentz factor @xmath28 at an angle @xmath29 with respect to the line of sight .\nlow energy particles ( @xmath30 ) are injected into the blob at a rate of @xmath31 @xmath32 s@xmath33 .\nalso @xmath34 . for @xmath35 erg s@xmath33 ,\nreverberation mapping gives @xmath36 cm .\nwe assume that at this luminosity @xmath37 and @xmath38 cm . in fig.1 , we let @xmath7 vary from @xmath39 erg s @xmath33 to @xmath40 erg s@xmath33 , and follow the behavior of the system . in the lower panel @xmath6 , @xmath10 , and @xmath11\nare plotted as a function of @xmath7 . for weak sources ,\nthe blob is located outside the blr ( @xmath41 ) . as the source power increases , the blob gradually approaches and eventually enters the blr . in the middle panel of fig.1\nwe see how this affects @xmath22 ( the magnetic field energy density @xmath42 is constant under the adopted scaling ) . for weak sources ,\n@xmath22 is much smaller than both @xmath42 and the self - consistently derived synchrotron photon density @xmath43 .\ngradually @xmath22 increases , and eventually , for bright sources , dominates over both @xmath42 and @xmath43 . in the upper panel of fig.1\nwe plot the self - consistently derived break @xmath44 in the eed .\nnote that @xmath44 decreases as the power of the source decreases . in fig.2\nwe plot basic observable quantities as a function of @xmath7 . in the lower panel\nwe plot the synchrotron luminosity @xmath45 , the ssc luminosity @xmath46 , and the ec luminosity @xmath47 . at low powers\n, @xmath48 is much weaker than @xmath46 and @xmath45 that are roughly equal .\nas the source power increases , @xmath48 gradually dominates over @xmath46 and @xmath45 , and we end up with an ec dominated source . in the middle panel we plot the peak frequencies of the three emission components . note how the synchrotron peak frequency @xmath49 decreases as the source power increases .\nsimilar behavior is also seen for the ssc peak frequency @xmath50 and the ec peak frequency @xmath51 .\nfinally in the upper panel of fig.1 we plot the ratio @xmath52 ( solid line ) of the synchrotron to accretion disk luminosity and the ratio @xmath53 of the ic luminosity to synchrotron luminosity .\n@xmath45 dominates over @xmath7 in weak sources in agreement with the lack of a thermal component and weak emission lines in weak sources like bls .\n@xmath7 becomes more significant for powerful sources , again in agreement with the strong emission lines of fsrqs and the accretion disk signature observed in some fsrqs ( e.g. in 3c 279 , pian et al 1999 ) .\nthe dominance of the compton over the synchrotron emission increases as the source power increases , in agreement with observations ( e.g. kubo et al .\nnote , however , that the observational case for an increasing compton dominance with source power is based on poor statistics due to the limited sensitivity of the _\ncgro_. in fig.3 we plot the synchrotron luminosity @xmath54 versus the synchrotron peak frequency @xmath55 for the blazars studied by sambruna , maraschi & urry ( 1996 ) and kubo et al .\n( 1998 ) . on top of the data points we plot the model tracks as a function of @xmath7 for a range of observing angles .\nnote that these tracks represent two model derived quantities , @xmath45 and @xmath49 as @xmath7 varies .\nthe model covers rather well the observed parameter space .\ngiven the track of the model under an angle @xmath56 , we do not expect that any powerful ( @xmath57 erg s@xmath33 ) sources with high peak frequencies @xmath58 hz exist .\nthe discovery of such sources would pose a serious problem for this model .\nin fig.4 we plot the peak luminosities of the three emission mechanisms for 5 model sources with @xmath7 ranging from @xmath39 up to @xmath40 erg s@xmath33 .\nthe behavior of the model is in good agreement with the general characteristics of the observed luminosity sequence ( compare with fig.12 of fossati et al .\nthe synchrotron peak frequency decreases from @xmath59 hz down to @xmath60 hz , as the synchrotron power increases .\nthe compton peak frequency in weak sources is in the tev regime ( @xmath61 hz ) and it is due to ssc , while in powerful sources it is in the gev regime ( @xmath62 hz ) and it is due to ec .\naccording to the model , although in these bright sources the energy losses are dominated by ec , the hard x - ray emission is due to ssc , in agreement with resent observations ( kubo et al .\n1998 ) .\nwe note here that fig.4 corresponds to sources that are oriented at an angle @xmath29 . in reality one should expect a range of angles , which will give rise to significant scattering around the presented trend .\nthis scattering is visible in the work of fossati et al .\n( 1998 ) and indicates that a proper unification scheme for blazars should include the effects of orientation .", "role": "user" }, { "content": "we present preliminary results of our work on blazar unification . \n we assume that all blazars have a broad line region ( blr ) and that the size of the blr scales with the power of the source in a manner similar to that derived through reverberation mapping in radio quiet active galactic nuclei ( agns ) . using a self - consistent emission model that includes particle acceleration \n we show that according to this scaling , in weak sources like mkn 421 , the inverse compton ( ic ) scattering losses are dominated by synchrotron - self compton scattering ( ssc ) , while in powerful sources , like 3c 279 , they are dominated by external compton ( ec ) scattering of blr photons . in agreement with other workers , we show that even in the powerful sources that are dominated by ec scattering , the hard x - ray emission is due to ssc . finally , we show that this scaling reproduces well the observed sequence of blazar properties with luminosity .", "role": "assistant" } ]

[ { "content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nA Nine-Step Enantioselective Total Synthesis of (\\xe2\\x88\\x92)-Vincorine\n\nContent Extracts:\n\n<p>The Vinca alkaloid natural products have historically served as valuable lead candidates in the development of anti-cancer agents (vinblastine),1a,b vasodilators (vincamine),1c anti-psychotics and anti-hypertensives (reserpine).1d Recently, members of the biologically active akuammiline family of Vinca alkaloids have emerged as high-profile targets for chemical synthesis and medicinal chemistry studies.2 Vincorine (1) is the parent compound of an akuammiline alkaloid subclass characterized by a synthetically challenging tetracyclic core that incorporates a strained seven-membered, azepanyl ring and a pyrroloindoline motif. In preliminary assays, the related alkaloids echitamine (2) and corymine (not shown) were found to exhibit anti-cancer activity3 and glycine receptor antagonism,4 respectively. With the goal of devising a concise synthesis of this common core structure for further biological investigation, a number of research labs have undertaken the synthesis of vincorine.5 Indeed, recent total syntheses by the Qin group6a (35 steps, racemic) and the Ma group6b (18 steps, 64% ee) have served to highlight the significant structural challenges posed by this cage-like system. In this communication, we disclose a highly enantioselective 9-step total synthesis of (−)-vincorine, which employs organocascade catalysis7 as a central enabling feature. We anticipate that the general synthetic strategy described herein will prove readily adaptable to other bioactive akuammiline alkaloid natural products and analogs thereof.</p>\n\nDesign Plan\n<p>From a retrosynthetic standpoint, we envisioned the disconnection of vincorine via two key steps (Scheme 1). While previous syntheses of vincorine have relied on C–N bond formation to forge the strained seven-membered azepanyl system, we reasoned that an intramolecular single electron-mediated C–C bond formation (initiated from compound 3) might offer additional strategic advantages in that the requisite allylic methine stereochemistry would be produced along with the embedded heterocycle. The remaining structural and stereochemical elements of the akuammiline core would arise from a single organocatalytic Diels–Alder,8 iminium cyclization cascade event beginning from simple, achiral starting materials (4 and 5). We have previously demonstrated the complexity-generating capacity of other organocatalytic9,10 cascade mechanisms in the recent total syntheses of strychnine, minfiensine,11a and additional selected alkaloids of the Strychnos, Aspidosperma, and Kopsia families.11b</p><p>In the specific context of this vincorine synthesis program, we envisioned employing a catalytic cascade sequence to effect the overall conversion of tryptamine 4 to the tetracyclic adduct 7 in one step. As outlined in Scheme 2, the sequence would begin with condensation of secondary amine catalyst 6 onto enal 5 to form an activated iminium ion. In the proposed transition state (TS–A), orientation of the reactive π-system away from the catalyst gem-dimethyl group would facilitate effective shielding of one π-face by the benzyl group, thereby enabling a highly stereoselective endo Diels–Alder reaction with diene 4, to deliver enamine cycloadduct 8. Brønsted acid-catalyzed interconversion of enamine 8 and iminium ion 9 by the ammonium salt of 6 would precipitate intramolecular 5-exo amine cyclization via the pendent carbamate group to generate the tetracyclic product 7.12 Notably, the core structure 7 would emerge from this transformation bearing three of the four vincorine stereocenters – including the all-carbon quaternary center C(8) – with the correct relative and absolute configuration.</p><p>The total synthesis of vincorine was initiated with the preparation of diene 4 in two steps from commercially available 5-methoxy-N′-Boc tryptamine (10), via methylation then directed metalation/Negishi coupling13 (Scheme 3). For the key Diels–Alder/cyclization cascade, a survey of chiral secondary amines revealed that the first-generation Diels–Alder imidazolidinone catalyst 6 was both highly efficient and stereoselective. Using optimized reaction conditions (6•HBF4, MeCN, −20 °C), the tetracyclic vincorine core system 7 was generated in 70% yield and 95% ee (Table 1, entry 6).</p><p>With the majority of the requisite vincorine architecture in hand, we next sought to rapidly install the final 7-membered azepanyl ring by way of a 7-exo-dig radical cyclization. As shown in Scheme 3, Pinnick oxidation14 served to convert aldehyde 7 to carboxylic acid 11, prior to the formation of an alkyl radical precursor in the form of an acyl telluride. Specifically, the telluride 12 was generated in a sequence involving formation of a mixed anhydride followed by displacement with sodium phenyl telluride in good yield for the overall transformation. Installation of a suitable π-system to enable radical-mediated C–C bond cyclization was accomplished via Boc-deprotection and subsequent nitrogen alkylation using 2-butynal-4-tert-butyl sulfide in a reductive amination step. Notably, the acyl telluride moiety was successfully maintained through multiple transformations, readily withstanding exposure to neat trifluoroacetic acid and sodium triacetoxyborohydride.</p><p>The suitability of the acyl telluride unit as the preferred alkyl radical precursor was determined by comparison to a range of alternative acyl-X fragmentation partners in the key cyclization event (13→14, see Table 2).15 Attempts to achieve useful isolated yields with a thiohydroxamic acid derivative (Barton ester)16 were largely unsuccessful, due to competitive formation of a thiopyridyl byproduct via radical recombination (Table 2, entry 1, 18%). Similarly disappointing results were obtained using a thermally stable acyl selenide17 precursor with hexabutyl ditin radical initiator. Although the stannyl radical – formed from hexabutyl ditin via photolysis with a high pressure mercury lamp – was able to successfully initiate the desired cyclization, extensive decomposition of the allene product under the reaction conditions led to low isolated yields of the desired adduct (entries 2 and 3). We ultimately achieved success with a thermally-initiated alkyl radical precursor, namely acyl telluride 13.18 Under optimal conditions (200 °C, 0.5 mM), radical cyclization of the acyl telluride precursor provided the allene product 14 in 51% isolated yield (entry 6). We postulate that the transformation of telluride 13 to the desired azepanyl allene 14 proceeds through carbon–Te bond homolysis, followed by loss of carbon monoxide to generate an alkyl radical. This result is notable given the difficulty of building seven-membered azepanes in comparison with the corresponding six-membered alkaloid analogs. Moreover, to our knowledge, this example represents the first use of an acyl telluride as an effective alkyl radical precursor.</p><p>In the final step of the synthesis, the terminal unsaturation of the allene functionality underwent selective hydrogenation from the less hindered face to provide (−)-vincorine in 80% yield as a single olefin isomer in nine steps and 9% overall yield from the commercially available indole 10. The product generated was identical in all spectroscopic respects to the natural isolate (see Supporting Information).</p><p>In conclusion, we have developed a nine-step synthetic route to (−)-vincorine from commercially available starting materials. Key features of the synthesis include an organocatalytic Diels–Alder/amine cyclization cascade and a 7-exo-dig radical cyclization initiated from an unusual acyl telluride precursor. The utility of this new cascade catalysis strategy is now being explored in the production of a large collection of natural and unnatural vincorine analogs including echitamine. Findings from these studies will be reported in due course.</p>", "role": "user" }, { "content": "A concise and highly enantioselective total synthesis of the akuammiline alkaloid (\\xe2\\x88\\x92)-vincorine has been accomplished. A key element of the synthesis is a stereoselective organocatalytic Diels\\xe2\\x80\\x93Alder, iminium cyclization cascade sequence, which serves to construct the tetracyclic alkaloid core architecture in one step from simple achiral precursors. The challenging seven-membered, azepanyl ring system is installed by way of a single electron-mediated cyclization event initiated from an acyl telluride precursor. The total synthesis of (\\xe2\\x88\\x92)-vincorine is achieved in nine steps and 9% overall yield from commercially available starting materials.", "role": "assistant" } ]

[ { "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 propose a method to detect edges in the images using a set of threshold values. Our approach uses three\n\nKeywords: edge detection images\n\nDataset Information:\nDOTA: DOTA is a large-scale dataset for object detection in aerial images. It can be used to develop and evaluate object detectors in aerial images.\nMVTecAD: MVTec AD is a dataset for benchmarking anomaly detection methods with a focus on industrial inspection. It contains over 5000 high-resolution images divided into fifteen different object and texture categories.\nSBU Captions Dataset: A collection that allows researchers to approach the extremely challenging problem of description generation using relatively simple non-parametric methods and produces surprisingly effective results.\nBSDS500: Berkeley Segmentation Data Set 500 (BSDS500) is a standard benchmark for contour detection. This dataset is designed for evaluating natural edge detection that includes not only object contours but also object interior boundaries and background boundaries.\n\nAvailable Datasets: A: DOTA B: MVTecAD C: SBU Captions Dataset D: BSDS500", "role": "user" }, { "content": "BSDS500", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nIn addition, the MMSE [16], the Geriatric Depression Scale (GDS) [35] and Spielberger’s State-Trait Anxiety Inventory [26] were administered to assess mental state.", "role": "user" }, { "content": "Method", "role": "assistant" } ]

[ { "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\nFirst complete genome sequence of a virulent bacteriophage infecting the opportunistic pathogen Serratia rubidaea A Serratia rubidaea phage, vB_Sru IME250, was isolated from hospital sewage. The morphology suggested that phage vB_Sru IME250 should be classified as a member of the family Myoviridae. High-throughput sequencing revealed that the phage genome has 154,938 nucleotides and consists of 193 coding DNA sequences, 90 of which have putative functions. The genome of vB_Sru IME250 is a linear, double-stranded DNA with an average GC content of 40.04%. The phage has a relatively high similarity to Klebsiella phage 0507-KN2-1, with a genome coverage of 84%.", "role": "user" }, { "content": "{\"AnatomicalStructure\": [\"genome\"], \"Bacterium\": [\"Serratia rubidaea\"], \"BiologicFunction\": [], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [\"double-stranded DNA\", \"nucleotides\"], \"ClinicalAttribute\": [], \"Eukaryote\": [], \"Finding\": [\"infecting\"], \"Food\": [], \"HealthCareActivity\": [], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"classified\"], \"MedicalDevice\": [], \"Organization\": [\"hospital\"], \"PopulationGroup\": [], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [\"High-throughput sequencing\"], \"SpatialConcept\": [\"genome sequence\", \"linear\", \"coding DNA sequences\"], \"Virus\": [\"vB_Sru IME250\", \"bacteriophage\", \"Serratia rubidaea phage, vB_Sru IME250\", \"phage\", \"phage vB_Sru IME250\", \"Myoviridae\", \"Klebsiella phage 0507-KN2-1\"]}", "role": "assistant" } ]

[ { "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: Opto-magnetic capture of individual cells based on visual phenotypes\nContent Overview:\nAbstract:\nThe ability to isolate rare live cells within a heterogeneous population based solely on visual criteria remains technically challenging, due largely to limitations imposed by existing sorting technologies. Here, we present a new method that permits labeling cells of interest by attaching streptavidin-coated magnetic beads to their membranes using the lasers of a confocal microscope. A simple magnet allows highly specific isolation of the labeled cells, which then remain viable and proliferate normally. As proof of principle, we tagged, isolated, and expanded individual cells based on three biologically relevant visual characteristics: i) presence of multiple nuclei, ii) accumulation of lipid vesicles, and iii) ability to resolve ionizing radiation-induced DNA damage foci. Our method constitutes a rapid, efficient, and cost-effective approach for isolation and subsequent characterization of rare cells based on observable traits such as movement, shape, or location, which in turn can generate novel mechanistic insights into important biological processes.\nIntroduction:\nCharacterization of biological samples relies heavily on microscopy where, in response to various stimuli, molecular probes and a myriad of contrast reagents are routinely used to identify and label individual live cells of interest. These methods often require prior knowledge of cellular markers or use of elaborate reporter constructs. On the other hand, based solely on visual inspection or using image processing algorithms, it is possible to distinguish rare cells which exhibit distinct biological properties from among thousands of counterparts within a microscopy field. Such visually discernable traits include movement, shape, intracellular protein distribution, and location within the sample, and in turn can reflect important physiological features of individual cells. For example, cell migration( movement) is an essential determinant in normal embryonic development, wound healing, immune responses, tumor progression, and vascular disease( Kurosaka and Kashina, 2008). Moreover, changes in cellular morphology( shape) constitute biomarkers of cellular growth, division, death, and differentiation, as well as of tissue morphogenesis and disease( Prasad and Alizadeh, 2019). Cell-to-cell contacts( location) or distance to sources of chemical cues such as senescent cells, inflammation or necrotic tissue are critical factors in chemokinesis, differentiation, neural function, and immune responses( Garcia et al., 2018). Finally, expression and visualization of fluorescent fusion proteins permits the identification of cells presenting molecular behaviors of interest, such as differential relocalization of proteins to subcellular compartments or structures upon various stimuli. Unfortunately, however, isolation and expansion of single cells characterized by such easily-observable features is technically challenging, and indeed has not been accomplished to date. We recently developed a method termed Cell Labeling via Photobleaching( CLaP)( Binan et al., 2016) allowing the arbitrary tagging of individual cells among a heterogeneous population within a microscopy field. This is accomplished by crosslinking biotin molecules to their plasma membranes with the lasers of a confocal microscope, followed by use of fluorescent streptavidin conjugates to reveal the marked cells. In this manner, the same instrument used for imaging can also be adapted to label particular cells based on any visible trait that distinguishes them from the ensemble. Importantly, previous knowledge of surface markers or transfection of reporter genes are not required. Tags can be added with single-cell precision and the incorporated label displays convenient tracking properties to monitor location and movement. The mark is stable, non-toxic, retained in cells for several days, and moreover, does not engender detectable changes in cell morphology, viability, or proliferative capacity. Moreover, gene expression profiling indicated no major changes associated with the procedure( Binan et al., 2016). Nevertheless, a technology for the efficient isolation and expansion of CLaP-tagged cells is still lacking. The fact that cell populations are often highly heterogeneous underscores the need for new approaches to capture and clonally expand individual cells of interest for further characterization. However, as mentioned above, current sorting techniques cannot efficiently isolate such rare cells( Pappas and Wang, 2007); indeed, classical protocols like Fluorescence and Magnetic Activated Cell Sorting( FACS and MACS) are typically optimized for high throughput at the expense of capture efficiency and specificity, and require large numbers of cells( Pappas and Wang, 2007). Small cell populations representing 10−3 of the total, which have been defined as rare, or ultrarare in the case of 10−5, can only be effectively captured and purified with repeated cycles of sorting and cell expansion protocols( Pappas and Wang, 2007). Starting with rare and hence precious cell populations, highly conservative gating strategies are needed, which can at best achieve approximately 45% purity( Kuka, 2013; Shields et al., 2015). Time-consuming manipulations, cost, hardware footprint, and handling complexity( Takahashi and Okada, 1970) make approaches based on microfluidics ill-suited for capturing small numbers of cells, which are often masked within tens of thousands. Here, we report a novel technology, termed Single-Cell Magneto-Optical Capture( scMOCa), for isolating cells based purely on visual traits from within large heterogenous populations. After tethering biotin moieties to their membranes, cells of interest are targeted with streptavidin-coated ferromagnetic beads and captured with high efficiency using a simple magnet. The procedure is fast, uses low-cost commercially available reagents and only requires access to a standard confocal microscope. As proof-of-principle for the utility and power of this novel approach, we used scMOCa to i): capture and expand individual cells that differ in their capacity to resolve ionizing radiation( IR)-induced foci of the DNA repair protein 53BP1, ii) purify rare multinucleated cells, and iii) isolate cells that differentiated into adipocytes and accumulated lipid vesicles. Overall, the ease of use and affordability of our method is expected to facilitate the characterization of phenotypes of interest occurring in a small fraction of cell populations.\nDiscussion:\nTo the best of our knowledge, scMOCa is the only technology that permits isolation, and subsequent clonal expansion, of extremely small numbers of cells from relatively large heterogeneous populations based solely on visual criteria. scMOCa is highly efficient, as the fraction of tagged cells collected in the top chamber exhibits minimal capture losses and high specificity. Rare false positive cells, presumably attached by cell junctions to true positive cells, can be eliminated by repeating the sorting procedure to reach 100% purity. The most widely used cell sorting technique, FACS, is not optimized for sorting rare cells. Adaptations needed for capturing cell populations representing <1% of the sample with high specificity make FACS experiments cumbersome and inefficient. Moreover, repetition of flow cytometry sorting to obtain pure samples of a given cell type imposes can only be performed with robust cell types due to reduced survival and proliferation capacity( Pappas and Wang, 2007). More refined procedures have been developed to sort rare cells via binding to microfluidic channels coated with antibodies against specific surface markers of interest( Antfolk et al., 2017). However, this requires high-affinity antibodies that are specific to the target cell types and leads to dilution of cells in laminar flows within microfluidics chips( Moon et al., 2011; Kang et al., 2012), which can become a drawback for downstream applications. Techniques based on magnetism display an improved capacity to isolate rare cells without dilution( Tham et al., 2014). Nevertheless, while the majority of protocols that use magnetic fields can capture cells of interest with efficiency near 90%, their specificity remains a major challenge, as published results vary between 10% and 80% purity for captured cells( Miltenyi et al., 1990), generally closer to 50%( Zborowski and Chalmers, 2011; Pamme and Wilhelm, 2006; Radbruch et al., 1994; Khojah et al., 2017). Finally, only a handful of approaches allow label-free cell sorting, where intrinsic physical properties, such as size( Zhao et al., 2017; Monti et al., 2017) or magnetic susceptibility( Moon et al., 2011; Pamme and Wilhelm, 2006; Hosokawa et al., 2010) differentiate the target population. Filtration, for example, relies on porous membranes to capture cells based on size and deformability( Davis et al., 2006; Gascoyne et al., 2009) and can achieve 80% efficiency. Dielectrophoresis exploits natural differences in dielectric properties of cell types for discrimination and circulates cells in microfluidics channels, deviating target cells within an electric field( Hu et al., 2005; Landry et al., 2015). The application we introduced here is focused on magnetic separation, but the same concept of adding particles to individual live cells may open the door to novel strategies where other actionable properties can be exploited in a simple and straightforward manner. For example, fluorescence or electron density can be manipulated on single cells( Binan et al., 2016), and recent advances in cellular nanotechnologies such as scattering and plasmon resonance using gold nanoparticles, thermal capacity with nanoshells, or electrical properties using carbon nanotubes can now be modulated only on chosen cells using low-cost commercially available reagents. ScMOCa presents critical advantages over more traditional sorting techniques. It allows isolation of live cells without previous knowledge of surface markers and can simply be based on morphological traits such as the presence of nuclear foci or lipid vesicles and the number nuclei. More importantly, it has the potential to sort based on time-dependent characteristics such as migration speed or foci resolution. In addition, because sorting is carried out in small chambers of similar size, there is no sample dilution. This prevents cells from sustaining strong shear stress upon passing through microfluidic tubing( Miltenyi et al., 1990), and allows their use in downstream applications such as cell culture, reinjection, or even lysis prior to transcriptomic or proteomic analysis. ScMOCa crosslinks biotin to cell membrane and the strength of the ensuing biotin-streptavidin bond is extremely high( Kd = 10−15M). In comparison, the bonds utilized in immunochemistry are much weaker, from 10−12 to 10-9 39, 40, which may cause tags to detach from cells because of shear stress within the microfluidics tubing( Wooldridge et al., 2009). Another example is provided by ligands targeting the major histocompatibility complex( MHC) on immune cells where binding strength is so weak that ligands usually need to be grouped in tetramers for increased strength( Tsai et al., 2004; van der Toom et al., 2017). Finally, while the precise mechanisms influencing 53BP1 focus resolution was not investigated in our proof-of-principle experiments, our data demonstrates that markers used for identification need not be exposed on the membrane since the spatial distribution of fluorescent signal originating from the nucleus were used here as a reporters. Simplicity is a key advantage of scMOCa, as it does not require highly specialized software, or hardware such as microfluidic chips. Indeed, a standard confocal microscope with no modification, simple handmade chambers and low-cost magnets are all that is needed to sort single cells of choice from among tens of thousands. The main limitation of scMOCa is that high throughput implementations would depend on efficient image processing tools for cell detection. While automated detection and tagging are possible on motorized microscopy systems, the duration of the procedure is roughly proportional to the number of target cells. Thus, even if laser illumination of a single cell typically requires one second, this might become a limitation for applications that deal with large cell numbers. The capacity of scMOCa to isolate and profile individual cells within a large population based purely on visual phenotypes constitutes a powerful tool for understanding cellular heterogeneity. We envision that one potential application of high interest would combine scMOCa with single cell sequencing to characterize the molecular basis of differential metastatic potential among particular cells within a tumour( Navin et al., 2011; Valastyan and Weinberg, 2011; Shapiro et al., 2013; Tirosh et al., 2016; Heitzer et al., 2013; Gierahn et al., 2017). Indeed, scMOCa can easily be combined with currently available techniques that allow sequencing RNA from single cells captured in wells( Brennecke et al., 2013) and microfluidic chips( Wu et al., 2014; Tan et al., 2017). More generally, it is becoming increasingly obvious that the capacity to analyze rare cells in heterogeneous populations will be useful in designing personalized treatments for cancer( Hood et al., 2004; Pugia et al., 2017) as well as for inflammatory, autoimmune, and neurologic disorders( Miltenyi et al., 1990; Weissleder, 2009; Hesketh et al., 2017).", "role": "user" }, { "content": "When scientists use microscopes to look at cells , they often want to then isolate certain cells based on how these look like . For example , researchers may want to select cells with specific shapes , movements or division rates , because these visual clues give important information about how the cells may be behaving in the body . However , it remains difficult to precisely pick a few live cells within a bigger sample . To address this problem , Binan et al . created a new approach , called single cell magneto-optical capture ( scMOCa ) , to set aside specific cells within a larger population . The technique uses the lasers present on confocal microscopes to attach tiny metallic beads to the surface of chosen cell . Then , a magnetic field is applied to gently pull the cell to a new location . The method is cheap – it relies on commonly available research tools – and it works on a broad variety of cells . In the future , scMOCa could be used to capture and then grow cells that can only be recognized by how they look or behave , which will help to study them in greater details .", "role": "assistant" } ]

[ { "content": "Examine the text provided from a scientific article. Identify entities and classify them.\n\nPresent your findings in a JSON format: {\"Gene\": [\"SSX\", ...]}. If no entities are found, use an empty list.\n\nText:\n\nHuman peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders. Two peroxisomal targeting signals, PTS1 and PTS2, are involved in the import of proteins into the peroxisome matrix. Human patients with fatal generalized peroxisomal deficiency disorders fall into at least nine genetic complementation groups. Cells from many of these patients are deficient in the import of PTS1-containing proteins, but the causes of the protein-import defect in these patients are unknown. We have cloned and sequenced the human cDNA homologue (PTS1R) of the Pichia pastoris PAS8 gene, the PTS1 receptor (McCollum, D., E. Monosov, and S. Subramani. 1993. J. Cell Biol. 121:761-774). The PTS1R mRNA is expressed in all human tissues examined. Antibodies to the human PTS1R recognize this protein in human, monkey, rat, and hamster cells. The protein is localized mainly in the cytosol but is also found to be associated with peroxisomes. Part of the peroxisomal PTS1R protein is tightly bound to the peroxisomal membrane. Antibodies to PTS1R inhibit peroxisomal protein-import of PTS1-containing proteins in a permeabilized CHO cell system. In vitro-translated PTS1R protein specifically binds a serine-lysine-leucine-peptide. A PAS8-PTS1R fusion protein complements the P. pastoris pas8 mutant. The PTS1R cDNA also complements the PTS1 protein-import defect in skin fibroblasts from patients--belonging to complementation group two--diagnosed as having neonatal adrenoleukodystrophy or Zellweger syndrome. The PTS1R gene has been localized to a chromosomal location where no other peroxisomal disorder genes are known to map. Our findings represent the only case in which the molecular basis of the protein-import deficiency in human peroxisomal disorders is understood.", "role": "user" }, { "content": "{\"Gene\": [\"PTS2\", \"PTS1R\", \"Two peroxisomal targeting signals\", \"PTS1\", \"peroxisomal targeting signal-1 receptor\", \"PTS1-containing proteins\", \"PTS1 receptor\", \"PAS8\", \"pas8\"]}", "role": "assistant" } ]

[ { "content": "Craft a concise summary for a chemistry research paper using the provided title and selected text segments.\n\nHeading:\nA Responsive Europium(III) Chelate that Provides a Direct Readout of pH by MRI\n\nContent Extracts:\n\n<p>Magnetic resonance imaging (MRI) is one of the most widely used, noninvasive imaging modalities in clinical medicine.1 One reason for its popularity is that image contrast arises from inherent differences in water proton densities and relaxation rates between various tissue components. Even with these natural contrast differences between tissues, exogenous contrast agents that alter proton relaxation times (T1, T2, or T2*) are still widely used to enhance contrast between various tissue compartments.2</p><p>A new type of image contrast based on a chemical exchange saturation transfer (CEST) mechanism was recently introduced.3 Paramagnetic versions of CEST agents have the potential of offering two major advantages over Gd3+-based imaging agents.4 First, image contrast produced by a PARACEST agent can be switched \"on\" or \"off\" by application of a frequency-selective radio frequency pulse. This feature allows potential multiplexing of agents in a single study. Second, since contrast in these systems is based on chemical exchange of either liable protons or water molecules, the agents are extremely sensitive to exchange rates (kex). This feature makes them attractive for developing biologically responsive sensors. PARACEST sensors using a variety of design platforms have been reported for measuring pH,5,6 temperature,7 Zn2+,8 glucose,9 nitric oxide,10 phosphate esters,11 and enzyme activity.12,13</p><p>Most PARACEST sensors reported to date have a CEST signal that changes intensity in response to external stimuli. This of course requires a separate measure of agent concentration to obtain quantitative results. Some exceptions include agents that use either a cocktail of agents5 or single agents having multiple weakly shifted −NH exchangeable protons for ratiometric imaging.6 The later design feature has the disadvantage of relying on exchange sites that are relatively close to the bulk water frequency (typically < 15 ppm). Here, we address this problem by presenting a novel europium(III) DOTA-monoketonetris(amide) complex that has a single highly shifted water exchange peak whose frequency varies as a function of solution pH. We demonstrate that this single agent is nearly ideal for measuring pH by use of ratiometric CEST imaging without the need of a second concentration marker.</p><p>Previously reported Eu3+-based PARACEST agents have a highly shifted water exchange peak that is independent of pH between 5 and 8.5 More recently, we discovered that the chemical shift of the Eu3+-bound water exchange peak can be altered considerably by varying the electron density on a single amide oxygen donor in these DOTA-tetraamide systems.14 This observation was later expanded to multi-frequency PARACEST agents15 but again none of those were pH sensitive. Given these prior observations, we envisioned a new type of complex, Eu-1, wherein one of the amide side chains is replaced by ketone oxygen donor that is directly conjugated to an ionizable group, in this case a phenol unit (Figure 1).</p><p>The absorption spectrum of Eu-1 displays a bathochromic shift from 310 nm to 360 nm as the phenolic proton is removed (Figure 2), consistent with extended delocalization of the phenolate anion through the π system to form the quinone-like structure. This would place more negative charge on the carbonyl oxygen atom coordinated to the Eu3+ ion (Figure 1). The pKa derived from these optical data (6.7 ± 0.1) is nearly ideal for pH measurements in biological systems. One would predict a priori that such a resonance structure would also alter the water exchange rate and potentially the frequency of the exchanging water molecule.15 The CEST spectra of Eu-1 recorded at five different pH values (Figure 3) showed a surprisingly large change in exchange frequency over this same pH range. The pKa of Eu-1 derived from the CEST data was 6.5 ± 0.1 (Figure S2), nearly identical to the value determined optically.</p><p>This unusual CEST feature suggests it may be possible to image pH directly using Eu-1 and ratiometric CEST imaging. For example, the ratio of CEST intensities after activation of Eu-1 at 55 versus 49 ppm was found to be nearly linear between pH 6.0 and 7.6, and, more importantly, independent of Eu-1 concentration (Figure S5). Other combinations of activation frequencies gave similar results. Thus, Eu-1 offers several advantages over previously reported ratiometric pH indicators. First, the pH measurement can be made using a single reagent rather than a cocktail of agents5 and, second, the exchange peak in Eu-1 is shifted well away from the frequency of solvent protons so it can be activated without concern about partial off-resonance saturation of bulk water protons.6,16,17</p><p>To demonstrate the simplicity of using this agent for imaging pH by MRI, CEST images of a phantom prepared from five Eu-1 samples adjusted to different pH values (plus a control sample lacking Eu-1) were collected at two presaturation frequencies, 54 and 47 ppm. The CEST intensity ratio in these two images is shown in Figure 4b as a color map. The sample containing water alone showed nearly perfect cancellation while the CEST ratio in samples of Eu-1 varied from 0.43 (sample at pH 6.0) to 2.32 (sample at pH 7.6), a substantial dynamic range. Using these ratios and the calibration curve of Figure S6, the pH values derived from the CEST images (Figure 4c) perfectly matched those measured by use of a pH electrode (Figure 4a).</p><p>The bound water lifetimes (τM) of the protonated and deprotonated Eu-1 species were determined by fitting CEST spectra recorded at pH 5.0 and 8.0, respectively, (Figure S7) to the Bloch equations using previously published methods.18 That fitting procedure gave τM values of 239 μs at pH 5.0 and 120 μs at pH 8.0. This result is consistent with the expected increase in water exchange rate as the acetyl oxygen donor atom gains more negative charge at the higher pH value. The width of the water exchange peak in Eu-1 does broaden somewhat at high pH values, again consistent with faster water exchange. Water exchange in Eu-1 is even faster at 310 K as expected (τM was found to be 123 μs and 45 μs for the protonated versus deprotonated species at these same two pH values) while the frequency shifts in the bound water exchange peak were similar to those found at 298 K. This indicates that Eu-1 will also be effective for ratiometric CEST imaging of pH at physiological temperatures as well (Figure S8).</p><p>In summary, a novel Eu3+-based PARACEST agent is reported that provides a concentration independent measure of pH by ratiometric CEST imaging. A unique aspect of this agent is that the ratiometric image data can be collected at CEST activation frequencies widely separated from the bulk water frequency and the pKa of the sensor is nearly ideal for imaging pH over a range of interest for detecting abnormal physiology. The basic platform technology reported here will likely prove useful in the design of other types of responsive imaging agents as well.</p>", "role": "user" }, { "content": "A europium(III) DO3A-tris(amide) complex is reported for imaging pH by MRI using ratiometric CEST principles. Deprotonation of a single phenolic proton between pH 6 and 7.6 results in an ~5 ppm shift in the water exchange CEST peak that is easily detected by MRI. Collection of two CEST images at two slightly different activation frequencies provides a direct readout of solution pH without the need of a concentration marker.", "role": "assistant" } ]

[ { "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: Genome-wide identification of RETINOBLASTOMA RELATED 1 binding sites in Arabidopsis reveals novel DNA damage regulators\nContent:\nAbstract:\nRetinoblastoma( pRb) is a multifunctional regulator, which was likely present in the last common ancestor of all eukaryotes. The Arabidopsis pRb homolog RETINOBLASTOMA RELATED 1( RBR1), similar to its animal counterparts, controls not only cell proliferation but is also implicated in developmental decisions, stress responses and maintenance of genome integrity. Although most functions of pRb-type proteins involve chromatin association, a genome-wide understanding of RBR1 binding sites in Arabidopsis is still missing. Here, we present a plant chromatin immunoprecipitation protocol optimized for genome-wide studies of indirectly DNA-bound proteins like RBR1. Our analysis revealed binding of Arabidopsis RBR1 to approximately 1000 genes and roughly 500 transposable elements, preferentially MITES. The RBR1-decorated genes broadly overlap with previously identified targets of two major transcription factors controlling the cell cycle, i. e. E2F and MYB3R3 and represent a robust inventory of RBR1-targets in dividing cells. Consistently, enriched motifs in the RBR1-marked domains include sequences related to the E2F consensus site and the MSA-core element bound by MYB3R transcription factors. Following up a key role of RBR1 in DNA damage response, we performed a meta-analysis combining the information about the RBR1-binding sites with genome-wide expression studies under DNA stress. As a result, we present the identification and mutant characterization of three novel genes required for growth upon genotoxic stress.\nIntroduction:\nThe first molecular function assigned to the human tumor suppressor Retinoblastoma( pRb) was that of a transcriptional repressor controlling entry into S-phase. It was shown that pRb binds and inhibits the function of E2F-DP transcription factors and that phosphorylation of pRb by CDK-cyclin complexes disrupts this interaction, releasing E2F-controlled genes from repression[1]. Since then, a wealth of additional functions in cell proliferation, differentiation, environmental response and genome stability have been discovered for the family of pRb related proteins in various organisms[2–5]. To date, more than 200 interactors of human pRb are listed in the BioGRID database[6], reflecting the multi-functionality of this molecular hub. Although there is evidence for a role outside the nucleus, e. g. in the cytoplasm to regulate nuclear import of viral proteins[7] and at mitochondria where pRb seems involved in the control of apoptosis[8], most functions of pRb-type proteins are chromatin associated[5]. The pRb–E2F module originated before the divergence of the plant and animal lineages, likely in the last common ancestor of all eukaryotes[9]. While there exists only one pRb homolog in C. elegans, i. e. lin-35, there are two homologs, Rbf1 and Rbf2, in Drosophila and in humans, pRb is member of a small gene family comprising pRb( p105), p107 and p130[10]. In the model plant Arabidopsis thaliana, there is only one homolog, termed RBR1( RETINOBLASTOMA RELATED 1) and its loss is female gametophytic lethal[11]. In their function as transcriptional regulators of the cell cycle, pRb-type proteins not only control G1-S transition in proliferating cells but also operate at other phases, i. e. as repressors of G2 and M phase genes in response to DNA damage[12] as well as in G0 to control quiescence as part of the DREAM complex. The human DREAM complex consists of DP, pRb-like( p130 or p107), E2F and the Multivulval class B( MuvB) core-complex, comprising five additional proteins, LIN9, LIN37, LIN52, LIN54, and RBAP48. When cells exit G0 and reenter the cell cycle, the DREAM-complex is disassembled upon phosphorylation of p130/p107 and the MuvB-core-complex sequentially associates with other transcription factors, like B-Myb and Fox-M1 to activate different sets of genes important for subsequent phases of the cell cycle[13, 14]. In Drosophila, a homologous complex, termed dREAM( Drosophila Rbf, E2F2 and Myb-interacting proteins), has been characterized but, in contrast to mammals, the fly pRb-type proteins and the only Myb transcription factor have been shown to concomitantly bind the MuvB-core complex[15, 16]. Recently, different versions of an Arabidopsis DREAM-like complex were described by Kobayashi and co-workers and have been implicated in the control of mitotic genes[17]. Arabidopsis contains five three-repeat MYBs( MYB3R), that function as transcriptional activators and/or repressors of mitosis[17–19]. Since members of both classes of MYB proteins were found to interact with DREAM components, these data suggest the existence of activating and repressive DREAM-complexes depending on which MYB3R transcription factor is present[4]. In addition to its role in controlling progression through the cell cycle, RBR1, like its animal counterparts[20], is involved in developmental decisions, e. g. by interacting with non-E2F transcriptions factors such as SCARECROW( SCR) to control asymmetric cell divisions in the root meristem[21, 22] and FAMA during stomata development[22, 23]. Furthermore, RBR1 has been attributed a role in promoting the meiotic fate of the megaspore mother cell by repressing the expression of the stem cell factor WUSCHEL[24]. Like human pRb, which interacts with different chromatin modifiers, such as histone deacetylases and methyltransferases[25], the SWI-SNF complex[26, 27], and the Polycomb repressive complexes( PRC)[28, 29], Arabidopsis RBR1 has also been linked to chromatin modification[30]. For example, RBR1 has been shown to complex with the PRC2 subunits FIE[31] as well as MSI1[32], and a RBR1-PRC2 cooperation has been proposed to allow the switch from late embryogenesis to autotrophic seedling development[33]. Another facet of Arabidopsis RBR1 is its role in DNA damage response( DDR)[34, 35], which involves two different modes of action. On the one hand RBR1 binds to and represses DDR genes and by that likely links their regulation to activation of E2F and entry into the cell cycle[34, 35]. On the other hand, RBR1 partially co-localizes with γH2AX, a marker for double strand breaks[34, 35], and is required for the recruitment of the DNA repair protein RAD51 to DNA lesions[34]. In addition to its role at damage-induced double strand brakes( di-DSBs), RBR1 has also been shown to localize to SPO11-dependent foci in early meiotic prophase, most likely reflecting processed sites of programmed double strand breaks( p-DSBs), i. e. sites of cross-over formation[36]. Thus, like its animal homologs, Arabidopsis RBR1 is a multi-functional protein. However, despite several studies on specific aspects, a comprehensive view of RBR1 action has been precluded by the lack of genome-wide DNA binding data. Using an optimized ChIP protocol on Arabidopsis cell culture material, we now generated the first comprehensive collection of direct RBR1 targets. These data allowed us to obtain insights into the properties of RBR1 binding in mitotically active cells revealing the localization of RBR1 to genes and transposable elements( TEs). Furthermore, we then used this dataset to identify three new genes to be required for growth under genotoxic stress providing functional evidence for the power of our genome-wide study.\nDiscussion:\nHere we have presented the first genome wide RBR1-binding study in plants. We show, that RBR1 associates with TEs, especially MITEs, and with genes highly enriched for GO-terms like cell cycle, replication, chromatin and DNA repair in actively dividing cells. However, previously described developmental RBR1 targets remain unmarked. To investigate RBR1's proposed role as a potential integrator of cell cycle regulation with developmental processes, genome-wide RBR1 distribution at specific developmental time points and in defined cell types will be beneficial and can be achieved by applying our optimized ChIP protocol in combination with FACS or INTACT methods[113, 114]. Further, our results demonstrate a vast commonality of genes bound by E2Fa, MYB3R3 and RBR1. In this respect, it will be valuable to gain and integrate information on genome wide binding of the different MYB3R and E2F transcription factors as well as RBR1 in distinct cell types as well as upon short and long term DNA damage. Recently, an involvement in DDR has been shown for repressive MYB3R proteins, but so far only the impact on G2/M genes has been analyzed in detail[115]. A comprehensive, context-dependent analysis will reveal if specific compositions of the DREAM complex govern the expression of the same genes in different cellular contexts or if different DREAM complexes have distinctive targets. Finally, the here presented set of RBR1-controlled genes is a valuable resource that can be exploited to identify new genes involved e. g. in cell cycle control, chromatin remodeling and DNA repair as exemplified by our successful approach to reveal new DNA damage regulators.", "role": "user" }, { "content": "The Retinoblastoma ( pRb ) tumor suppressor is a master regulator of the cell cycle and its inactivation is associated with many types of cancer . Since pRb’s first description as a transcriptional repressor of genes important for cell cycle progression , many more functions have been elucidated , e . g . in developmental decisions and genome integrity . Homologs of human pRb have been identified in most eukaryotes , including plants , indicating an ancient evolutionary origin of pRb-type proteins . We describe here the first genome-wide DNA-binding study for a plant pRb protein , i . e . RBR1 , the only pRb homolog in Arabidopsis thaliana . We see prominent binding of RBR1 to the 5’ region of genes involved in cell cycle regulation , chromatin organization and DNA repair . Moreover , we also reveal extensive binding of RBR1 to specific classes of DNA transposons . Since RBR1 is involved in a plethora of processes , our dataset provides a valuable resource for researches from different fields . As an example , we used our dataset to successfully identify new genes necessary for growth upon DNA damage exerted by drugs such as cisplatin or the environmentally prevalent metal aluminum .", "role": "assistant" } ]

[ { "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: Hydroxychloroquine, by itself or with azithromycin, did not improve the clinical status of patients with mild to moderate COVID-19\n\nResearch Abstract:\nCoronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high fatality.\nThe most urgent need is to find effective treatments.\nWe sought to determine whether hydroxychloroquine (HCQ) application may reduce the death risk of critically ill COVID-19 patients.\nIn this retrospective study, we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital, Wuhan, from February 1, 2020 to April 4, 2020.\nAll 550 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them were treated with oral HCQ treatment (200 mg twice a day for 7-10 days) in addition to the basic treatments.\nPrimary endpoint is fatality of patients, and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine (NHCQ) treatments.\nWe found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001).\nThe time of hospital stay before patient death is 15 (10-21) days and 8 (4-14) days for the HCQ and NHCQ groups, respectively (P<0.05).\nThe levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 (8.3-118.9) pg mL-1 at the beginning of the treatment to 5.2 (3.0-23.4) pg mL-1 (P<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group.\nThese data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm.\nTherefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives.\nhydroxychloroquine, IL-6, mortalities, COVID-19.", "role": "user" }, { "content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"We found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001).\", \"The time of hospital stay before patient death is 15 (10-21) days and 8 (4-14) days for the HCQ and NHCQ groups, respectively (P<0.05).\", \"The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 (8.3-118.9) pg mL-1 at the beginning of the treatment to 5.2 (3.0-23.4) pg mL-1 (P<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group.\", \"Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives.\"]}", "role": "assistant" } ]

[ { "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: Hydroxychloroquine is a medication that doctors prescribe to treat a variety of conditions, including malaria, arthritis, and lupus.\n\nResearch Abstract:\nHydroxychloroquine (HCQ) has sparked much interest in the therapeutics of the Coronavirus Disease 2019 (COVID-19) pandemic.\nIts antiviral properties have been studied for years; regarding the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2), it has been shown that HCQ may act at multiple levels.\nThese extend from the initial attachment of the virus to the respiratory epithelium to the inhibition of its replication by the alkalinisation of the phagolysosome's microenvironment and the post-translational modification of certain viral proteins.\nPreliminary clinical evidence from China and France showed significant virological and clinical benefit in HCQ-treated patients, while other studies, mostly including critically ill patients, did not show favorable results.\nIn this review, we critically appraise the existing evidence on HCQ against SARS-CoV-2 with particular emphasis on its protective and therapeutic role.\nSafety concerns that are relevant to the short-term HCQ use are also discussed.\nIn the context of the rapid evolution of the COVID-19 pandemic that strains the health care systems worldwide and considering limited population-wide testing rates in most of the vulnerable countries, early empiric short-term administration of HCQ in symptomatic individuals, may be a promising, safe and low-cost strategy.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "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 isogeometric analysis, it is frequently required to handle the geometric models enclosed by four-sided or non-four-sided boundary patches, such as trimmed surfaces. In this paper, we develop a Gregory solid based method to parameterize those models. First, we extend the Gregory patch representation to the trivariate Gregory solid representation. Second, the trivariate Gregory solid representation is employed to interpolate the boundary patches of a geometric model, thus generating the polyhedral volume parametrization. To improve the regularity of the polyhedral volume parametrization, we formulate the construction of the trivariate Gregory solid as a sparse optimization problem, where the optimization objective function is a linear combination of some terms, including a sparse term aiming to reduce the negative Jacobian area of the Gregory solid. Then, the alternating direction method of multipliers (ADMM) is used to solve the sparse optimization problem. Lots of experimental examples illustrated in this paper demonstrate the effectiveness and efficiency of the developed method.\n\nCited Works Summary:\n[1]: This paper provides a tutorial and survey of methods for parameterizing surfaces with a view to applications in geometric modelling and computer graphics. We gather various concepts from differential geometry which are relevant to surface mapping and use them to understand the strengths and weaknesses of the many methods for parameterizing piecewise linear surfaces and their relationship to one another.\n\n[2]: \n\n[3]: A method based on graph theory is investigated for creating global parametrizations for surface triangulations for the purpose of smooth surface fitting. The parametrizations, which are planar triangulations, are the solutions of linear systems based on convex combinations. A particular parametrization, called shape-preserving, is found to lead to visually smooth surface approximations.\n\n[4]: We present a survey of recent methods for creating piecewise linear mappings between triangulations in 3D and simpler domains such as planar regions, simplicial complexes, and spheres. We also discuss emerging tools such as global parameterization, inter-surface mapping, and parameterization with constraints. We start by describing the wide range of applications where parameterization tools have been used in recent years. We then briefly review the pertinent mathematical background and terminology, before proceeding to survey the existing parameterization techniques. Our survey summarizes the main ideas of each technique and discusses its main properties, comparing it to other methods available. Thus it aims to provide guidance to researchers and developers when assessing the suitability of different methods for various applications. This survey focuses on the practical aspects of the methods available, such as time complexity and robustness and shows multiple examples of parameterizations generated using different methods, allowing the reader to visually evaluate and compare the results.\n\n[5]: Remeshing is a key component of many geometric algorithms, including modeling, editing, animation and simulation. As such, the rapidly developing field of geometry processing has produced a profusion of new remeshing techniques over the past few years. In this paper we survey recent developments in remeshing of surfaces, focusing mainly on graphics applications. We classify the techniques into five categories based on their end goal: structured, compatible, high quality, feature and error-driven remeshing. We limit our description to the main ideas and intuition behind each technique, and a brief comparison between some of the techniques. We also list some open questions and directions for future research.\n\n[6]: \n\n[7]: Given an arbitrary mesh, we present a method to construct a progressive mesh (PM) such that all meshes in the PM sequence share a common texture parametrization. Our method considers two important goals simultaneously. It minimizes texture stretch (small texture distances mapped onto large surface distances) to balance sampling rates over all locations and directions on the surface. It also minimizes texture deviation (“slippage” error based on parametric correspondence) to obtain accurate textured mesh approximations. The method begins by partitioning the mesh into charts using planarity and compactness heuristics. It creates a stretch-minimizing parametrization within each chart, and resizes the charts based on the resulting stretch. Next, it simplifies the mesh while respecting the chart boundaries. The parametrization is re-optimized to reduce both stretch and deviation over the whole PM sequence. Finally, the charts are packed into a texture atlas. We demonstrate using such atlases to sample color and normal maps over several models.", "role": "user" }, { "content": "Triangular mesh parametrization is a commonly employed technique in curve and surface fitting [3] , texture mapping [7] , remeshing [5] , and so on. A triangular mesh parametrization constructs a bijective mapping from the mesh in three dimension to a planar domain. According to the requirements of applications, the frequently used mapping methods in mesh parametrization includes discrete harmonic mapping [3] , discrete equiareal mappings [6] , and discrete conformal mapping [2] . For more details on triangular mesh parametrization methods and their applications, please refer to [1] [4] .", "role": "assistant" } ]

[ { "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:\nsevere aplastic anemia ( saa ) is a fatal disease characterized by pancytopenia and hypocellular bone marrow .\nbone marrow transplantation is the treatment of choice for young patients who have a human leukocyte antigen ( hla ) matched sibling donor .\nimmunosuppressive treatment ( ist ) with antithymocyte globulin ( atg ) and cyclosporine is an effective therapy for patients who have no suitable donor .\natg exerts its action by depleting clonal suppressor t cells implicated in the pathogenesis of saa123 ) .\nthe depletion of suppressor t cells by atg could change the b - cell activation12 ) .\nthere have been rare reports on the association between atg treatment for saa and the development of autoimmune hyperthyroidism4567 ) . because horse atg ( hatg ) is no longer available for the treatment of saa in most countries , rabbit atg ( ratg )\nmoreover , as ratg has more potent and prolonged suppression of t cells than hatg8 ) , more frequent encounters of autoimmune hyperthyroidism can be anticipated .\nwe report the rare case of graves disease following ratg treatment for saa in a korean child .\na 12-year - old boy visited chonnam national university hwasun hospital because of petechiae , easy bruising and knee joint pain in december 2007 .\na complete blood count showed white blood cell 1,600/l , hemoglobin 11.7 g / dl , platelets 4,000/l , absolute neutrophil count 940/l , and corrected reticulocyte count 0.89% .\nthe patient was diagnosed as a saa . as he had no hla - matched sibling , he was treated with ist using ratg ( thymoglobuline , genzyme , cambridge , ma , usa ; 3.5 mg / kg / day for 5 days ) and cyclosporine ( 5 mg / kg / day ) and methylprednisolone ( 2 mg / kg / day for 5 days , then tapered over 30 days ) . while being treated with ist , he developed peripheral neuropathy with pain and tingling sensation in both extremities , requiring a sympathetic nerve block , which relieved symptoms .\ntwenty - three months after ist with ratg , he complained of mild hand tremors , sweating , weight loss , palpitations and goiter .\nsubsequent thyroid function tests showed the hyperthyroidism ( free thyroxine , 3.42 ng / dl ; tsh , < 0.01 niu / ml ; triiodothyronine , 3.99 ng / ml ; thyroxine , 17.3 g / dl ) .\nautoantibody results were as follows : antimicrosome antibody ( + ) , tsh - binding inhibitory immunoglobulin ( + ) , antithyroglobulin antibody ( - ) , and antinuclear antibody ( - ) .\na tc-99 m pertechnetate thyroid scan showed enlarged thyroid gland with diffuse uptake ( fig .\nthe patient has been disease free 39 months after ist and 9 months after methimazole treatment\n. currently , his blood counts and thyroid function tests are normal , and he has no discomfort from graves disease .\ngraves disease is an autoimmune disorder characterized by hyperthyroidism , diffuse goiter , ophthalmopathy , and occasionally a dermopathy referred to as pretibial or localized myxedema9 ) . in immune pathogenesis of graves disease ,\nb and t cells have a major role in the production of tsh receptor antibodies ( tshr - ab ) that are responsible for the thyroid stimulation and growth .\nthese activated t cells in turn increase the secretion of tshr - ab from b cells .\nthe hyperthyroidism and goiter of graves disease are caused by stimulation of the thyroid by tshr - ab9 ) .\nit has been suggested that a genetic clonal lack of suppressor t cells may be responsible for the unregulated production of tshr - ab in in vitro studies10 ) .\nthe pathogenesis of aplastic anemia is thought to be t - cell - mediated destruction of hematopoietic progenitors and stem cells .\na variety of in vitro and in vivo research supported the implication of immune effector cells and cytokines , such as interferon- or tumor necrosis factor-1 ) .\nthe mechanism action of atg therapy for aplastic anemia is likely complex and multifactorial , but its main mechanism is thought to have immunosuppressive effect by depleting peripheral t cells from the circulation through complement - dependent lysis or activation associated apoptosis11 ) .\natg is manufactured through the immunization of horses or rabbits with thymocytes or t - cell lines , followed by the purification of the igg fraction of the sera from these animals . between hatg and ratg preparations ,\nthus , they are dissimilar in inducing activation of t cells , as exemplified in the case of expansion of regulatory t cells11 ) . also , gene expression profiling was markedly different between cells treated with both preparations11 ) .\nas a consequence , hatg and ratg would provide different mechanisms of action through multiple modes of immunomodulation . despite the differences mentioned above , hatg and ratg\nhave generally been used interchangeably in the clinic . however , in a recent randomized , prospective trial , ratg plus cyclosporine compared unfavorably with hatg plus cyclosporine when used as a first - line treatment .\nthe use of ratg led to a more profound depletion of cd4 + t cells , whereas both preparations resulted in a similar depletion of cd8 + t cells8 ) .\nthe depletion of suppressor t cells by atg was thought to have a role in the development of many autoimmune disorders3 ) .\ninterferon- is vital for cell - mediated immunity , inhibition of inappropriate b - cell proliferation and antibody production .\nit is secreted by a subset of suppressor t cells to inhibit th2-cells which in turn activate b cells13 ) .\nthus , depletion of suppressor t cells and resultant decreased production of interferon- by atg could also allow b - cell activation , which increases the risk of autoimmune disorder .\nthis was supported by studies showing that interferon- down - regulates tshr - ab production14 ) .\nit also attenuated tsh receptor ( the tshr - ab target ) synthesis in graves disease15 ) .\nthus , impaired interferon- production can cause derestricted tshr - ab production and increased tsh receptor production , resulting in immune hyperthyroidism .\nthere are a few reports of graves disease after treatment with atg for saa4567 ) .\nthree cases have been described occurring 26 , 42 , and 106 months after treatment with antilymphocyte globulin or atg in patients aged 25 , 30 , and 35 years , respectively4 ) . a 62-year - old man developed graves disease and fibrosing alveolitis 15 days after the administration of atg for saa5 ) .\nthe first case in children was described 6 years after atg in a 10-year - old boy7 ) .\nthis case represents the first case of possible implication of ratg in the pathogenesis of autoimmune hyperthyroidism .\nrecently , hatg is no longer available for the treatment of saa in europe , japan , latin america , and korea .\nmoreover , ratg has more potent and prolonged suppression of t cells than hatg8 ) , and the development of autoimmune hyperthyroidism may be encountered more frequently .\ntherefore , thyroid function tests should be incorporated in the routine follow - up of saa following ratg treatment .", "role": "user" }, { "content": "antithymocyte globulin ( atg ) is used as an immunosuppressive treatment ( ist ) to deplete clonal suppressor t cells in patients with severe aplastic anemia ( saa ) . \n the depletion of suppressor t cells by atg may affect the activation of b cells , which results in an increased risk for autoimmune conditions . \n a 12-year - old boy was diagnosed with idiopathic saa . \n as he did not have an human leukocyte antigen - matched sibling , he was treated with rabbit atg ( 3.5 mg / kg / day for 5 days ) and cyclosporine . \n five months later , he became transfusion independent . \n however , 23 months after ist , he complained of mild hand tremors , sweating , weight loss , palpitations , and goiter . \n results of thyroid function tests revealed hyperthyroidism ( free thyroxine , 3.42 ng / dl ; thyroid stimulating hormone [ tsh ] , \n < 0.01 niu / ml ; triiodothyronine , 3.99 ng / ml ) . results of tests for autoantibodies were positive for the antimicrosome antibody and tsh - binding inhibitory immunoglobulin , but negative for the antithyroglobulin antibody and antinuclear antibody . \n he was treated with methimazole , and his symptoms improved . \n the patient has been disease free for 39 months after ist and 9 months after methimazole treatment . \n this case report suggests that although rare , rabbit atg may have implications in the pathogenesis of autoimmune hyperthyroidism . \n our findings suggest that thyroid function tests should be incorporated in the routine follow - up of saa patients treated with atg .", "role": "assistant" } ]

[ { "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:\nfuture releases of tcsnp will integrate new t. cruzi sequences as they become available . many of these are expected to come from a resequencing effort that is underway in our lab .\nplanned updates to the website functionality include the development of a standardized api and web services through which other databases can consume the information provided by tcsnp and the development of functionality to design primers by interfacing with primer3 ( 19 ) , while using the snp information in this process .\nthe tcsnp database is composed of a web application written in perl , running against a postgresql database .\nthe database schema is based on the genomics unified schema ( gus , http://gusdb.org ) with local customizations .\nthe web application has been developed using a model - view - controller architectural pattern , where the work of each layer is performed by a specialized perl component [ all components are available from cpan ( 20 ) ] .\naccess to the database from perl ( i.e. the model ) is done through a hybrid combination of ( i ) an abstraction of the database schema using perl 's dbix::class package and ( ii ) custom sql queries executed using perl 's database access interface ( dbi ) .\nthe controller component managing user 's requests and dispatching calls to other components is perl 's catalyst ( 21 ) .\na number of custom controller modules were developed , which contain the business logic of the tcsnp application . finally , the viewer component is perl 's template toolkit , which uses custom templates to render web pages using information provided by the controller .\nthe database runs on dedicated freebsd servers , with the catalyst web application running under the apache web server .\nthe reference genome sequence of the cl brener strain of t. cruzi was obtained from genbank using the umbrella accession number aahk00000000 ( july , 2005 ) . other t. cruzi sequences ( mrnas and ests )\nwere also obtained from genbank using custom entrez queries ( may , 2007 ) . before loading into the database\nthis was necessary because of the variations in how different authors write the names of strains in genbank submissions and publications .\ncl brener strain appears in different genbank sequences as cl brener , cl - brener , clbrener , cl - brenner , cl brenner , cl brenner , or cl brener ( note the different capitalization , use of middle dash , spaces and the writing of the strain name using a single or a double n ) . because the database allows users to perform searches using strain names , it was important to reduce redundancy where possible .\nin some cases , however , it was important to keep the distinction between similar strain names , for example to discriminate between cloned stocks and their parental uncloned strains .\nas an example , we have kept caniii and caniii cl1 ( cl1 stands for clone 1 ) , and sc43 and sc43 cl1 as different \nredundancy is still present , however , and further curation of strain names can be done .\nwe also encourage users of the database to send feedback about this issue . before clustering all sequences\nwere masked against a library of vector sequences and t. cruzi repetitive elements , as described previously ( 22 ) .\nannotated coding sequences from the reference genome , and other publicly available sequences were mapped against the genome scaffolds using blat .\nsequences mapping to the same genomic regions were clustered together and multiple sequence alignments were obtained using phrap .\nthis initial clustering allowed us to group mrnas , ests and reference coding sequences to the reference genome assembly sequences .\nbut because allelic variants in the cl - brener genome were separated during assembly ( 12 ) , those initial clusters showed many instances of allelic variants separated into different alignments ( i.e. each mapping to its own contig ) . to obtain alignments between allelic variants , we merged alignments with highly similar consensus sequences ( by blast analysis ) . afterwards , and based on user feedback , we have also merged , splitted and re - analyzed many alignments .\nusers of tcsnp should also be aware of the fact that many sequences from the cl - brener genome assembly are located in contigs with assembly problems or may represent assembly artifacts . for sequences containing assembly warnings in the original genbank records ,\nwe have attached similar notes to the corresponding alignments in tcsnp to help users in the interpretation of the snp data .\nmultiple sequence alignments were scanned to identify polymorphic columns . to calculate the probability of these sites being true polymorphisms\nas opposed to sequencing errors , we have used the software package polybayes , version 5 ( 13 ) . polybayes uses a bayesian statistical framework that relies on allele frequency , alignment depth and base quality values amongst other attributes to calculate a probability score .\nbecause chromatogram trace data are not available for many of the sequences in this release , we have devised a scoring strategy that uses arbitrary base quality values .\nsequence bases obtained from the t. cruzi cl - brener genome ( 19x shotgun coverage ) were arbitrarily assigned a base quality value of 40 ; those from genbank records , a value of 30 ( individual submissions ) ; and those from dbest , a value of 20 ( single - pass , unedited ) . as an example , using this scoring scheme , a single base from an est differing from two allelic variants of cl - brener reference sequence ( depth = 3 ) would give a probability of 0.22 of being a true snp ( see for example : http://snps.tcruzi.org/snps/view/4028216 ) . to analyze the effect of each snp on the corresponding protein product\n, we noted the codon position of the snp in each reference coding sequence and evaluated the change introduced by the polymorphic base .\nalso , for a subset of the alignments ( those containing coding sequences of similar length , with indels being a multiple of 3 ) , we calculated dn and ds values ( 14 ) using bioperl 's population genetics modules ( 23 ) .\nthe tcsnp database is composed of a web application written in perl , running against a postgresql database .\nthe database schema is based on the genomics unified schema ( gus , http://gusdb.org ) with local customizations .\nthe web application has been developed using a model - view - controller architectural pattern , where the work of each layer is performed by a specialized perl component [ all components are available from cpan ( 20 ) ] .\naccess to the database from perl ( i.e. the model ) is done through a hybrid combination of ( i ) an abstraction of the database schema using perl 's dbix::class package and ( ii ) custom sql queries executed using perl 's database access interface ( dbi ) .\nthe controller component managing user 's requests and dispatching calls to other components is perl 's catalyst ( 21 ) .\na number of custom controller modules were developed , which contain the business logic of the tcsnp application . finally , the viewer component is perl 's template toolkit , which uses custom templates to render web pages using information provided by the controller .\nthe database runs on dedicated freebsd servers , with the catalyst web application running under the apache web server .\nthe reference genome sequence of the cl brener strain of t. cruzi was obtained from genbank using the umbrella accession number aahk00000000 ( july , 2005 ) . other t. cruzi sequences ( mrnas and ests )\nwere also obtained from genbank using custom entrez queries ( may , 2007 ) . before loading into the database ,\nthis was necessary because of the variations in how different authors write the names of strains in genbank submissions and publications .\ncl brener strain appears in different genbank sequences as cl brener , cl - brener , clbrener , cl - brenner , cl brenner , cl brenner , or cl brener ( note the different capitalization , use of middle dash , spaces and the writing of the strain name using a single or a double n ) . because the database allows users to perform searches using strain names , it was important to reduce redundancy where possible .\nin some cases , however , it was important to keep the distinction between similar strain names , for example to discriminate between cloned stocks and their parental uncloned strains .\nas an example , we have kept caniii and caniii cl1 ( cl1 stands for clone 1 ) , and sc43 and sc43 cl1 as different \nredundancy is still present , however , and further curation of strain names can be done .\nbefore clustering all sequences were masked against a library of vector sequences and t. cruzi repetitive elements , as described previously ( 22 ) .\nannotated coding sequences from the reference genome , and other publicly available sequences were mapped against the genome scaffolds using blat .\nsequences mapping to the same genomic regions were clustered together and multiple sequence alignments were obtained using phrap .\nthis initial clustering allowed us to group mrnas , ests and reference coding sequences to the reference genome assembly sequences .\nbut because allelic variants in the cl - brener genome were separated during assembly ( 12 ) , those initial clusters showed many instances of allelic variants separated into different alignments ( i.e. each mapping to its own contig ) . to obtain alignments between allelic variants , we merged alignments with highly similar consensus sequences ( by blast analysis ) . afterwards , and based on user feedback , we have also merged , splitted and re - analyzed many alignments .\nusers of tcsnp should also be aware of the fact that many sequences from the cl - brener genome assembly are located in contigs with assembly problems or may represent assembly artifacts . for sequences containing assembly warnings in the original genbank records ,\nwe have attached similar notes to the corresponding alignments in tcsnp to help users in the interpretation of the snp data .\nmultiple sequence alignments were scanned to identify polymorphic columns . to calculate the probability of these sites being true polymorphisms\nas opposed to sequencing errors , we have used the software package polybayes , version 5 ( 13 ) .\npolybayes uses a bayesian statistical framework that relies on allele frequency , alignment depth and base quality values amongst other attributes to calculate a probability score .\nbecause chromatogram trace data are not available for many of the sequences in this release , we have devised a scoring strategy that uses arbitrary base quality values .\nsequence bases obtained from the t. cruzi cl - brener genome ( 19x shotgun coverage ) were arbitrarily assigned a base quality value of 40 ; those from genbank records , a value of 30 ( individual submissions ) ; and those from dbest , a value of 20 ( single - pass , unedited ) . as an example , using this scoring scheme , a single base from an est differing from two allelic variants of cl - brener reference sequence ( depth = 3 ) would give a probability of 0.22 of being a true snp ( see for example : http://snps.tcruzi.org/snps/view/4028216 ) . to analyze the effect of each snp on the corresponding protein product , we noted the codon position of the snp in each reference coding sequence and evaluated the change introduced by the polymorphic base .\nalso , for a subset of the alignments ( those containing coding sequences of similar length , with indels being a multiple of 3 ) , we calculated dn and ds values ( 14 ) using bioperl 's population genetics modules ( 23 ) .\nnational agency for the promotion of science and technology ( anpcyt , argentina ) ( grant pict 38209 ) ; and the university of san martn ( grant s05/22 ) . funding for open access charge : anpcyt .", "role": "user" }, { "content": "the tcsnp database ( http://snps.tcruzi.org ) integrates information on genetic variation ( polymorphisms and mutations ) for different stocks , strains and isolates of trypanosoma cruzi , the causative agent of chagas disease . \n the database incorporates sequences ( genes from the t. cruzi reference genome , mrnas , ests and genomic sequences ) ; multiple sequence alignments obtained from these sequences ; and single - nucleotide polymorphisms and small indels identified by scanning these multiple sequence alignments . \n information in tcsnp can be readily interrogated to arrive at gene sets , or snp sets of interest based on a number of attributes . \n sequence similarity searches using blast are also supported . \n this first release of tcsnp contains nearly 170 000 high - confidence candidate snps , derived from the analysis of annotated coding sequences . \n as new sequence data become available , tcsnp will incorporate these data , mapping new candidate snps onto the reference genome sequences .", "role": "assistant" } ]

[ { "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: Stimulus Coding Rules for Perceptual Learning\nContent:\nAbstract:\nPerceptual learning of visual features occurs when multiple stimuli are presented in a fixed sequence( temporal patterning), but not when they are presented in random order( roving). This points to the need for proper stimulus coding in order for learning of multiple stimuli to occur. We examined the stimulus coding rules for learning with multiple stimuli. Our results demonstrate that:( 1) stimulus rhythm is necessary for temporal patterning to take effect during practice;( 2) learning consolidation is subject to disruption by roving up to 4 h after each practice session;( 3) importantly, after completion of temporal-patterned learning, performance is undisrupted by extended roving training;( 4) roving is ineffective if each stimulus is presented for five or more consecutive trials; and( 5) roving is also ineffective if each stimulus has a distinct identity. We propose that for multi-stimulus learning to occur, the brain needs to conceptually “tag” each stimulus, in order to switch attention to the appropriate perceptual template. Stimulus temporal patterning assists in tagging stimuli and switching attention through its rhythmic stimulus sequence.\nIntroduction:\nPractice improves discrimination of fine visual features, such as contrast, orientation, vernier offset( e. g., the alignment of two lines), texture, etc.[1–6]. This process is referred to as perceptual learning and has been studied intensively in recent years because of its close links to neural plasticity[7, 8] As in other forms of learning, stimulus information needs first to be encoded and consolidated into memory and later to be retrieved in order for perceptual learning to occur. Indeed, much has been done to understand stimulus coding effects on memory consolidation in a number of relevant domains. It is now clear that there are separate phases during which memory traces are susceptible to perturbation, during which they stabilize, and during which they are enhanced[9–11]. However, little is known about the coding stages of visual perceptual learning. In a typical perceptual learning study, the observer practices a discrimination task at a single stimulus level( e. g., 30% contrast for a contrast discrimination task or 45° orientation for an orientation discrimination task), and after a few sessions of practice, discrimination at this stimulus level is usually improved. However, if the observer has to simultaneously learn discrimination of multiple stimuli( e. g., four different contrasts or orientations), perceptual learning is disabled if the stimuli are presented in a random temporal order( roving)[3, 6, 12, 13]. In contrast, if the same stimuli are presented in a fixed temporal pattern( temporal patterning), substantial learning takes place[3]. The contrasting effects of temporal patterning and roving point to the need for proper stimulus coding to enable multiple stimulus learning. In this study we compare the effects of temporal patterning and roving and their interactions at different stages of perceptual learning, in order to reveal some basic stimulus coding principles for perceptual learning. Specifically, we investigated the roles of stimulus rhythm in perceptual learning, the effects of interruption by roving on temporal-patterned perceptual learning during consolidation and retrieval, and the minimal number of consecutive trials of the same stimulus required to escape disruption of learning through roving. Understanding the stimulus coding rules has broad implications since such multi-stimulus learning is often encountered in natural learning and is not limited to vision. Consider, for example, a baseball batter. In order to succeed, the batter needs to quickly learn to identify whether the pitch is likely to be fast or slow and whether it will curve or spin. To the best of our knowledge comparable research has not been done in other modalities, such as motor and auditory learning. The contrasting effects of temporal patterning and roving also pose serious challenges to existing models of perceptual learning. The models based on the activities of primary visual cortex( V1) neurons, such as the model of Adini, Tsodyks, and Sagi[14, 15], assume that training modifies the recurrent connections in V1 neurons, so that the local network becomes more sensitive to the trained stimulus. However, such V1-based models cannot easily explain the effects of roving and temporal patterning on multi-stimulus learning. This is because different stimuli are responded to by different sets of stimulus-tuned V1 neurons, and there is no reason to believe that training induced modification in independent local recurrent networks would be differently affected by stimulus roving and temporal patterning. Alternatively, response reweighting models, such as the Lu and Dosher model[4, 16], suggest that practice improves the readout of the most relevant V1 neuron responses to the stimulus by reweighting the responses of various neurons. The response reweighting models are designed to explain single stimulus learning. In their current form they are not capable of explaining the roving and temporal patterning effects on multi-stimulus learning. A more relevant model to our multi-stimulus learning results would be Ahissar and Hochstein's reverse hierarchy theory[17, 18]. This theory proposes an easy-to-difficult stimulus learning cascade from higher to lower level brain sites, with easy stimulus learning serving as a visual attentional pointer to lower level sites for difficult stimulus learning. Stimulus temporal patterning could serve as such a pointer because it serves to “tag” the stimuli and thus improve top-down selection. Our studies elucidate the type of tagging that the reverse hierarchy theory can make use of for the top-down training of early brain regions. To deepen our understanding of the properties of tagging, in the second part of the study, we conducted a series of experiments aimed at understanding the possible mechanism underlying stimulus temporal patterning. We instantiated the findings in a stimulus tagging model for multi-stimulus perceptual learning.\nDiscussion:\nOur results demonstrate that a rhythmic stimulus sequence is required to enable perceptual learning. Rhythmic stimulus presentation, especially with evenly spaced trials, would allow the observer to accurately switch attention to the outputs of the most appropriate set of neurons when the observer learns multi-level stimuli( see Figure 5 and our stimulus tagging model below). Jones et al.[24, 25] proposed that attention in auditory perception is an inherently oscillatory process with adjustable periodic pulses, and that a system's responses reach maximal accuracy when attention pulses synchronize with the rhythm of the external stimuli. Our results might be consistent with an oscillation case for attention in visual perception when multi-level stimuli are being learned. Perceptual learning was significantly reduced when the ITI length changed from 2 to 3 s for the current multi-contrast discrimination task, which implies a limited length of the optimal oscillation period. We also found that the first few hours of learning consolidation after each practice session are subject to disruption by roving. Seitz et al.[20] recently reported that consolidation after a block of training of a stimulus was interrupted if followed immediately by another block of training of a similar but different stimulus. But consolidation was little affected if the second block of training was conducted 1 h later. Although we and Seitz et al.[20] both study the effects of post-session interference on perceptual learning consolidation, there are two interesting differences. First, in Seitz et al. 's study[20], learning of one stimulus was interfered by another stimulus, whereas in our interference experiments, the stimuli were unchanged but the temporal pattern associated with the practiced stimuli, which we assume to help stimulus tagging, was interfered by a roving pattern. Second, consolidation took less time( <1 h) in Seitz et al. 's condition[20] than in ours( 4 h). It is unclear whether the cognitive tagging process is responsible for extended consolidation in our results, or whether it simply takes more time to consolidate learning for multiple stimuli. After perceptual learning has been completed, improved performance can no longer be reversed by extended training( or interference) with roving. Seitz et al.[20] reported that perceptual learning resists interference after some period of consolidation, as occurs in many learning tasks[26]. Again, the difference here is that only the temporal pattern or tagging of the stimuli is being interfered with in our study. It is likely that, once the multiple stimuli have been properly tagged after temporal-patterned training, stored stimulus information can be accurately and efficiently retrieved to guide visual discrimination regardless of the stimulus temporal context. Our results showed that five–eight trials is the minimal block size for each roving stimulus to be learned, which, according to our model, would suggest the minimal number of trials required for stimulus tagging. An alternative explanation is that each stimulus needs to be repeated a certain number of times, so that the stimulus trace can accumulate to resist interference by the next roving stimulus, similar to Seitz et al. 's interference with consolidation by a different stimulus[20], but at a much shorter time scale( several seconds). Such stimulus trace accumulation may be facilitated by stimulus tagging in a roving situation, since newly acquired stimulus traces can now easily and correctly add to the old traces to enable learning. Cases in which perceptual learning escaped roving disruption( Figure 5) suggest that for multi-stimulus learning to occur, the brain needs to conceptually tag each stimulus, in order to switch attention to the appropriate perceptual template. Similar to the reverse hierarchy theory( RHT)[17, 18], this proposal emphasizes top-down influence in perceptual learning, with the addition to the RHT that the top-down influence could be conceptual or semantic. The fact that direct sensory cueing( with a Gabor patch identical to the target)[3] and increased stimulus duration( Figure 5A) failed to enable learning with roving suggests that these visual cues are not sufficient to serve as effective attentional pointers for the top-down process described by the RHT[17, 18]. Rather, the effect of semantic( letter) cueing on learning with roving suggests that a more conceptual process is needed to direct attention. When that conceptual cue is missing, it is difficult to achieve substantial learning. To return to our earlier example of the baseball player at bat, in order to learn quickly and efficiently to anticipate each pitch, the batter has not only to quickly recognize the subtle nuances of the pitcher's actions, and the ball's trajectory, but also to categorize the pitch appropriately as, for example, a knuckleball, curve ball, slider, or fast ball. Stimulus temporal patterning may similarly aid learning by tagging each roving stimulus according to its “what”( sequence) and “when”( rhythm) information. Proper stimulus tagging is difficult in a roving situation because the “what” information is missing. In a recent report, perceptual learning of bisection acuity for two pairs of bisection stimuli was first interrupted by roving, but learning was later restored after extended training( ten sessions)[27]. We suspect that proper stimulus tagging was achieved with extended training in this case. A possible explanation of the roving and patterning effect is that in a 2AFC experiment, for the first interval the relevant feature of the stimulus is unknown. Thus it is difficult to attend to the appropriate filters. When there is pre-cueing or longer durations the cuing is sensory, i. e., bottom-based rather than top-down based. Our finding is that these bottom-based cues, although helpful for reducing uncertainty, are not helpful for the RHT learning. Our data show that for learning to occur, top-down attention is needed, as made possible by a semantic cue or a conceptual cue, which could be provided by the repeating rhythm. In this sense our data add to the RHT model and clarify what types of training procedures can facilitate the top-down learning. Stimulus tagging for multi-stimulus learning can add to the current understanding of perceptual learning models. At the V1 level, the Adini, Tsodyks, and Sagi model suggests training-induced modification of recurrent connections for perceptual learning. At a post-V1 level the Lu and Dosher model suggests training-induced re-weighting of V1 neuron responses to a specific stimulus. Higher than the post-V1 level, Ahissar and Hochstein's reverse hierarchy theory proposes that visual attention serves as a top-down attentional pointer to the relevant early brain sites for perceptual learning. Now we also show that the top-down process is even affected by conceptual( semantic) processes, in that when multi-stimuli are not easily identifiable, temporal patterning or explicit identity cueing tags the stimuli. Note that our results do not argue against the lower-level models. Rather, they may together describe multi-level mechanisms operating at different stages of brain processing for effective perceptual learning.", "role": "user" }, { "content": "When a person learns to judge several stimuli in succession , like baseball pitches arriving at various speeds and spins , judgments may improve with practice only if these stimuli are presented in a fixed temporal sequence , rather than in a random order . These contrary effects suggest the need for proper stimulus coding for multi-stimulus learning in the brain . We studied how the temporal order of the stimuli affects the encoding , consolidation , and retrieval stages of perceptual learning that describe the basic stimulus coding rules throughout the learning process . We also studied why fixed stimulus sequences are required for multi-stimulus learning . Our results suggest that for multi-stimulus learning to occur , the brain needs to identify or tag each stimulus conceptually or semantically , so that the neural activity specific to each stimulus can be properly attended to . This high-level conceptual process adds to the current understanding of the mechanisms underlying perceptual learning and may have important implications for sensory training and rehabilitation .", "role": "assistant" } ]

[ { "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\nOBJECTIVES: The disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed COVID-19, is asymptomatic or mild in most cases. These patients do not need treatment in hospital and can be isolated at home. To date, most studies have been conducted among inpatients with severe COVID-19. In this study, the authors surveyed patients with mild COVID-19 who remained in home isolation, and analyzed the sources and occupational risk factors for SARS-CoV-2 infections. MATERIAL AND METHODS: This cross-sectional study was carried out on April 17-18, 2020, among patients infected with SARS-CoV-2 who remained in home isolation in Poland. Data were acquired through a structured interview that included questions about the isolation course, symptoms, comorbidities, infection source, household characteristics, occupation, and workplace. Data were presented with descriptive statistics. RESULTS: Of the 4878 patients in home isolation, the authors were able to contact 3313. Of them, 1191 patients declined their invitation, and 2122 agreed to take part. The median age of the patients included in the study was 50 years; 59% were female. Most patients (92%) had not been abroad before the infection. More than half (55%) knew how they became infected; of them, 75% became infected at work. Of all patients, 70% were occupationally active. Nearly half of the occupationally active patients (48%) worked in healthcare, 3% worked in public administration or defense, 3% worked in transportation, and 2% worked in education. Sixty-five percent of the occupationally active patients worked in companies with >100 employees. CONCLUSIONS: Most of the patients with COVID-19 in home isolation in Poland were occupationally active, wherein the majority of people who were aware of the source of SARS-CoV-2 infection worked in healthcare. As most of the infected patients worked in companies with >100 employees, which is not a Polish employment pattern, the authors expect that smaller companies may have a lower risk of SARS-CoV-2 infections. Int J Occup Med Environ Health. 2020;33(6):781-9.", "role": "user" }, { "content": "[\"Prevention\"]", "role": "assistant" } ]

[ { "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: SUMO modification of LBD30 by SIZ1 regulates secondary cell wall formation in Arabidopsis thaliana\nContent:\nAbstract:\nA wide range of biological processes are regulated by sumoylation, a post-translational modification involving the conjugation of SUMO( Small Ubiquitin-Like Modifier) to protein. In Arabidopsis thaliana, AtSIZ1 encodes a SUMO E3 ligase for SUMO modification. siz1 mutants displayed defective secondary cell walls( SCWs) in inflorescence fiber cells. Such defects were caused by repression of SND1/NST1-mediated transcriptional networks. Yeast two-hybrid assay indicated that SIZ1 interacts with the LBD30 C-terminal domain, which was further confirmed using bimolecular fluorescence complementation and immunoprecipitation. Mass spectrometry and co-immunoprecipitation indicated that SIZ1 mediates SUMO conjugation to LBD30 at the K226 residue. Genes controlling SCW formation were activated by the overexpression of LBD30, but not in the LBD30( K226R) mutant. LBD30 enhancement of SCW formation resulted from upregulation of SND1/NST1-mediated transcriptional networks. This study presents a mechanism by which sumoylation of LBD30, mediated by SIZ1, regulates SCW formation in A. thaliana.\nIntroduction:\nPlant cells are surrounded by walls that provide structural support and regulate growth. All plant cells form primary cell walls, which are synthesized during cell expansion and differentiation, while specialized cell types can also deposit a secondary wall on the inside of the primary wall once cell elongation has finished. Examples of the SCW are found in vascular tissues, such as in fiber cells and tracheary elements, as well as in other mechanically important tissues, for example, collenchyma cells. The major constituents of the SCW are cellulose, non-cellulosic polysaccharides and lignin. These polymers are cross-linked, providing cell walls with both mechanical strength and hydrophobic properties. Such characteristics are needed for upright growth, long-distance transport of solutes[1], selectivity of nutrient and water transport in root endodermis[2], defense against pathogens[3], and phenomena such as pod shattering[4], anther dehiscence[5] and flower abscission[6]. In the cells undergoing SCW biosynthesis, SCW cellulose synthase complexes in the plasma membrane produce β-( 1–4) glucan chains that assemble into microfibrils in the orientation guided by cortical microtubules[7]. The microfibrils are extruded into the cell wall matrix and interact with Golgi-synthesized hemicellulose, generally xylan and mannan, to form a stable network[8]. Lignin monomers are transported to the space within the polysaccharide network where they are oxidized and polymerized to make matured SCW[9]. Genes responsible for the SCW biosynthesis process are regulated by a group of transcriptional activators and repressors, which constitute a hierarchical regulatory network controlling SCW formation in various locations[10]. For example, SND1 and NST1 control SCW deposition in fiber cells[11–13] while VND6 and VND7 are responsible for vessel cells SCW formation in A. thaliana[14, 15]. Increasingly, post translational regulation of SCW formation is also being studied. For example, N-glycosylation regulates the enzyme activity of PtrMAN6 in suppression of SCW formation in Populus[16]. The phosphorylation of cellulose synthase AtCesA7 affected SCW cellulose biosynthesis in A. thaliana[17]. Sumoylation, conjugation of SUMO to substrate proteins, is a reversible and dynamic protein modification that regulates a range of biological processes[18]. SUMO conjugation forms a covalent bond between the C-terminal glycine carboxyl group of SUMO and the ε-amino group of a lysine residue, mostly occurring at the consensus motif ΨKXD/E( Ψ, hydrophobic amino acid; K, lysine for conjugation; X, any amino acid; D/E, acidic amino acids) of target proteins[19]. Completion of sumoylation requires an enzymatic cascade of SUMO E1 activating enzyme, SUMO E2 conjugating enzyme and SUMO E3 ligase[18]. This process can be reversed through desumoylating proteases[20]. Generally sumoylation results in either stabilization of the target protein by protecting it against ubiquitylation[21, 22] or destabilization by promoting the sumoylated protein for proteoasomal degradation[23]. Sumoylation can also alter protein cellular localization and modulate protein function or enzymatic activity[24]. In plants sumoylation plays a variety of roles in stress responses, growth, flowering, photomorphogenesis, nutrient homeostasis, and other biological processes[25, 26]. AtSIZ1 is an SP-RING( SIZ/PIAS-type) E3 ligase identified from Arabidopsis thaliana. It contains five structural domains including SAP( Scaffold attachment factor A/B//acinus/PIAS) domain, PINIT domain, SP-RING( SIZ/PIAS-RING) domain, SXS domain and PHD( Plant Homeodomain)[27]. These domains determine AtSIZ1 subcellular localization, enzyme activity, and action in responding to biotic and abiotic stresses[27]. AtSIZ1 plays various roles in growth[28], flowering[29, 30], light response[31, 32], immunity[33, 34] and metabolism of nutrient elements, such as phosphate[35], nitrogen[36] and copper[37]. AtSIZ1 is also implicated in sugar signaling[38]. Recent studies have shown that AtSIZ1 meidated sumoylation is involved in plant response to various stresses[26], including cold[39], heat stress[40], drought stress[41] as well as in signaling processes such as abscisic acid[42, 43], salicylic acid[44], auxin[45] and gibberellin signaling pathways[46]. In this study, we observed SCW defects in the A. thaliana siz1 mutants. Genetic and biochemical analyses indicate that the SCW defects were caused by failure of the LBD30 sumoylation which was mediated by SIZ1. The study reveals a mechanism that sumoylation functions as a regulatory expedient in SCW formation in A. thaliana.\nDiscussion:\nIn higher plants all cells form primary cell wall. In some type cells, additional SCWs are formed inside the primary wall, providing plants with mechanical support for erect growth and channels for long-distance transportation of water, nutrients, and photosynthetic products. Formation of the SCWs in various type cells need to be precisely regulated in a spatio-temporal manner during growth and development[52]. To ensure a precise deposition of SCWs in some type cells, multiple levels of regulation have to be developed in plants. Disturbance of the regulatory networks causes abnormal growth and development[1]. At the transcriptional level, complex regulatory networks are involved in SCW formation[8, 53]. SCW formation in different cell types is initiated through cell type-specific transcription regulators[11–15]. Many signaling molecules regulating SCW formation have yet-to-be characterized[54]. At the protein level, post-translation modifications, such as protein phosphorylation and N-glycosylation[16, 17], are also being studied for their roles in regulating SCW formation. While a large number of proteins are modified with SUMO-conjugation and such modification affects a variety of biological processes[18], this study presents a detailed picture of how sumolyation can lead to the upregulation of SCW formation. Specifically, we found LBD30 sumoylation is required for activation of the SND1/NST1-mediated transcriptional networks in SCW formation. AtSIZ1-mediated sumoylation is involved in a variety of growth and development processes such as flowering, response to light, immunity and nutrient element metabolisms in A. thaliana[31–34, 36, 55]. In this study, we observed that siz1 mutants displayed defective SCWs in interfascicular fiber cells. Analysis indicated that SIZ1 interacted with LBD30 and catalyzed its sumoylation at K226 position in the sumoylation motif. LBD30 is a transcription factor belonging to the Lateral Organ Boundaries Domain( LBD) family[56, 57]. LBD30 and its homolog LBD18 in A. thaliana were preferentially expressed in vascular tissues and LBD18 played a role in regulating tracheary element differentiation[57]. Defective SIZ1 or mutated LBD30 at K226 position led to loss of LBD30 function during the formation of SCW in interfascicular fiber cells. The evidence indicated that LBD30, when it was sumoylated by SIZ1, played a role in activating the SND1/NST1-mediated transcriptional networks( Fig 6) which regulate SCW formation in the fiber cells of inflorescence stem. Generally, stress conditions cause activation of SCW formation[58, 59]. Several transcription factors sumoylated by AtSIZ1 are related to stress responses, including ICE1 in freezing stress[39], HsfA2 in heat stress[60], PHR1 in phosphate( Pi) deficiency[35], MYB30 and ABI5 in the abscisic acid-dependent drought stress[42, 43]. It is worthy of further study whether LBD30 sumoylation acts as a linking device between stress responses and SCW formation. Generally LBD family proteins regulate plant development through interaction with other transcription factors[50]. A number of transcription factors have been identified to bind to SND1 and NST1 promoters to activate their expression[1, 61]. In this study, we found that transcription factor LBD30 was sumoylated by SIZ1 and such protein modification affected activation of the SND1/NST1-mediated transcriptional networks for SCW formation in fiber cells. Though it remains to be investigated how LBD30 sumoylation performs its function in activation of the transcriptional networks, one possibility is that LBD30 sumoylation may affect the transcription factor interactions that are necessary for activation of SND1/NST1 expression. This possibility might justify the observation that LBD30 sumoylation showed different strength of effect on SND1 and NST1 expression between transgenics and protoplast system. Interaction of LBD30 with other factors in planta affected the SND1 and NST1 promoter activity. The finding that LBD30 sumoylation acts as another layer of regulation to aid in the precise control of SCW formation provides additional insight into a key process that is essential for upright growth and the long-distance transport of water and solutes in plants and has implications in cell wall modification via regulation of LBD30 sumoylation in crop improvement.", "role": "user" }, { "content": "Secondary cell wall ( SCW ) is essential for upright plant growth and long-distance transport of water and solutes . Regulation of SCW formation at the transcriptional level has been much studied . Here we show that AtSIZ1 , a small ubiquitin-related modifier ( SUMO ) E3 ligase , mediates the sumoylation of transcription factor LBD30 , a process that regulates SCW formation . Elucidating a role of sumoylation in the post-translational regulation of SCW formation , complementing the body of research on regulation at the transcriptional level , provides additional insight into a key process that is essential for upright growth and the long-distance transport of water and solutes in plants .", "role": "assistant" } ]

[ { "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\nBrushing techniques have a long history with the first interactive selection tools appearing in the 1990's.\nSince then, many additional techniques have been developed to address selection accuracy, scalability and flexibility issues.\nSelection is especially difficult in large datasets where many visual items tangle and create overlapping.\nThis paper investigates a novel brushing technique which not only relies on the actual brushing location but also on the shape of the brushed area.\nFirstly, the user brushes the region where trajectories of interest are visible.\nSecondly, the shape of the brushed area is used to select similar items.\nThirdly, the user can adjust the degree of similarity to filter out the requested trajectories.\nThis technique encompasses two types of comparison metrics, the piece-wise Pearson correlation and the similarity measurement based on information geometry.\nWe apply it to concrete scenarios with datasets from air traffic control, eye-tracking data and GPS trajectories.\n\nAircraft trajectories can be visually represented as connected line segments that form a path on a map.\nGiven the flight level (altitude) of the aircraft, the trajectories can be presented in 3D and visualized by varying their appearances [7] or changing their representation to basic geometry types [11] .\nSince the visualization considers a large number of trajectories that compete for the visual space, these visualizations often present occlusion and visual clutter issues, rendering exploration difficult.\nEdge bundling techniques [34] have been used to reduce clutter and occlusion but they come at the cost of distorting the trajectory shapes which might not always be desirable.\nAnalysts need to explore this kind of datasets in order to perform diverse tasks.\nSome of these tasks compare expected aircraft trajectories with the actual trajectories.\nOther tasks detect unexpected patterns and perform out traffic analysis in complex areas with dense traffic [7, 30] .\nTo this end, various trajectory properties such as aircraft direction, flight level and shape are examined.\nHowever, most systems only support selection techniques that rely on starting and end points, or predefined regions.\nWe argue that the interactive shape brush technique would be helpful for these kinds of tasks, as they require the visual inspection of the data, the detection of the specific patterns and then their selection for further examination.\nAs these specific patterns might differ from the rest of the data precisely because of their shape, a technique that enables their selection through this characteristic will make their manipulation easier, as detailed in the example scenario.\nWe consider a dataset that includes 4320 aircraft trajectories of variable lengths from one day of flight traffic over the French airspace.\nThe proposed brushing technique leverages existing methods with the novel usage of the shape of the brush as an additional filtering parameter.\nThe interaction pipeline shows different data processing steps where the comparison algorithm between the brushed items and the shape of the brush plays a central role.\nWhile the presented pipeline contains two specific and complementary comparison metric computations, another one can be used as long as it fulfills the continuity and metric se- Figure 10 .\nThree different trajectories containing three different event sequences from [60] .\nmantic requirements (DR2).\nThere are indeed many standard approaches (ED, DTW, Discrete FrÃl'chet distance) that are largely used by the community and could be used to extend our technique when faced with different datasets.\nFurthermore, the contribution of this paper is a novel shape-based brushing technique and not simply a shape similarity measure.\nIn our work, we found two reasonable similarity measures that fulfill our shape-based brushing method: The FPCA distance comparison provides an accurate curve similarity measurement while the Pearson metric provides a complementary criteria with the direction of the trajectory.\nIn terms of visualization, the binning process provides a valuable overview of the order of the trajectory shapes.\nThis important step eases the filtering and adjustment of the selected items.\nIt is important to mention that this filtering operates in a continuous manner as such trajectories are added or removed one by one when adjusting this filtering parameter.\nThis practice helps to fine tune the selected items with accurate filtering parameters.\nThe presented scenario shows how small multiple interaction can provide flexibility.\nThis is especially the case when the user brushes specific trajectories to be then removed when setting the compatibility metrics to uncorrelated.\nThis operation performs a brush removal.\nThe proposed filtering method can also consider other types of binning and allows different possible representations (i.e. various visual mapping solutions).\nThis paper illustrates the shape based brushing technique with three application domains (air traffic, eye tracking, gps data), but it can be extended to any moving object dataset.\nHowever, our evaluation is limited by the number of studied application domains.\nFurthermore, even if various users and practitioners participated in the design of the technique, and assessed the simplicity and intuitiveness of the method, we did not conduct a more formal evaluation.\nThe shape based brush is aimed at complementing the traditional brush, and in no way do we argue that it is more efficient or effective than the original technique for all cases.\nThe scenarios are examples of how this technique enables the selection of trails that would be otherwise difficult to manipulate, and how the usage of the brush area and its shape to perform comparison opens novel brushing perspectives.\nWe believe they provide strong evidence of the potential of such a technique.\nThe technique also presents limitations in its selection flexibility, as it is not yet possible to combine selections.\nMany extensions can be applied to the last step of the pipeline to support this.\nThis step mainly addresses the DR4 where the selection can be refined thanks to user inputs.\nAs such, multiple selections can be envisaged and finally be composed.\nBoolean operations can be considered with the standard And, Or, Not.\nWhile this composition is easy to model, it remains difficult for an end user to master the operations when there are more than 2 subset operations [57] [31] .\nAs a solution, Hurter et al.\nproposed an implicit item composition with a simple drag and drop technique [31] .\nThe pipeline can be extended with the same paradigm where a place holder can store filtered items and then be composed to produce the final result.\nThe user can then refine the selection by adding, removing or merging multiple selections.\nIn this paper, a novel sketch-based brushing technique for trail selection was proposed and investigated.\nThis approach facilitates user selection in occluded and cluttered data visualization where the selection is performed on a standard brush basis while taking into account the shape of the brush area as a filtering tool.\nThis brushing tool works as follows.\nFirstly, the user brushes the trajectory of interest trying to follow its shape as closely as possible.\nThen the system pre-selects every trajectory which touches the brush area.\nNext, the algorithm computes a distance between every brushed shape and the shape of the brushed area.\nComparison scores are then sorted and the system displays visual bins presenting trajectories from the lowest scores (unrelated -or dissimilar trajectories) to the highest values/scores (highly correlated or similar trajectories).\nThe user can then adjust a filtering parameter to refine the actual selected trajectories that touch the brushed area and which have a suitable correlation with the shape of the brushed area.\nThe cornerstone of this shape-based technique relies on the shape comparison method.\nTherefore, we choose two algorithms which provide enough flexibility to adjust the set of selected trajectories.\nOne algorithm relies on functional decomposition analysis which insures a shape curvature comparison, while the other method insures an accurate geometric based comparison (Pearson algorithm).\nTo validate the efficiency of this method, we show three examples of usage with various types of trail datasets.\nThis work can be extended in many directions.\nWe can first extend it with additional application domains and other types of dataset such as car or animal movements or any type of time varying data.\nWe can also consider other types of input to extend the mouse pointer usage.\nVirtual Reality data exploration with the so called immersive analytic domain gives a relevant work extension which will be investigated in the near future.\nFinally, we can also consider adding machine learning to help users brush relevant trajectories.\nFor instance, in a very dense area, where the relevant trajectories or even a part of the trajectories are not visible due to the occlusion, additional visual processing may be useful to guide the user during the brushing process.", "role": "user" }, { "content": "Interactive technique to improve brushing in dense trajectory datasets by taking into account the shape of the brush.", "role": "assistant" } ]

[ { "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: Mental Fatigue Increases Gait Variability During Dual-task Walking in Old Adults\nSummary: Background Mental fatigue is a psychobiological state induced by sustained periods of dem and ing cognitive activity and is characterized by feelings of tiredness which are common in everyday life . Recently , it has been hypothesized that mental fatigue might have an impact on gait performance in old adults . Therefore , the effect of mental fatigue on gait performance under single- and dual-task conditions was investigated in young and old participants . Methods Spatio-temporal gait parameters of 16 young and 16 old healthy participants were measured using a photoelectric system during single- and dual-task walking before and after a r and omly assigned mental fatigue ( performing a stop-signal task for 90 minutes ) and control intervention ( watching a video for 90 minutes ) , respectively . Changes in subjective fatigue , wakefulness , mood , arousal , and psychophysiological workload ( heart rate variability indices ) were assessed . Results Psychometric measures indicated increased subjective fatigue and arousal as well as decreased mood and wakefulness after the mental fatigue task . Heart rate variability indices revealed a higher psychophysiological workload during the mental fatigue intervention in old compared to young participants . Gait measures ( coefficient of variation of speed , stride length , and stance time ) revealed impaired dual-task walking performance following the mental fatigue intervention only in old participants . Conclusion Data indicate that mental fatigue , induced by sustained cognitive activity , can impair gait performance during dual-task walking in old adults . The susceptibility to mental fatigue could be a new intrinsic risk factor for falls in older people and should be taken into account when dual-task gait analyses are performed\n\n\nReport 2:\nTitle: Changes in postural stability with fatigue of lower extremity frontal and sagittal plane movers.\nSummary: The purpose of this study was to quantify changes in postural stability with fatigue of the frontal and sagittal movers of the lower extremities . There were four test sessions , with a r and omized order assigned according to the muscles tested and the plane of motion . Subjects were 20 healthy men ( age : 22.6+/-2.4 years , height : 173.7+/-3.6 cm , weight : 63.3+/-7.9 kg ) . During each session , one set of muscle groups was fatigued using isokinetic contractions : ankle plantar/dorsi flexors , ankle evertor/invertors , hip flexor/extensors or hip abductor/adductors . The Biodex Stability System was used to assess anterior/posterior and medial/lateral stability before and after muscle fatigue . Repeated measures ANOVAs revealed that fatigue was associated with a significant increase in all stability indices . Fatigue of the hip movers , whether in the frontal or sagittal planes , led to greater increments in stability indices than fatigue of the ankle musculature . Fatigue of the frontal movers result ed in greater increases in the medial/lateral stability index compared to fatigue of the sagittal movers . In conclusion , fatigue of proximal lower extremity muscles affects postural stability and fatigue of the frontal movers is associated with postural instability in the frontal plane\n\n\nReport 3:\nTitle: Fatigue effects on muscle excitability.\nSummary: Repeated isometric or shortening contractions of skeletal muscle cause muscle fatigue but several prior studies have reported an apparent absence of muscle fatigue when humans performed up to 70 lengthening contractions . We pursued the hypothesis that perhaps muscle excitability is a factor that aids force preservation with repeated eccentric actions . Soleus compound muscle action potential ( M-wave ) latency , peak-to-peak amplitude ( PPA ) , duration , and area under the curve were examined in 12 subjects ( mean age 24.3 y ) over 4 testing days that included : no exercise , isometric exercise ( neutral ankle angle ) , isokinetic ( 0.5 rad.s-1 ) concentric and eccentric exercise of the plantar flexors in the seated position on a Biodex dynamometer . Supramaximal shocks were delivered to the tibial nerve in the popliteal fossa at baseline ( 3 shocks , 1 min apart ) , during exercise ( 1 shock-after each of 5 bouts/10 contractions ) , and during 10-min recovery . From initial to final contractions , concentric , isometric , and eccentric fatigue was -32 , -41 and + 2 % ( Condition by Trial Interaction , F2,22 = 25.1 , p = 0.000 ) . No changes occurred in latency or duration ( p > 0.05 ) , but PPA ( Condition by Time interaction , F51,561 = 3.7 , p = 0.000 ) increased during isometric and eccentric exercise and remained elevated during recovery . Area increased ( F51,561 = 3.1 , p = 0.000 ) significantly during all three exercise conditions and approximated baseline by minute 8 of recovery . It was concluded that although the potentiation of the action potential of individual muscle fibers seems to be the common mechanism underlying the increase in muscle excitability during plantar flexion exercise , it is possible that different factors could cause such a non-specific response\n\n\nReport 4:\nTitle: The effect of lower limb muscle fatigue on obstacle negotiation during walking in older adults.\nSummary: Tripping over obstacles is a common cause of falls in older adults , and muscle fatigue , which can alter walking patterns , may add to this risk . To date , no study has examined the effect of lower limb muscle fatigue on obstacle negotiation in older adults . 30 older adults ( 13 women , aged 78.3 [ 6.2 ] years ) negotiated a 12 m obstacle course , while completing a visual secondary task , under two r and omized conditions : rested or fatigued . For the fatigue condition , participants performed a repeated sit-to-st and movement , as fast as possible , until they could no longer continue . Participants then immediately began walking trials . Kinematic and kinetic data were collected on approach to , during , and after crossing a height-adjustable target obstacle ( 10 % and 20 % of leg length ) . Repeated measures ANOVA showed a statistically significant increase in lead limb vertical loading rate after stepping over the 10 % obstacle when fatigued , relative to rested ( P=0.046 ) . No other significant between-condition differences ( > 0.05 ) were observed for the other kinematic variables when negotiating the 10 % obstacle . Furthermore , no significant between-condition differences ( P>0.05 ) were observed for any kinetic or kinematic variables when negotiating the 20 % obstacle . This study describes a feasible method for investigating the consequences of lower limb muscle fatigue on obstacle crossing . The current finding of increased vertical loading rate when fatigued supports the need for further investigation into the effect of muscle fatigue on gait under different environmental conditions , fatiguing a range of muscles , analyzing a more comprehensive array of kinetic and kinematic measures , and in healthy and clinical population\n\n\nReport 5:\nTitle: Maximum voluntary activation in nonfatigued and fatigued muscle of young and elderly individuals.\nSummary: BACKGROUND AND PURPOSE Research ers study ing central activation of muscles in elderly subjects ( > or = 65 years of age ) have investigated activation in only the nonfatigued state . This study examined the ability of young and elderly people to activate their quadriceps femoris muscles voluntarily under both fatigued and nonfatigued conditions to determine the effect of central activation failure on age-related loss of force . SUBJECTS AND METHODS Twenty young subjects ( 11 men , 9 women ; mean age = 22.67 years , SD = 4.14 , range = 18 - 32 years ) and 17 elderly subjects ( 8 men , 9 women ; mean age = 71.5 years , SD = 5.85 , range = 65 - 84 years ) participated in this study . Subjects were seated on a dynamometer and stabilized . Central activation was quantified , based on the change in force produced by a 100-Hz , 12-pulse electrical train that was delivered during a 3- to 5-second isometric maximum voluntary contraction ( MVC ) of the quadriceps femoris muscle . Next , subjects performed 25 MVCs ( a 5-second contraction with 2 seconds of rest ) to fatigue the muscle . During the last MVC , central activation was measured again . RESULTS In the nonfatigued state , elderly subjects had lower central activation than younger subjects . In the fatigued state , this difference became larger . DISCUSSION AND CONCLUSION Central activation of the quadriceps femoris muscle in elderly subjects was reduced in both the fatigued and nonfatigued states when compared with young subjects . Some part of age-related weakness , therefore , may be attributed to failure of central activation in both the fatigued and nonfatigued states\n\n\nReport 6:\nTitle: Effects of unilateral leg muscle fatigue on balance control in perturbed and unperturbed gait in healthy elderly.\nSummary: This study assessed effects of unilateral leg muscle fatigue ( ULMF ) on balance control in gait during the stance and swing phases of the fatigued leg in healthy elderly , to test the assumption that leg muscle strength limits balance control during the stance-phase . Ten subjects ( aged 63.4 , SD 5.5 years ) walked on a treadmill in 4 conditions : unperturbed unfatigued , unperturbed fatigued , perturbed unfatigued , and perturbed fatigued . The perturbations were lateral trunk pulls just before contralateral heel contact . ULMF was evoked by unilateral squat exercise until task failure . Isometric knee extension strength was measured to verify the presence of muscle fatigue . Between-stride st and ard deviations and Lyapunov exponents of trunk kinematics were used as indicators of balance control . Required perturbation force and the deviation of trunk kinematics from unperturbed gait were used to assess perturbation responses . Knee extension strength decreased considerably ( 17.3 % SD 8.6 % ) as a result ULMF . ULMF did not affect steady-state gait balance . Less force was required to perturb subjects when the fatigued leg was in the stance-phase compared to the swing-phase . Subjects showed a faster return to the unperturbed gait pattern in the fatigued than in the unfatigued condition , after perturbations in swing and stance of the fatigued leg . The results of this study are not in line with the hypothesized effects of leg muscle fatigue on balance in gait . The healthy elderly subjects were able to cope with substantial ULMF during steady-state gait and demonstrated faster balance recovery after laterally directed mechanical perturbations in the fatigued than in the unfatigued condition\n\n\nReport 7:\nTitle: Monitoring Muscle Fatigue Progression during Dynamic Exercise\nSummary: ABSTRACT Purpose To develop and vali date a novel model for assessment of peripheral fatigue progression during dynamic exercise . Methods Seven males and four females ( 24 ± 3 yr ) completed one-legged knee-extensor exercise at 40 % of peak power output ( PPO ) for 12 min ( 40 % PPO ) . Additionally , an exhaustive bout lasting approximately 6 min ( 84 % ± 2 % PPO ; 59 ± 10 W ) was contrasted to two bouts completed at ±5 % of the target workload . Trials were completed in r and omized order . Percutaneous electrical stimulation of m. vastus lateralis during the passive knee-flexion phase allowed quantification of maximal twitch force every 30 s in parallel with RPE . Results Elicited twitch force remained unchanged during the 40 % PPO trial . During the three exhaustive bouts , exercise differed in duration ( 561 ± 154 s , 366 ± 64 s , 245 ± 61 s ; P < 0.001 ) and amplitude of elicited twitch force showed a curvilinear decline across time . Elicited twitch force at exhaustion was approximately 60 % reduced and similar between the exhaustive trials ( intraclass correlation coefficient , 0.76 ; 95 % confidence interval , 0.48–0.92 ) . The increase in RPE during exercise was strongly correlated to the gradually reduced evoked twitch force ( repeated- measures correlation , 0.89 ; 95 % confidence interval , 0.62–0.97 ) . Conclusions The developed model permits quantification of muscle fatigue progression during continuous dynamic one-legged knee-extension and a biphasic fatigue pattern is demonstrated during intense exercise . The model is sensitive to small changes in intensity , and it provides a novel approach for study ing muscular mechanisms and their temporal relation to fatigue progression in vivo", "role": "user" }, { "content": "Conclusion Muscle performance fatigability affects spatial and temporal features of gait and , mainly , inter-stride trunk acceleration variability .\nIn contrast , sustained mental activity tends only to affect step variability during dual tasking .", "role": "assistant" } ]

[ { "content": "Examine the provided biomedical text and determine the answer to the question. Your response should be either \"yes\" or \"no\" based on the information given.\n\nQuestion: Has IVIG been tested in clinical trials for the treatment of Alzheimer's disease?\n\nText: Clinical trials of intravenous immunoglobulin for Alzheimer's disease.\nPreclinical and clinical studies have shown that IVIG has anti-amyloid and immune modulatory properties relevant to treating neurodegenerative disorders. In early stage AD clinical trials, IVIG was found to reduce cognitive decline and increase brain glucose metabolism. Unfortunately, IVIG failed to meet primary outcome objectives in the North American Phase 3 clinical trial in mild to moderate AD.\nWhile the results of clinical trials to date do not provide support for the use of IVIG to treat AD at the doses tested, additional studies of IVIG's mechanisms are warranted and may guide the development of more effective therapies for AD in the future.", "role": "user" }, { "content": "yes", "role": "assistant" } ]

[ { "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\nIonic liquid mediated synthesis and surface modification of multifunctional mesoporous Eu:GdF3 nanoparticles for biomedical applications. A procedure for the synthesis of multifunctional europium(III)-doped gadolinium(III) fluoride (Eu:GdF3) nanoparticles (~85 nm) with quasispherical shape by precipitation at 120 °C from diethylene glycol solutions containing lanthanide chlorides and an ionic liquid (1-Butyl, 2-methylimidazolium tetrafluoroborate) as fluoride source has been developed. These nanoparticles were polycrystalline and crystallized into a hexagonal structure, which is unusual for GdF3. They were also mesoporous (pore size = 3.5 Å), having a rather high BET surface area (75 m(2) g(-1)). The luminescent and magnetic (relaxivity) properties of the Eu:GdF3 nanoparticles have been also evaluated in order to assess their potentiality as \"in vitro\" optical biolabels and contrast agent for magnetic resonance imaging. Finally, a procedure for their functionalization with aspartic-dextran polymers is also reported. The functionalized Eu:GdF3 nanoparticles presented negligible toxicity for Vero cells, which make them suitable for biotecnological applications.", "role": "user" }, { "content": "{\"Chemical\": [\"2-methylimidazolium tetrafluoroborate\", \"Eu\", \"1-Butyl\", \"fluoride\", \"diethylene glycol\", \"GdF3\", \"lanthanide chlorides\", \"gadolinium(III) fluoride\", \"europium(III)\"]}", "role": "assistant" } ]

[ { "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\nDomain adaptation is an open problem in deep reinforcement learning (RL).\nOften, agents are asked to perform in environments where data is difficult to obtain.\nIn such settings, agents are trained in similar environments, such as simulators, and are then transferred to the original environment.\nThe gap between visual observations of the source and target environments often causes the agent to fail in the target environment.\nWe present a new RL agent, SADALA (Soft Attention DisentAngled representation Learning Agent).\nSADALA first learns a compressed state representation.\nIt then jointly learns to ignore distracting features and solve the task presented.\nSADALA's separation of important and unimportant visual features leads to robust domain transfer.\nSADALA outperforms both prior disentangled-representation based RL and domain randomization approaches across RL environments (Visual Cartpole and DeepMind Lab).\nRL agents learn to maximize rewards within a task by taking actions based on observations.\nThe advent of deep learning has enabled RL agents to learn in high dimensional feature spaces and complex action spaces (Krizhevsky et al., 2012; Mnih et al., 2016) .\nDeep RL methods have beat human performance in a variety of tasks, such as Go (Silver & Hassabis, 2016) .\nHowever, deep RL has two crippling drawbacks: high sample complexity and specificity to training task.\nThere are many domains where data collection is expensive and time consuming, such as healthcare, autonomous vehicles, and robotics (Gottesman et al., 2019; Barrett et al., 2010) .\nThus, agents are often trained in simulation and must transfer the resulting knowledge to reality.\nWhile this solves the issue of sample complexity, reality and simulated domains are sufficiently different that it is infeasible to naively train a deep RL agent in a simulation and transfer.\nThis is known as the reality gap (Sadeghi & Levine, 2016) .\nJumping the reality gap is difficult for two orthogonal reasons.\nThe first is that dynamics of a simulation are an approximation to the dynamics of the real world.\nPrior work has shown success in transfer between domains with different dynamics (Killian et al., 2017; Yao et al., 2018; Doshi-Velez & Konidaris, 2016) .\nIn this paper, we address the second difficulty: the difference in visual observations of states.\nDue to limitations in current photorealistic rendering, simulation and the real world are effectively two different visual domains (Sadeghi & Levine, 2016 ).\nWe present a method of robust transfer between visual RL domains, using attention and a β variational autoencoder to automatically learn a state representation sufficient to solve both source and target domains.\nBy learning disetangled and relevant state representation, our approach does not require target domain samples when training.\nThe state representation enables the RL agent to attend to only the relevant state information and ignore all other, potentially distracting information.\nWe test the SADALA framework on two transfer learning tasks, using A3C as the deep RL algorithm.\nThe first task is Visual Cartpole.\nThis domain is the same as Cartpole-v1 in OpenAI Gym with two key differences (Brockman et al., 2016) .\nThe observed state is now the pixel rendering of the cartpole as well as the velocities of the cart and pole.\nThus, the agent must learn to predict the position of the cart and pole from the rendering.\nAdditionally, we modify this domain to include a transfer task.\nThe agent must learn to transfer its knowledge of the game across different color configurations for the cart, pole, and track.\nThus, Visual Cartpole is defined as a family of MDPs M where the true state S z is the positions and velocities of the cart and pole and the observed state S U = G U (S z ) for an MDP U ∈ M is the pixel observations and velocity values.\nOptimally, the agent should learn to ignore the factors in extracted latent state factorsŜ z that correspond to color, as they do not aid the agent in balancing the pole.\nThis task tests the agent's ability to ignore irrelevant latent state factors.\nThe second task is the \"Collect Good Objects\" task from Deepmind Lab (Beattie et al., 2016) .\nThe agent must learn to navigate in first person and pick up \"good\" objects while avoiding \"bad\" objects.\nThis task is defined as a family of MDPs M where the true state S z contains the position of the agent, the position of good and bad objects, the type of good and bad objects, and the color of the walls and floor.\nIn a single MDP U ∈ M , all good objects are hats or all good objects are balloons.\nSimilarly, all bad objects are either cans or cakes.\nThe walls and floor can either take a green and orange colorscheme or a red and blue colorscheme.\nThe agent is trained on hats/cans with the green/orange colorscheme and balloons/cakes with both colorschemes.\nIt is then tested on hats/cans with the red/blue colorscheme.\nOptimally, the agent should learn to ignore the color of the floor and walls.\nAdditionally, it should use the type of object to determine if it is good or bad.\nThis task tests the agent's ability to ignore distracting latent state factors (the color of the walls and floor) while attending to relevant factors (the positions and types of objects and its own position).\nTo test the results of the SADALA algorithm, we first test the reconstruction and disentanglement properties of the β-VAE used in the state representation stage.\nNote that this stage is identical to that of DARLA (Higgins et al., 2017) .\nAs such, we expect the disentanglement properties to be similar.\nSee figure 3 for reconstructions of the cartpole state.\nBased on the reconstructions, it is apparent that the β-VAE has learned to represent cart position and pole angle.\nThough the angle of the poles is slightly incorrect in the first set of images, the pole is tilted in the correct direction, yielding sufficiently correct extracted latent state factors.\nAdditionally, the color of the cart, pole, and background is incorrect in the third pair of images.\nWhile this demonstrates that the identification and reconstructions of colors is not infallible, the position of the cart and pole remains correct, yielding a set of extracted latent state parameters that is sufficient to solve the MDP.\nSee figure 5 for a visualization of reconstruction with attention.\nIn the original image, the pole is standing straight and the cart is centered.\nIn the reconstruction, the cart is centered, and the pole is almost upright.\nHowever, the reconstruction does not include the colors of the cart or pole.\nInstead it fills the cart and pole with the mean color of the dataset.\nThis shows that the attention weights are properly learning to ignore color and instead pay attention to the position of the cart and pole.\nFigures 6 and 7 gives a comparison of the performance of the algorithms across environments.\nNote that all of the algorithms are sufficient at solving the source task, with the single-task learner performing slightly better.\nThis is due to the fact that the single-task learner can optimize its con- The single-task learner achieves better rewards on all source tasks than any of the transfer-specific agents.\nDomain randomization performs less well because of the complexity of the domain randomization task.\nRather than optimizing reward for a single domain, the agent must optimize reward across a large set of domains.\nDARLA, SADALA, and SADALA with reduced variance also perform less well on the source task than the baseline agent.\nThis is due to imperfections in the β-VAE.\nThough the β-VAE attempts to reconstruct the input image, it does not do so perfectly, as shown in figure 3 .\nThis shows that its extraction of latent state features is not perfect, leading to potentially confusing states given to the RL agent.\nAdditionally, while the β-VAE's goal is to learn a disentangled representation, it does not do so perfectly.\nAs such, (partially) entangled latent state factors may further confuse the RL agent.\nThe single-task learner fails to transfer its policy to the target domain.\nDARLA transfers some of its knowledge to the target domain.\nDomain randomization also transfers some knowledge.\nFinally, SADALA transfers more of its knowledge.\nThe single-task agent has no incentive to learn a factored state representation that enables transfer.\nIts convolutional filters will directly optimize to maximize reward in the source policy.\nThus, if the filters are searching for a hat on a blue floor but tested on a hat on a red floor the convolutional filters will fail to transfer.\nDARLA learns a state representation that is mostly disentangled.\nThis allows the RL agent to learn to ignore unimportant features such as cart color and utilize important features such as cart position.\nThe factored state representation forces the RL agent to learn a more robust policy.\nHowever, the neural network parameterization of the RL policy must implicitly learn to ignore unimportant factors.\nTherefore, when presented with unseen information, the RL agent may not properly ignore unimportant factors.\nDomain randomization forces the neural network to implicitly learn a state representation sufficient to transfer between tasks.\nThis requires large amounts of training data and is less robust than explicit modeling of latent state factors.\nSADALA builds on DARLA by adding an explicit attention mechanism, allowing it to more effectively ignore unimportant features.\nDue to the use of the sigmoid activation in the attention mechanism, the attention weights W are bounded between 0 and 1.\nIn addition to providing a direct weight on the importance of a feature, this bound prevents high variance of attention weights across different inputs.\nSADALA with the variance reduction term performs worse than both DARLA and SADALA without variance reduction on the Deepmind lab task but better on the other two.\nIn the scenario where the extracted latent state factors from the β-VAE are perfectly disentangled, static attention weights should be sufficient to solve the source task and should transfer better to the target task, as in the Visual Cartpole task.\nHowever, the β-VAE does not output perfectly disentangled factors, especially in more complex visual domains such as the Deepmind lab.\nThus, the amount of attention paid to each feature from the β-VAE may differ across tasks, violating the assumption that attention weights should be zero variance.\nIn this paper we propose SADALA, a three stage method for zero-shot domain transfer.\nFirst, SADALA learns a feature extractor that represents input states (images) as disentangled factors.\nIt then filters these latent factors using an attention mechanism to select those most important to solving a source task.\nJointly, it learns a policy for the source task that is robust to changes in states, and is able to transfer to related target tasks.\nWe validate the performance of SADALA on both a high-dimensional continuous-control problem (Visual Cartpole) and a 3D naturalistic first-person simulated environments (Deepmind Lab).\nWe show that the attention mechanism introduced is able to differentiate between important and unimportant latent features, enabling robust transfer.\nare constrained to be outside of a hypersphere of radius 0.1 the test environment.\nWhen evaluating source domain performance, the agents trained on multiple source domains are all evaluated on the same domain, randomly sampled from the set of source domains.\nThe single task learner is evaluated on the source domain it is trained on.", "role": "user" }, { "content": "We present an agent that uses a beta-vae to extract visual features and an attention mechanism to ignore irrelevant features from visual observations to enable robust transfer between visual domains.", "role": "assistant" } ]

[ { "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:\na number of respiratory viruses including influenza viruses , respiratory syncytial virus ( rsv ) , parainfluenza viruses , adenovirus and the recently described human metapneumovirus ( hmpv ) play an important role in acute respiratory tract infections ( ari ) in children .\nhowever , in a substantial portion of respiratory infections the aetiological agent is not known .\nthere has been renewed interest in human coronaviruses ( hcov ) as a cause of some of these infections .\ncoronaviruses are large enveloped singlestranded rna viruses that can infect both humans and a variety of domestic animals causing respiratory and enteric illness . until recently human coronavirus ( hcov )\n229e and oc43 , identified in the 1960s , \n were the only known coronaviruses to infect humans .\nalthough primarily responsible for mild infections including the common cold \n reports of more severe upper and lower respiratory tract infections associated with hcov229e and hcovoc43 have been documented . \n , \n the identification of a coronavirus , sarscov , as the causative agent of severe acute respiratory syndrome in 2003 \n has resulted in an increased interest in this group of viruses .\nsubsequently two new human coronaviruses , hcovnl63 \n , \n and hcovhku1 , \n have been described .\nboth infect young children , the elderly and immunocompromised and can lead to severe respiratory tract infections requiring hospitalisation .\nthe prevalence and clinical importance of hcovnl63 in the south african hospital setting is not known .\nin this retrospective study 1055 nasopharyngeal , tracheal aspirate and bronchoalveoloar lavage samples were taken from children ( age 13 days to 5 years ) hospitalised with respiratory tract infections in 2003 and 2004 in the red cross war memorial children s hospital in cape town .\nsamples had previously been screened by using an indirect immunofluorecence assay ( light diagnostics , chemicon international , temecula , ca , usa ) for the common respiratory viruses including rsv , influenza viruses a and b , parainfluenza viruses 1 , 2 , 3 , adenovirus and cmv .\nhmpv was also tested for using reversetranscriptionpcr ( rtpcr ) . in the south african setting , where the prevalence of hiv is high , all infant respiratory samples\nare routinely screened for cmv as in our setting this virus is a major cause of pneumonia in hivinfected children . for the detection of hcovnl63\n, rna was extracted from 200 l of sample using the seek viral rna kit according to the manufacturer s instructions ( talent , trieste , italy ) .\nten microlitres rna was reverse transcribed into cdna using random primers ( roche diagnostics gmbh , penzberg , germany ) and the iscript kit ( biorad , hercules , ca , usa ) .\npcr amplification of a region of the 1b gene of hcovnl63 was used for screening and positive samples were confirmed by amplification of a portion of the 1a gene . briefly\n10 l of cdna was added to a 50 l of pcr mix containing 2 iu supertherm polymerase ( jmr holdings , kent , uk ) , 15 mm mgcl2 , 200 m each dntp and 02 m primers .\npcr was performed with two sets of outer primers , one set to the 1b gene and one targeting the 1a gene from the study of van der hoek et al . \n\n to improve sensitivity a nested pcr\nwas performed using 25 l outer product and inner primers described by smuts et al . \n\n \nthe 1a amplicons were sequenced directly and the nucleotide sequences were deposited into genbank ( eu477762eu477770 ) .\na respiratory virus was detected in 401/1055 ( 380% ) samples collected over the 2year period from 2003 to 2004 .\nthe detection rate was higher in 2004 , 248/559 ( 444% ) , compared with 2003 , 153/496 ( 308% ) .\ncmv was most frequently found ( 158/1055 ; 150% ) followed by adenovirus ( n = 65 ; 62% ) , rsv ( 42 ; 40% ) , parainfluenza 3 ( n = 32 ; 30% ) , hmpv ( n = 28 ; 26% ) , influenza virus a ( n = 8 ; 076% ) , parainfluenza virus 1 ( n = 6 ; 057% ) , parainfluenza virus 2 ( n = 4 ; 038% ) and influenza virus b ( n = 1 ; 009% ) . in 48 ( 45% )\nsamples a known respiratory virus was grown in shell vial culture but could not be further identified .\nof cmvpositive respiratory samples 449% ( 71/158 ) were from hivinfected children , 240% ( 38/158 ) from hivnegative children and for the remainder the hiv status was unknown . in both hivpositive and hivnegative groups\nthe rates of coinfection with another known respiratory virus were similar , 12/71 ( 169% ) and 7/38 ( 184% ) respectively .\nhcovnl63 was detected in 4/496 ( 081% ) and 5/559 ( 089% ) samples from 2003 and 2004 respectively .\nall hcovnl63infected children , with the exception of one aged 30 months , were under 2 years ( table 1 ) .\nthe hiv status of only those children from 2004 was known and 4/5 hcovnl63infected children from this year were hivpositive . in two instances\nin 2003 3/4 positive samples were collected in march ( autumn ) while in 2004 hcovnl63positive samples were found in march , may , august and september ( table 1 ) .\na diagnosis of pneumonia or lower respiratory tract infection was made in six ( 67% ) children .\ntwo hcovnl63positive infants aged 50 and 71 days respectively , required admission to the intensive care unit ; both were hivpositive . clinical data of hcov nl63infected children nk , not known ; ta , tracheal aspirate ; npa , nasopharyngeal aspirate ; bal , bronchoalveolar lavage ; ltri , lower respiratory tract infection ; hmpv , human metapneumovirus .\nto determine the role hcovnl63 plays in respiratory illness in infants , respiratory samples that had previously been screened for rsv , influenza viruses a and b , parainfluenza viruses 1 , 2 , 3 , adenovirus , hmpv and cmv were also tested by rtpcr for hcovnl63 . due to limited resources ,\nscreening for other viruses such as enteroviruses , rhinoviruses and the other hcovs was not undertaken .\nthis may be considered a limitation of the study as there is accumulating evidence that these viruses , in particular rhinoviruses , may play a more significant role in lower respiratory tract infections than previously recognised . \n \nthe role and clinical significance of the recently identified human bocavirus \n and polyomaviruses \n , \n in respiratory disease is still under investigation .\nideally comprehensive screening of respiratory samples for most if not all respiratory viruses and relevant respiratory bacteria should be undertaken in order to obtain greater insight into the epidemiological significance of these pathogens in respiratory disease in the local setting .\nfurther this would be beneficial to the clinical management of patients , including the administration of appropriate antiviral drugs and antibiotics .\na postmortem study of hivinfected children in kwazulunatal , south africa showed frequent ( 52% ) cmv detection in lung tissue compared with uninfected controls ( 4% ) . \n \nthe significance of cmv detection in respiratory samples from uninfected children is not known but probably represents viral shedding from either a recently acquired primary infection or reactivation .\nthis study is the first to report the presence of hcovnl63 in children hospitalised with respiratory illness in africa .\nhcovnl63 was found to circulate in infants and young children in both 2003 and 2004 with similar low prevalence rates of 08% .\nthis finding is lower than that reported in previous studies where detection of hcovnl63 ranged from 1% to 73% \n , \n , \n , \n , \n , \n , \n , \n although higher prevalences of 88% and 93% have also been reported . \n\n, \n most hcovnl63positive children ( 75% ) were under 6 months , indicating that this younger age group may be more susceptible to severe infections requiring hospitalisation ; a finding supported by other studies where 38/76 ( 50% ) , 4/5 ( 80% ) and 11/12 ( 92% ) of hcovnl63 infections occurred in this age group respectively . \n\n, \n , \n further , immunosuppression may also contribute to increased susceptibility to severe hcovnl63 infection . in this study 4/5\nall four were < 4 months of age and two required admission to icu .\nit is not known whether maternal antibodies , if present , would provide protection or reduce the severity of infection .\nthis protection is likely to be most effective in infants under 2 months . in this study\nthis observation is supported by the findings of other studies . \n , \n , \n , \n in a very recent study by dijkman et al .\nthese antibodies disappeared within 3 months providing further evidence of their possible protective role in early life . in a recently published study \n of ambulatory children presenting with acute wheezing at the outpatient s department of the same hospital in 2004 ,\nthis is significantly different ( p = 00186 ) from the prevalence in the hospitalised group .\nthis indicates that the virus is circulating in the community , probably causing mild symptoms which may trigger a wheezing episode requiring medical attention .\nin contrast the lower rate of hcovnl63 infection identified in the hospitalised children suggests that the virus rarely causes severe lower respiratory tract infections .\nhowever , all hcovinfected children in the ambulatory group were over 12 months of age supporting the possibility that younger children are more susceptible to severe infections requiring hospitalisation .\nno hcovnl63 infection was detected during the winter months in either 2003 and 2004 , a finding also noted in the ambulatory population \n this pattern differs from that previously reported where hcovnl63 infection was predominantly found during the winter season . \n , \n , \n , \n , \n , \n , \n , \n detection during early spring and summer indicates that hcovnl63 may circulate at low levels throughout the year . in this\nstudy the clinical symptoms of hcovnl63infected infants were similar to those previously reported with lower respiratory tract infections including pneumonia predominating in this group . \n\n, \n , \n , \n , \n , \n in this study only specimens from hospitalised children were examined resulting in a bias towards children with more severe respiratory illness .\nmild hcovnl63 symptoms have also been reported \n , \n , \n indicating that hcovnl63 infections are probably more severe in the very young and immunocompromised .\nthe role of hcovnl63 in enteric disease has not been established but reports of gastroenteritis associated with coronavirus infection have been documented with frequencies ranging from 6% to 33% . \n , \n , \n , \n in this study one child had a history of gastroenteritis and vomiting . a significant association with hcovnl63\ninfection and croup has been made \n but in this study it could not be determined if any of the samples were from children with croup . in conclusion\nthese findings suggest that although hcovnl63 is circulating in the community it plays a minor role in severe respiratory tract infections in young children who require hospitalisation .\nethical approval ( 018/2004 ) was granted by the research ethics committee of the faculty of health sciences , university of cape town , south africa .", "role": "user" }, { "content": "background human coronavirus nl63 ( hcovnl63 ) is a novel respiratory virus which is associated with respiratory tract infections in children . \n \n objective to determine the role of hcovnl63 in infants and young children hospitalised with acute respiratory tract infections ( ari ) in cape town , south africa . \n \n methods respiratory specimens were collected from 1055 infants and young children hospitalised with ari in 20032004 . \n samples were screened by rtpcr to detect hcovnl63 and human metapneumovirus ( hmpv ) . \n standard shell vial culture and immunofluoresence was used to detect the common respiratory viruses including rsv , influenza a and b viruses , parainfluenza viruses 1 , 2 , 3 , adenovirus and cmv . \n \n results a respiratory virus was found in 401/1055 ( 380% ) samples . \n hcovnl63 was detected in 9/1055 ( 085% ) with peak activity during autumn ( 67% ) . \n most patients had a diagnosis of pneumonia or lower respiratory tract infection ( 6/9 ; 67% ) . \n \n conclusions this is the first report of hcovnl63 infections in hospitalised children in africa . during the 2year period hcovnl63 played a minor role in ari in children .", "role": "assistant" } ]

[ { "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:\nBecausethetimingofthiseventcorrelatedwiththeactivationofaLEF-1/beta-catenintranscriptionfactorcomplex[20],wewereintriguedbythepresenceofaputativeLEF-1/TCFbindingsiteintheE-cadherinpromoter.", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "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 inspecting structures using robotic systems \nChapter Title: Coverage exploration and viewpoint generation \n1. Abstract of Cited Paper (BIB001): This paper presents a multi-phase, model-based approach to view planning for automated, high fidelity object inspection or reconstruction by means of laser scanning range sensors. We describe the critical phase, fine modeling, in detail. Quality objectives and performance measures are defined. Camera and positioning system performance is modeled statistically. A theoretical framework is presented. The method is applicable to a broad class of objects with reasonable geometry and reflectance properties. Sampling of object surface and viewpoint space is characterized, including measurement and pose errors. The technique is generalizable for common range cameras and positioning systems.\n\nReview Chapter:", "role": "user" }, { "content": "In the majority of the surveyed literature, coverage exploration algorithms are classified into model-based exploration and non-model-based exploration. The model-based exploration methods depend on the existence of a model of the workspace or the structure, while the non-modelbased exploration is performed by exploring and planning paths without a prior knowledge of the structure. BIB002 BIB001 Viewpoints generation and path planning are considered critical in the robotic inspection process since it aims to output an optimized path based on the generation of admissible set of viewpoints that covers the structure or environment of interest. It is performed in the literature using various techniques based on the inspection application and the coverage exploration method used.", "role": "assistant" } ]

[ { "content": "Examine the provided biomedical text and determine the answer to the question. Your response should be either \"yes\" or \"no\" based on the information given.\n\nQuestion: Does Yersinia pestis causes a respiratory infection?\n\nText: Inhalation of Yersinia pestis results in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia\nYersinia pestis causes the fatal respiratory disease pneumonic plague.\nPulmonary infection by Yersinia pestis causes pneumonic plague, a rapidly progressing and often fatal disease.\nPulmonary infection with the bacterium Yersinia pestis causes pneumonic plague, an often-fatal disease for which no vaccine is presently available.\nYersinia pestis causes the fatal respiratory disease pneumonic plague\nPneumonic plague is a deadly respiratory disease caused by Yersinia pestis\nOn July 8, 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory identified Yersinia pestis, the bacterium that causes plague, in a blood specimen collected from a man (patient A) hospitalized with pneumonia.\nEarly emergence of Yersinia pestis as a severe respiratory pathogen.\nThe aerosol form of the bacterium Yersinia pestis causes the pneumonic plague, a rapidly fatal disease\nplague bacterium, Yersinia pestis, has historically been regarded as one of the deadliest pathogens known to mankind, having caused three major pandemics. After being transmitted by the bite of an infected flea arthropod vector, Y. pestis can cause three forms of human plague: bubonic, septicemic, and pneumonic,\nPlague is an infectious disease caused by the Yersinia pestis microorganism, which is transmitted to the human host from a natural reservoir (different rodent species) by a flea bite. Plague is still encountered in humans in the areas of its enzootic prevalence in local rodent populations. Infection by flea bite results in a bubonic or septicemic plague, possibly complicated by secondary pneumonia. The person with pneumonic symptoms may be a source of a droplet-borne inhalatory infection for other people who consequently develop primary pneumonic plague.\nuring pneumonic plague, the bacterium Yersinia pestis elicits the development of inflammatory lung lesions that continue to expand throughout infection.\nIn November 2006, the Uganda Ministry of Health received reports of an increase in bubonic plague cases and a possible outbreak of pneumonic plague among residents in the Arua and Nebbi districts.\nPneumonic plague is a fatal disease caused by Yersinia pestis that is associated with a delayed immune response in the lungs", "role": "user" }, { "content": "yes", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nand serotonergic receptors, which are also present on macrophages, belong to the group of receptors inhibiting cell activity [9, 14, 30].", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "content": "Write an abstract for the research paper below. Your response should only include the abstract and no additional text.\n\nArticle text:\non going experimental efforts at relativistic heavy ion collider ( rhic ) and large hadron collider ( lhc ) energies is aimed at to create and characterized the properties of quark gluon plasma ( qgp ) .\nthe heavy mesons ( mesons which contain one heavy quark , mainly c and b ) constitute a novel probe of the qgp properties , because they are produced in the early stage of the heavy - ion collisions and they are the witness to the entire space - time evolution of the qgp .\nthe two main experimental observables related to heavy quarks dynamics in qgp are : ( i ) the nuclear suppression factor , @xmath0 @xcite which is the ratio of the @xmath3 spectra of heavy flavored mesons ( d and b ) produced in nucleus + nucleus collisions to those produced in proton + proton collisions scaled with the number of binary collision and ( ii ) the elliptic flow , @xmath4 @xcite , which is a measure of the anisotropy in the angular distribution of particle production .\nseveral theoretical efforts have been made to study the @xmath0 and the @xmath1 measured in experiments within different models @xcite ( see also for heavy baryons @xcite ) .\nhowever all the approaches shown some difficulties to describe both the @xmath0 and @xmath1 simultaneously .\nto address the simultaneous description of @xmath0 and @xmath1 , we need to focus on the time evolution of @xmath0 and @xmath1 to know how they develop during the expansion of the qgp . as shown in ref .\n@xcite , the @xmath0 develops mostly at the very early stage of the qgp evolution within 3 - 4 fm / c , while the @xmath1 builds up later and consequently can be transferred to the heavy quarks also only at later stages when the fireball has reached temperatures close to the critical temperature .\nthis indicates a more liquid - like behavior of the quark - gluon plasma and the t - dependence of the drag coefficient plays a significance role for a simultaneous description of @xmath0 and @xmath1 as they are sensitive to the two different stages of the qgp evolution ( @xmath5 and @xmath6 ) . to investigate the influence of the temperature dependence of the drag ( and diffusion ) coefficients on heavy quark observables , four different models have been used to calculate the drag and diffusion coefficients .\nmodel - i ( pqcd ) : in this case , the elastic collisions of heavy quarks with the bulk consist of light quarks , anti - quarks and gluons have been considered within the framework of pqcd having temperature dependence of the coupling @xcite : g^-2(t)=2_0 ln()+lnwhere @xmath7 , @xmath8 and @xmath9 .\n@xmath10 is the number of flavor and @xmath11 is the transition temperature .\n+ model - ii ( ads / cft ) : in this second case , we consider the drag force from the gauge / string duality i.e. ads / cft @xcite , @xmath12 , where @xmath13 and the diffusions coefficient deduced from fluctuations - dissipation @xcite .\n+ model - iii ( qpm ) : in this case , we employ a quasi particle model ( qpm ) @xcite with t - dependent quasi - particle masses , @xmath14 , @xmath15 , along with a t - dependent background field known as bag constant , tuned to reproduce the thermodynamics of the lattice qcd . the fit lead to the coupling , @xmath16 ^ 2}$ ] , where @xmath17=2.6 and @xmath18=0.57 .\n+ model - iv ( @xmath19 ) : in this fourth case , we consider a model where the light quarks and gluons are massless but the coupling is taken from the qpm model discussed above .\nthis case is merely a way to obtain a drag increasing toward @xmath6 . +\nthis fourth case has been considered to have drag coefficient with a t dependence similar to the t - matrix approach @xcite . in fig [ drag ] , we have shown the variation of the drag coefficients obtained within the four different model discussed above .\nour methodology is to reproduce the same @xmath0 as of the experiments within all the four models , hence , these are the rescaled drag coefficients . as a function of @xmath3 for the minimum bias . ] as a function of @xmath3 for the minimum bias . ] as a function of @xmath3 for the minimum bias . ]\nwe have solved the langevin dynamics to study the heavy quark momentum evolution in qgp starting from charm quark production in p - p collision @xcite as the initial charm quark distributions in the momentum space . to simulate the heavy quark dynamics in qgp\n, we need the bulk evolution .\nwe are using the transport bulk which can reproduce the gross features of the bulk i.e the spectra and elliptic flow .\nfor the @xmath20 collisions at the highest rhic energy , we simulate the qgp evolution with initial temperature in the center of the fireball is @xmath21 mev and the initial time is @xmath22 fm / c . for the detail of the fireball evolution\n, we refer to our early works @xcite . in fig [ raa_time1 ]\n, we have shown the variation of @xmath0 as a function of @xmath3 for the four different models at rhic energy .\nthe @xmath1 for the same @xmath0 has been plotted in fig [ v2_time1 ] for all the four models .\nit has been observed that for the same @xmath0 , the @xmath1 build - up can be quite different depending on the t - dependence of the drag coefficients .\nlarger the drag coefficient at @xmath6 larger is the @xmath1 @xcite .\nsimilar effect has also been observed in the light quark sector @xcite .\nthis implys , the correct temperature dependence of the drag coefficient has a vital role for a simultaneous description of heavy quark @xmath0 and @xmath1 .\nthe heavy quark observables are also sensitive to the hadronic rescattering @xcite , pre - equilibrium phase @xcite as well as to the time evolution equation i.e where within langevin or boltzmann equation @xcite . in particular\n, the solution of the full two - body collision integral shows that the anisotropic flows are larger respect to those predicted by a langevin dynamics . for details\nwe refer to our earlier works @xcite .\nin the recent past it has been recognized that a very strong magnetic field @xcite is created at early times in high energy heavy ion collisions . since\nheavy quarks are produced at the very early stage of evolution due to their large mass their dynamics can be affected by such a strong magnetic field @xcite . the @xmath23 field generated in non - central heavy ion collisions dominated by the component along the @xmath24 axis ,\nso its main effect is the induction of a current in the @xmath25 plane . on the other hand the time dependence of @xmath23 generates a electric field by faraday s law ,\n@xmath26 which induces a current . for the calculation of the electromagnetic field generated in ultra - relativistic heavy - ion collision , we refer to the space - time solution developed in ref .\n@xcite . in fig.[em ] we show the time dependence of the @xmath27 and electric field @xmath28 at finite space rapidity @xmath29 in a @xmath30 at @xmath31 at @xmath32 for a medium of @xmath33 .\nthe impact of the electromagnetic field has been taken into account through the lorentz force as the external force in the langevin equation .\nfor the detail we refer to ref .\n@xcite . magnetic field introduce a anisotropy which eventually leads to a substantial directed flow , @xmath34 , can be measurable at the experiments . in fig .\n[ v1 ] we have presented the resulting directed flow @xmath35 as a function of rapidity for charm ( black solid line ) and anti - charm quarks ( dashed line line ) .\nwe find a substantial @xmath35 at finite rapidity with a peak at @xmath36 .\nthe directed flow is negative for negative charged particle ( charm ) at forward rapidity which means that the the magnetic field dominates over the displacement induced by the faraday current ( generated due to the time dependence of the magnetic field ) .\nthis is a non trivial result and depends not only on the absolute magnitude of the magnetic field but also on the strength of heavy - light quark interaction .\nif we artificially increase the drag coefficient by a factor 5 to achieve a thermalization of the charm quarks similar to the light quark one , this will lead to a quite smaller @xmath37 . as a function of the rapidity in @xmath30 at @xmath38 for d meson [ @xmath39 and anti - d meson [ @xmath40 . ] as a function of the rapidity in @xmath30 at @xmath38 for d meson [ @xmath39 and anti - d meson [ @xmath40 . ]\nin summary , we have presented how the @xmath1 build - up for the same @xmath0 depends on the t - dependence of the interaction ( drag and diffusion coefficients ) which is the key for a simultaneous description of heavy quark @xmath0 and @xmath1 .\nwe have also mentioned how the @xmath1 gets a boost from the boltzmann dynamics by studying the heave quark momentum evolution and from the hadronic rescattering .\nwe have also studied the heavy quark dynamics in the presence of electromagnetic field .\nheavy quark develops a sizable directed flow @xmath41 which could be measurable at experiments .\nthe present study suggests the heavy quark @xmath35 can be considered as a significant probe to characterize the magnetic field .\nwe acknowledge the support by the erc stg under the qgpdyn grant n. 259684 .\n9 tripathy s , bhattacharyya t , garg p , kumar p , sahoo r and cleymans j , arxiv:1606.06898 [ nucl - th ] .\ndas s k , torres - rincon j m , tolos l , scardina f and greco v , arxiv:1604.05666 [ nucl - th ] .\ndas s k , scardina f , plumari p , greco v 2016 j. phys .\nser . * 668 * , 1 , 012051", "role": "user" }, { "content": "simultaneous description of heavy quark nuclear suppression factor @xmath0 and the elliptic flow @xmath1 is a top challenge for all the existing models . \n we highlight how the temperature dependence of the energy loss / transport coefficients is responsible to address a large part of such a puzzle along with the the full solution of the boltzmann collision integral for the momentum evolution of heavy quark . \n we consider four different models to evaluate the temperature dependence of drag coefficients of the heavy quark in the qgp . \n we have also highlighted the heavy quark dynamics in the presence of an external electromagnetic field which develops a sizable heavy quark directed flow , @xmath2 , can be measurable at lhc .", "role": "assistant" } ]

[ { "content": "Review the following segment from a research document in AI. Answer the subsequent query based solely on the provided information. Limit your response to the answer itself.\n\nResearch Segment: In this paper, we evaluate attention-based models on aphoneme recognition task using the widely-used TIMITdataset. At each time step in generating an output sequence (phonemes),an attention mechanism selects or weighs the signals producedby a trained feature extraction mechanism at potentially all of the time stepsin the input sequence (speech frames). The weighted feature vector thenhelps to condition the generation of the next element of the output sequence.Since the utterances in this dataset are rathershort (mostly under 5 seconds), we measure theability of the considered models in recognizing much longerutterances which were created by artificially concatenatingthe existing utterances.\n\nInquiry: Do the authors use any datasets other than TIMIT to gauge the generalizability of their model?", "role": "user" }, { "content": "The authors used no dataset other than TIMIT for the evaluation of the model.", "role": "assistant" } ]

[ { "content": "Consider the following research inquiry and associated key terms. Review the dataset summaries provided and determine which datasets are suitable for addressing the research question. Base your decision on your understanding of machine learning datasets.\nProvide your answer as a JSON list. For example, for the inquiry \"Semi supervised image classification\", a possible response could be: [\"CIFAR-10\", \"CIFAR-100\"]. Ensure the response contains only the dataset names in JSON format.\n\nResearch Inquiry: We present a methodology to aid clinicians in performing lumbar spinal stenosis detection.\n\nKey Terms: semantic segmentation mri scans lumbar spine\n\nDataset Summaries:\nMVTecAD: MVTec AD is a dataset for benchmarking anomaly detection methods with a focus on industrial inspection. It contains over 5000 high-resolution images divided into fifteen different object and texture categories.\nRarePlanes Dataset: The dataset specifically focuses on the value of synthetic data to aid computer vision algorithms in their ability to automatically detect aircraft and their attributes in satellite imagery. Although other synthetic/real combination datasets exist, RarePlanes is the largest openly-available very-high resolution dataset built to test the value of synthetic data from an overhead perspective.\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.\nMIMIC-CXR: MIMIC-CXR from Massachusetts Institute of Technology presents 371,920 chest X-rays associated with 227,943 imaging studies from 65,079 patients. The studies were performed at Beth Israel Deaconess Medical Center in Boston, MA.\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.\nWGISD: Embrapa Wine Grape Instance Segmentation Dataset (WGISD) contains grape clusters properly annotated in 300 images and a novel annotation methodology for segmentation of complex objects in natural images.\n\nDataset Options: A: MVTecAD B: RarePlanes Dataset C: COCO D: MIMIC-CXR E: ImageNet F: WGISD", "role": "user" }, { "content": "[\"COCO\", \"ImageNet\"]", "role": "assistant" } ]

[ { "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: if you are sick with covid-19, you should refrain from taking other painkillers, such as Aleve or Tylenol. there is no reason to treat a fever with any kind of fever-reducing drug.\n\nResearch Abstract:\nOBJECTIVE: It was recently suggested that ibuprofen might increase the risk for severe and fatal coronavirus disease 2019 (COVID-19) and should therefore be avoided in this patient population.\nWe aimed to evaluate whether ibuprofen use in individuals with COVID-19 was associated with more severe disease, compared with individuals using paracetamol or no antipyretics.\nMETHODS: In a retrospective cohort study of patients with COVID-19 from Shamir Medical Centre, Israel, we monitored any use of ibuprofen from a week before diagnosis of COVID-19 throughout the disease.\nPrimary outcomes were mortality and the need for respiratory support, including oxygen administration and mechanical ventilation.\nRESULTS: The study included 403 confirmed cases of COVID-19, with a median age of 45 years.\nOf the entire cohort, 44 patients (11%) needed respiratory support and 12 (3%) died.\nOne hundred and seventy-nine (44%) patients had fever, with 32% using paracetamol and 22% using ibuprofen, for symptom-relief.\nIn the ibuprofen group, 3 (3.4%) patients died, whereas in the non-ibuprofen group, 9 (2.8%) patients died (p 0.95).\nNine (10.3%) patients from the ibuprofen group needed respiratory support, compared with 35 (11%) from the non-ibuprofen group (p 1).\nWhen compared with exclusive paracetamol users, no differences were observed in mortality rates or the need for respiratory support among patients using ibuprofen.\nCONCLUSIONS: In this cohort of COVID-19 patients, ibuprofen use was not associated with worse clinical outcomes, compared with paracetamol or no antipyretic.", "role": "user" }, { "content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"When compared with exclusive paracetamol users, no differences were observed in mortality rates or the need for respiratory support among patients using ibuprofen.\"]}", "role": "assistant" } ]

[ { "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: The coronavirus disease 2019 (COVID-19) pandemic has drastically altered daily living and medical care for Ohio residents and the practice of medicine for the interventional pain management physician. As a state, Ohio tends to be demographically representative of the broader US population. OBJECTIVE: Reviewing the efforts deployed by Ohio to flatten the COVID-19 infection curve and reduce the spread of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important component of determining optimal procedures for mitigating the effects of the COVID-19 pandemic. METHODS: Over the course of several announcements and orders during the months of March and April, new policies were put into place to prevent COVID-19 transmission, which included efforts to facilitate social distancing and ensure the health care system could manage the number of COVID-19 cases at peak infection rate. Efforts directed toward medical providers included delay of elective procedures, expansion of telehealth options, and new temporary guidance for prescribing controlled substances. RESULTS: The Ohio COVID-19 containment approach resulted in a substantial reduction in COVID-19 cases compared with early models of disease spread, and the state has begun a phased reopening. Continued vigilance in applying social distancing and infection control measures will be a critical component of preventing or reducing the impact of a second wave of COVID-19 in Ohio. LIMITATIONS: A narrative review with paucity of literature.", "role": "user" }, { "content": "[\"Prevention\"]", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nCognitive impairment is common to both disorders after onset but the magnitude of the impairment seems greater in schizophrenia than in bipolar disorder (22).", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "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: 10 Hz flicker improves recognition memory in older people\nSummary: Background 10 Hz electroencephalographic ( EEG ) alpha rhythms correlate with memory performance . Alpha and memory decline in older people . We wished to test if alpha-like EEG activity contributes to memory formation . Flicker can elicit alpha-like EEG activity . We tested if alpha-frequency flicker enhances memory in older people . Pariticpants aged 67–92 identified short words that followed 1 s of flicker at 9.0 Hz , 9.5 Hz , 10.0 Hz , 10.2 Hz , 10.5 Hz , 11.0 Hz , 11.5 Hz or 500 Hz . A few minutes later , we tested participants ' recognition of the words ( without flicker ) . Results Flicker frequencies close to 10 Hz ( 9.5–11.0 Hz ) facilitated the identification of the test words in older participants . The same flicker frequencies increased recognition of the words more than other frequencies ( 9.0 Hz , 11.5 Hz and 500 Hz ) , irrespective of age . Conclusion The frequency-specificity of flicker 's effects in our participants paralleled the power spectrum of EEG alpha in the general population . This indicates that alpha-like EEG activity may subserve memory processes . Flicker may be able to help memory problems in older people\n\n\nReport 2:\nTitle: Both the cutaneous sensation and phosphene perception are modulated in a frequency-specific manner during transcranial alternating current stimulation.\nSummary: PURPOSE Transcranial alternating current stimulation ( tACS ) is a non-invasive stimulation technique for shaping neuroplastic processes and possibly entraining ongoing neural oscillations in humans . Despite the growing number of studies using tACS , we know little about the procedural sensations caused by stimulation . In order to fill this gap , we explored the cutaneous sensation and phosphene perception during tACS . METHODS Twenty healthy participants took part in a r and omized , single-blinded , sham-controlled study , where volunteers received short duration stimulation at 1.0 mA intensity between 2 to 250 Hz using the st and ard left motor cortex-contralateral supraorbital montage . We recorded the perception onset latency and the strength of the sensations assessed by visual rating scale as dependent variables . RESULTS We found that tACS evoked both cutaneous sensation and phosphene perception in a frequency-dependent manner . Our results show that the most perceptible procedural sensations were induced in the beta and gamma frequency range , especially at 20 Hz , whereas minimal procedural sensations were indicated in the ripple range ( 140 and 250 Hz ) . CONCLUSIONS We believe that our results provide a relevant insight into the procedural sensations caused by oscillatory currents , and will offer a basis for developing more sophisticated stimulation protocol s and study design s for future investigations\n\n\nReport 3:\nTitle: Mapping of lateral geniculate nucleus activation during visual stimulation in human brain using fMRI.\nSummary: Functional magnetic resonance imaging has been successfully used to map the activation in the lateral geniculate nucleus ( LGN ) in both hemispheres as well as the primary visual cortex ( V1 ) during a checkerboard visual stimulation . The average blood oxygenation level dependent ( BOLD ) change in LGN was less than that in V1 . However , the BOLD temporal responses were similar between LGN and V1 . The activation in the pulvinar nucleus during visual perception was also detected , and its activated location could be separated from LGN in 3D images . The LGN activation between intersubject and intrasubject multiple trials was compared . The results demonstrate that fMRI can reliably and robustly detect small subcortical nucleus activation in the human brain\n\n\nReport 4:\nTitle: Intermittent photic stimulation affects motor cortex excitability in photosensitive idiopathic generalized epilepsy\nSummary: PURPOSE To assess the effect of intermittent photic stimulation ( IPS ) at a common activating frequency , i.e. 20Hz , on motor cortex excitability by means of transcranial magnetic stimulation ( TMS ) in photosensitive patients with idiopathic generalized epilepsy ( IGE ) . METHODS We studied 15 photosensitive IGE patients showing a photoparoxysmal response ( PPR ) to IPS at 20Hz . Nineteen normal subjects of similar age and sex acted as controls . After the resting motor threshold ( rMT ) was measured , we studied the corticomotor excitability in two conditions r and omly delivered , during IPS ( 5s ) at 20Hz and without IPS . Motor evoked potentials ( MEPs ) were recorded from the right first dorsal interosseous muscle ( FDI ) . We determined the cortical silent period ( cSP ) , the short-latency intracortical inhibition ( SICI ) at the interstimulus interval ( ISI ) of 3 and 4ms and the intracortical facilitation ( ICF ) at ISIs of 12 and 14ms . Data were analyzed by means of rmANOVAs . RESULTS IPS at 20Hz is significantly shortening the cSP in normal subjects , while no significant changes were detected in patients . The rMT was significantly higher in patients than controls , as expected by the concurrent antiepileptic treatment . Other corticomotor excitability measures were unaffected . CONCLUSIONS We confirm that IPS has a weak influence on the motor cortical output in patients with IGE and PPR . The loss of the normal shortening of the cSP , otherwise present in healthy subjects in response to IPS , may have a possible protective nature\n\n\nReport 5:\nTitle: Montage Matters: The Influence of Transcranial Alternating Current Stimulation on Human Physiological Tremor\nSummary: Background Classically , studies adopting non-invasive transcranial electrical stimulation have placed greater importance on the position of the primary “ stimulating ” electrode than the secondary “ reference ” electrode . However , recent current density modeling suggests that ascribing a neutral role to the reference electrode may prove an inappropriate oversimplification . Hypothesis We set out to test the hypothesis that the behavioral effects of transcranial electrical stimulation are critically dependent on the position of the return ( “ reference ” ) electrode . Methods We examined the effect of transcranial alternating current stimulation ( sinusoidal waveform with no direct current offset at a peak-to-peak amplitude of 2000 μA and a frequency matched to each participant 's peak tremor frequency ) on physiological tremor in a group of healthy volunteers ( N = 12 ) . We implemented a sham-controlled experimental protocol where the position of the stimulating electrode remained fixed , overlying primary motor cortex , whilst the position of the return electrode varied between two cephalic ( fronto-orbital and contralateral primary motor cortex ) and two extracephalic ( ipsilateral and contralateral shoulder ) locations . We additionally controlled for the role of phosphenes in influencing motor output by assessing the response of tremor to photic stimulation , through self-reported phosphene ratings . Results Altering only the position of the return electrode had a profound behavioral effect : only the montage with extracephalic return contralateral to the primary stimulating electrode significantly entrained physiological tremor ( 15.9 % ± 6.1 % increase in phase stability , 1 S.E.M. ) . Photic stimulation also entrained tremor ( 11.7 % ± 5.1 % increase in phase stability ) . Furthermore , the effects of electrical stimulation are distinct from those produced from direct phosphene induction , in that the latter were only seen with the fronto-orbital montage that did not affect the tremor . Conclusion The behavioral effects of transcranial alternating current stimulation appear to be critically dependent on the position of the reference electrode , highlighting the importance of electrode montage when design ing experimental and therapeutic protocol", "role": "user" }, { "content": "In this literature review , the importance of this issue is further illustrated by the fact that photic stimulation can have a direct impact on perceptual and cognitive performance .\nThis leaves open the possibility that peripheral photic stimulation can at least in part explain the central effects that are attributed to tACS .", "role": "assistant" } ]

[ { "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\nSkin improvement with two different oestroprogestins in patients affected by acne and polycystic ovary syndrome : clinical and instrumental evaluation . BACKGROUND Despite it is accepted that acne is mostly caused by an hyper-responsiveness of the pilo-sebaceous unit to normal circulating androgen hormones , in a few patients , especially women , acneic lesions can be associated with increased serum androgen levels ( hyperandrogenism ) , of which polycystic ovary syndrome ( PCOS ) is the most common cause . In women with acne and proven PCOS therapy with estroprogestins ( EPs ) can be an excellent option . OBJECTIVE The aim of the study was to assess the effects of two estroprogestins ( EPs ) , ethinyl-estradiol ( EE ) 30 mcg/drospirenone ( DRSP ) 3 mg , and ethinyl-estradiol ( EE ) 30 mcg/chlormadinone acetate ( CMA ) 2 mg , both on increased serum androgen levels and on several skin parameters in women affected by mild to severe acne and polycystic ovary syndrome ( PCOS ) . METHODS Fifty-nine women were randomized to receive EE/DRSP ( n = 32 ) or EE/CMA ( n = 27 ) for six months . Evaluation of serum androgen levels , grading of acne and hirsutism ( respectively with Pillsbury and Ferriman-Gallwey score ) and non-invasive assessment of skin hydration , transepidermal water loss ( TEWL ) and skin homogeneity were performed at baseline , at 3 and 6 months ( end of treatment ) . RESULTS Both treatments were well tolerated and showed a significant improvement of skin and hormonal parameters , although EE/DRSP showed a more potent effect on acne and seborrhea . CONCLUSIONS Estroprogestins represent an effective and safe treatment in women with acne and polycystic ovary syndrome ( PCOS ) . Nevertheless , the combination EE 30 mcg/DRSP 3 mg appears to be a more potent therapeutic option .", "role": "user" }, { "content": "{\"Intervention\": [\"EE 30 mcg/DRSP 3 mg\", \"oestroprogestins\", \"ethinyl-estradiol ( EE ) 30 mcg/drospirenone ( DRSP ) 3 mg\", \"ethinyl-estradiol ( EE ) 30 mcg/chlormadinone acetate ( CMA ) 2 mg\", \"Estroprogestins\", \"estroprogestins ( EPs )\", \"EE/DRSP\", \"EE/CMA\"], \"Outcome\": [\"skin parameters\", \"potent therapeutic option\", \"serum androgen levels , grading of acne and hirsutism\", \"Skin improvement\", \"acne and seborrhea .\", \"non-invasive assessment of skin hydration , transepidermal water loss ( TEWL ) and skin homogeneity\", \"serum androgen levels\", \"skin and hormonal parameters\", \"effective and safe treatment\"], \"Participant\": [\"women\", \"acne\", \"polycystic ovary syndrome ( PCOS )\", \"mild to severe acne\", \"Fifty-nine\", \"polycystic ovary syndrome :\"]}", "role": "assistant" } ]

[ { "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: Technologies for Web and cloud service interaction: a survey \nChapter Title: Container formats \n1. Abstract of Cited Paper (BIB001): STD 11, RFC 822 defines a message representation protocol specifying considerable detail about US-ASCII message headers, but which leaves the message content, or message body, as flat US-ASCII text. This set of documents, collectively called the Multipurpose Internet Mail Extensions, or MIME, redefines the format of messages to allow for\n\nReview Chapter:", "role": "user" }, { "content": "A container is an encoding to encapsulate other arbitrary contents. The MIME standards specify a multipart BIB002 content Fig. 6 This text-based MIME multipart/mixed container example has two parts and demonstrates the boundary principle type for containers, where contents of varying types are interleaved. In multipart, a text-based boundary string separates individual parts as shown in Fig. 6 . Each part has a textbased header that denotes its Content-Type and additional metadata such as binary-to-text or transfer encodings. Multipart defines several subtypes: -multipart/alternative BIB002 to model a choice over multiple contents to a consumer; -multipart/byteranges to encapsulate a subsequence of bytes that belongs to a larger message or file; -multipart/digest BIB002 to store a sequence of textbased messages; -multipart/form-data for submitting a set of completed form fields from an HTML website; -multipart/message BIB002 for an email message; -multipart/mixed for inline placement of media in a text-based message, e.g., embedded images in emails; -multipart/parallel BIB002 to process all parts simultaneously on hardware or software capable of doing so; -multipart/related BIB001 as a mechanism to aggregate related objects in a single content; -multipart/report as a container for email messages; and -multipart/x-mixed-replace [198] for a stream of parts, where the most recent part always invalidates all preceding ones, e.g., an event stream. An application of multipart is XML-binary Optimized Packaging (XOP) . XOP specifies a container format for XML as a MIME multipart/related package BIB001 , where binary element content is directly embedded to remove the necessity of binary-to-text encoding. The W3C specifies a set of attributes and rules for XML and XSD to handle MIME types [341] which are effectively used in XOP. S/MIME is a security extension for MIME. It defines encryption (multipart/encrypted) and digital signatures (multipart/signed) for confidentiality, integrity, and non-repudiation of data using public key cryptography. In general, a drawback of MIME multipart is that the boundary string must not appear in any of the parts because it would break the format. Microsoft's Direct Internet Message Encapsulation (DIME) is another standard for encapsulation and streaming of arbitrary binary data in the spirit of MIME multipart, but with an improved boundary mechanism to reliably distinguish parts.", "role": "assistant" } ]

[ { "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 Review of the Automated Detection of Change in Serial Imaging Studies of the Brain \nChapter Title: 12 \n1. Abstract of Cited Paper (BIB001): Abstract An automatic magnetic resonance imaging (MRI) multispectral segmentation method and a visual metric are compared for their effectiveness to measure tumor response to therapy. Automatic response measurements are important for multicenter clinical trials. A visual metric such as the product of the largest diameter and the largest perpendicular diameter of the tumor is a standard approach, and is currently used in the Radiation Treatment Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (EGOG) clinical trials. In the standard approach, the tumor response is based on the percentage change in the visual metric and is categorized into cure, partial response, stable disease, or progression. Both visual and automatic methods are applied to six brain tumor cases (gliomas) of varying levels of segmentation difficulty. The analyzed data were serial multispectral MR images, collected using MR contrast enhancement. A fully automatic knowledge guided method (KG) was applied to the MRI multispectral data, while the visual metric was taken from the MRI films using the T 1 gadolinium enhanced image, with repeat measurements done by two radiologists and two residents. Tumor measurements from both visual and automatic methods are compared to “ground truth,” (GT) i.e., manually segmented tumor. The KG method was found to slightly overestimate tumor volume, but in a consistent manner, and the estimated tumor response compared very well to hand-drawn ground truth with a correlation coefficient of 0.96. In contrast, the visually estimated metric had a large variation between observers, particularly for difficult cases, where the tumor margins are not well delineated. The inter-observer variation for the measurement of the visual metric was only 16%, i.e., observers generally agreed on the lengths of the diameters. However, in 30% of the studied cases no consensus was found for the categorical tumor response measurement, indicating that the categories are very sensitive to variations in the diameter measurements. Moreover, the method failed to correctly identify the response in half of the cases. The data demonstrate that automatic 3D methods are clearly necessary for objective and clinically meaningful assessment of tumor volume in single or multicenter clinical trials.\n\nReview Chapter:", "role": "user" }, { "content": "Particularly with brain lesions, however, tumor location greatly influences the relationship between such a surrogate and its intended clinical correlates. To disregard location information is to potentially obfuscate this relationship beyond intelligibility. These techniques are additionally designed to apply only to solid tumors. Many features of brain tumors, such as edema, necrosis, and in many cases the tumors themselves, do not obey demarcations. It is not surprising, therefore, that RECIST measurements applied to brain tumors do not correlate well with either radiologist impressions or clinical status. Although these approaches attempt to construct an objective and quantitative metric and make it one which the radiologist can compute quickly and easily, the multiplicity of assumptions and the use of metrics which are so sensitive to measurement uncertainty serve to undermine the ability to detect small changes. Thiesse et al BIB002 found major disagreements between observers for 40% of evaluations, and minor disagreements for a further 10.5% of evaluations. Much of this disagreement stems from the sensitivity of the measures to potentially small spatial measurement errors. Filipek et al BIB001 found volumetric changes of up to 145% associated with radius changes of only 2.7 mm, which may be difficult to appreciate, particularly in light of the irregular borders exhibited by many tumors. Clarke et al 16 investigated the two-diameter approach with serial MR images of six glioma patients. They asked radiologists to compute the maximum area using the twodiameter method; they then determined that the coefficient of variability of the area measurements was 16%, which they attributed primarily to human difficulty in determining the tumor margin. They then asked the radiologists to use their area measures to rate each patient using the standardized categories: complete response, partial response, stable disease, and progressive disease. In 30% of the cases, the radiologists were unable to reach a consensus because the categories were so sensitive to the variability of the area metric. The one-and two-diameter measures are sometimes thought of as surrogate markers for tumor volume, which in some studies has been shown to be predictive of survival. In contrast, Chow et al also found that the area of enhancing tumor was not predictive of survival. This may be explained by Clarke et al 16 who demonstrated that there was no significant relationship between the twodiameter-derived area measure and the tumor volume, which may be due to variability in tumor shape and lack of interobserver consistency. In light of the findings of these studies, it seems that the one-and two-diameter measurement sampling approaches are suboptimal. The use of automation, as opposed to shortcuts, should prove much more efficacious in establishing a clinically usable and quantitative technique to predict response and survival from radiologic studies.", "role": "assistant" } ]

[ { "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: Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans.\nSummary: Transcranial direct current stimulation ( tDCS ) of the human motor cortex results in polarity-specific shifts of cortical excitability during and after stimulation . Anodal tDCS enhances and cathodal stimulation reduces excitability . Animal experiments have demonstrated that the effect of anodal tDCS is caused by neuronal depolarisation , while cathodal tDCS hyperpolarises cortical neurones . However , not much is known about the ion channels and receptors involved in these effects . Thus , the impact of the sodium channel blocker carbamazepine , the calcium channel blocker flunarizine and the NMDA receptor antagonist dextromethorphane on tDCS-elicited motor cortical excitability changes of healthy human subjects were tested . tDCS- protocol s inducing excitability alterations ( 1 ) only during tDCS and ( 2 ) eliciting long-lasting after-effects were applied after drug administration . Carbamazepine selectively eliminated the excitability enhancement induced by anodal stimulation during and after tDCS . Flunarizine result ed in similar changes . Antagonising NMDA receptors did not alter current-generated excitability changes during a short stimulation , which elicits no after-effects , but prevented the induction of long-lasting after-effects independent of their direction . These results suggest that , like in other animals , cortical excitability shifts induced during tDCS in humans also depend on membrane polarisation , thus modulating the conductance of sodium and calcium channels . Moreover , they suggest that the after-effects may be NMDA receptor dependent . Since NMDA receptors are involved in neuroplastic changes , the results suggest a possible application of tDCS in the modulation or induction of these processes in a clinical setting . The selective elimination of tDCS-driven excitability enhancements by carbamazepine proposes a role for this drug in focussing the effects of cathodal tDCS , which may have important future clinical applications\n\n\nReport 2:\nTitle: Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability.\nSummary: Weak transcranial direct current stimulation ( tDCS ) induces persisting excitability changes in the human motor cortex . These plastic excitability changes are selectively controlled by the polarity , duration and current strength of stimulation . To reveal the underlying mechanisms of direct current (DC)-induced neuroplasticity , we combined tDCS of the motor cortex with the application of Na(+)-channel-blocking carbamazepine ( CBZ ) and the N-methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan ( DMO ) . Monitored by transcranial magnetic stimulation ( TMS ) , motor cortical excitability changes of up to 40 % were achieved in the drug-free condition . Increase of cortical excitability could be selected by anodal stimulation , and decrease by cathodal stimulation . Both types of excitability change lasted several minutes after cessation of current stimulation . DMO suppressed the post-stimulation effects of both anodal and cathodal DC stimulation , strongly suggesting the involvement of NMDA receptors in both types of DC-induced neuroplasticity . In contrast , CBZ selectively eliminated anodal effects . Since CBZ stabilizes the membrane potential voltage-dependently , the results reveal that after-effects of anodal tDCS require a depolarization of membrane potentials . Similar to the induction of established types of short- or long-term neuroplasticity , a combination of glutamatergic and membrane mechanisms is necessary to induce the after-effects of tDCS . On the basis of these results , we suggest that polarity-driven alterations of resting membrane potentials represent the crucial mechanisms of the DC-induced after-effects , leading to both an alteration of spontaneous discharge rates and to a change in NMDA-receptor activation\n\n\nReport 3:\nTitle: Facilitation of probabilistic classification learning by transcranial direct current stimulation of the prefrontal cortex in the human\nSummary: The aim of our study was to test if the electrical stimulation of the prefrontal cortex ( PFC ) could modify probabilistic classification learning ( PCL ) . Transcranial direct current stimulation ( tDCS ) was administered to the left prefrontal and to the primary visual cortex of 22 healthy subjects while they performed a PCL task . In this task subjects learned which of two outcomes would occur on each trial after presentation of a particular combination of cues . Ten minutes of anodal , but not cathodal , stimulation improved implicit learning only when the left PFC was stimulated . Our results show that implicit PLC can be modified by weak anodal tDCS , which probably increases neural excitability , as has been shown in the motor and visual cortices previously . Our results suggest that further studies on the facilitation of learning and memory processes by tDCS are warranted\n\n\nReport 4:\nTitle: Electrode-distance dependent after-effects of transcranial direct and random noise stimulation with extracephalic reference electrodes\nSummary: OBJECTIVE To evaluate the importance of the distance between stimulation electrodes , in various montages , on the ability to induce sustained cortical excitability changes using transcranial direct and r and om noise stimulation . METHODS Twelve healthy subjects participated in four different experimental conditions . The stimulation electrode was always placed over the primary motor cortex ; the reference electrode was placed at the contralateral orbit or at the ipsilateral/contralateral arm . MEPs were recorded in order to measure changes in cortical excitability over time . RESULTS The distance between the two electrodes correlates negatively with the duration and magnitude of induced after-effects . CONCLUSIONS In particular when using extracephalic reference electrodes with transcranial electric stimulation techniques , the stimulation intensity has to be adapted to account for interelectrode distance . SIGNIFICANCE Electrode distance plays a critical role in the induction for stimulation after-effects in tDCS and tRNS studies , and must be taken into account in future studies and also when making comparisons with the published literature\n\n\nReport 5:\nTitle: Bilateral temporal cortex transcranial direct current stimulation worsens male performance in a multisensory integration task\nSummary: Somatosensory integration is a critical cognitive function for human social interaction . Though somatosensory integration has been highly explored in cognitive studies ; only a few studies have explored focal modulation of cortical excitability using a speech perception paradigm . In the current study , we aim ed to investigate the effects of tDCS applied over the temporal cortex of healthy subjects during a go-no-go task in which stimuli were shapes and non-words . Twenty-eight subjects were r and omized to receive cathodal , anodal or sham tDCS bilaterally over the superior temporal cortex ( the reference electrode was on deltoid ) in a counterbalanced order . The effects on judgment of congruency between shapes and non-words in healthy volunteers were measured by a go-no-go task . Our findings show a significant modification of performance according to the polarity of stimulation , task and subject gender . We found that men performed worse on the no-go condition for congruent stimuli during cathodal tDCS . For reaction time , on the other h and , there was a similar effect for anodal and cathodal stimulation . There were significantly faster responses on incongruent trials during both anodal and cathodal tDCS . Along with previous literature showing gender differences in tasks associated with speech perception , the findings of this study provide additional evidence suggesting that men may have a more focal and restricted neural processing in this multisensory integration task\n\n\nReport 6:\nTitle: Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation.\nSummary: In this paper we demonstrate in the intact human the possibility of a non-invasive modulation of motor cortex excitability by the application of weak direct current through the scalp . Excitability changes of up to 40 % , revealed by transcranial magnetic stimulation , were accomplished and lasted for several minutes after the end of current stimulation . Excitation could be achieved selectively by anodal stimulation , and inhibition by cathodal stimulation . By varying the current intensity and duration , the strength and duration of the after-effects could be controlled . The effects were probably induced by modification of membrane polarisation . Functional alterations related to post-tetanic potentiation , short-term potentiation and processes similar to postexcitatory central inhibition are the likely c and i date s for the excitability changes after the end of stimulation . Transcranial electrical stimulation using weak current may thus be a promising tool to modulate cerebral excitability in a non-invasive , painless , reversible , selective and focal way\n\n\nReport 7:\nTitle: Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia.\nSummary: OBJECTIVE Some 25%–30 % of patients with schizophrenia have auditory verbal hallucinations that are refractory to antipsychotic drugs . Outcomes in studies of repetitive transcranial magnetic stimulation suggest the possibility that application of transcranial direct-current stimulation ( tDCS ) with inhibitory stimulation over the left temporo-parietal cortex and excitatory stimulation over the left dorsolateral prefrontal cortex could affect hallucinations and negative symptoms , respectively . The authors investigated the efficacy of tDCS in reducing the severity of auditory verbal hallucinations as well as negative symptoms . METHOD Thirty patients with schizophrenia and medication-refractory auditory verbal hallucinations were r and omly allocated to receive 20 minutes of active 2-mA tDCS or sham stimulation twice a day on 5 consecutive weekdays . The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the left temporo-parietal cortex . RESULTS Auditory verbal hallucinations were robustly reduced by tDCS relative to sham stimulation , with a mean diminution of 31 % ( SD=14 ; d=1.58 , 95 % CI=0.76–2.40 ) . The beneficial effect on hallucinations lasted for up to 3 months . The authors also observed an amelioration with tDCS of other symptoms as measured by the Positive and Negative Syndrome Scale ( d=0.98 , 95 % CI=0.22–1.73 ) , especially for the negative and positive dimensions . No effect was observed on the dimensions of disorganization or gr and iosity/excitement . CONCLUSIONS Although this study is limited by the small sample size , the results show promise for treating refractory auditory verbal hallucinations and other selected manifestations of schizophrenia", "role": "user" }, { "content": "First , different montages that are used to target a specific brain area such as dorsolateral prefrontal cortex ( DLPFC ) could have different effects ; therefore providing a unified classification enables us to take these differences into account .", "role": "assistant" } ]

[ { "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: What are the characteristics of Christianson syndrome?\n\nExcerpts: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6).\nWe also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.\nThe single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.\nAmong these are classic disorders such as Angelman syndrome and MECP2-related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with mutations in CASK, CDKL5, CREBBP, and EP300 (Rubinstein-Taybi syndrome), FOXG1, SLC9A6 (Christianson syndrome), and TCF4 (Pitt-Hopkins syndrome).\nMutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.\nMutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia.\nGenetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.\nMutations in the SLC9A6 gene cause Christianson syndrome in boys.\nA novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES).\nMutations in the SLC9A6 gene cause Christianson syndrome in boys.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.\nMutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures.\nIn contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years.\nNovel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.\nMutations in the SLC9A6 gene cause Christianson syndrome in boys.\nMutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.\nIn contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 / years.\nChristianson syndrome (CS) is an X-linked neurodevelopmental disorder caused by deleterious mutations in SLC9A6.\nThis X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia.\nMutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6.\nThe microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include Phelan–McDermid syndrome (chromosome 22q13.3 deletion), MBD5 haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.\nThe single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome. They also include disorders due to mutations in HERC2, adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and ATRX.\nChristianson syndrome (CS) is an X-linked neurodevelopmental disorder caused by deleterious mutations in SLC9A6. Affected families organized the inaugural Christianson Syndrome Association conference to advance CS knowledge and develop questions that may be prioritized in future research.\nAmong these are classic disorders such as Angelman syndrome and MECP2-related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with mutations in CASK, CDKL5, CREBBP, and EP300 (Rubinstein-Taybi syndrome), FOXG1, SLC9A6 (Christianson syndrome), and TCF4 (Pitt-Hopkins syndrome).\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly,\nThe single-gene disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome.\nGenetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.\nMutations in the SLC9A6 gene cause Christianson syndrome in boys.\nNovel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.\nChristianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types.", "role": "user" }, { "content": "Christianson syndrome (CS) is caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). Patients present with prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, are common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.", "role": "assistant" } ]

[ { "content": "Analyze the provided abstract from a materials science paper. Identify synthesis events and represent them in JSON format. Each event should be captured as an object with:\n\n- \"trigger\": The verb indicating the synthesis action, directly quoted from the text.\n- \"arguments\": A list of pairs, each containing the text of an argument and its type, both extracted from the abstract. The types are predefined: [\"Atmospheric_Material\", \"Recipe_Precursor\", \"Solvent_Material\", \"Participant_Material\", \"Recipe_Target\"].\n\nAbstract:\n10.1039/c5gc00379b\nNanoclusters of Cu(ii) supported on nanocrystalline W(vi) oxide: a potential catalyst for single-step conversion of cyclohexane to adipic acid\nHydrogen peroxide (50 wt% in water) was purchased from Merck KGaA, Darmstadt, Germany. Ammonium metatungstate, hydrate, anhydrous cupric chloride, cetyltrimethylammonium bromide (CTAB), hydrazine (80% aq. solution), ammonium hydroxide, cyclohexane (purity > 99.9%), acetonitrile (HPLC grade) were purchased from Sigma-Aldrich Co. All the chemicals were used without further purification.\nCu(II) nanoclusters supported on nanocrystalline WO3 were prepared by modifying our own process, taking CuCl2 and (NH4)6H2W12O40*xH2O as precursors of Cu and W respectively.20 In a typical procedure 5.3 g (NH4)6H2W12O40*xH2O and 0.40 g of CuCl2 were dissolved in 16 g deionized water. Then the solution was made basic to a pH range of 8 using NH4OH solution dropwise. After that, a transparent and homogeneous precursor solution formed when 0.8 g CTAB was added into the solution. After the solution had been stirred for half an hour, aqueous hydrazine solution (0.4 g) was added to it. All the reagents were added maintaining the molar ratio: Cu:CTAB:H2O:N2H4 = 1:0.75:300:1. The resulting precursor solution was transferred into a Teflon-lined autoclave with a stainless steel shell. The autoclave was sealed and maintained at 180 degC for 24 h. After cooling naturally to room temperature, the white products were collected after centrifugation, washed sequentially with distilled water and absolute ethanol to remove ions possibly remnant in the products, and dried in an oven at 100 degC overnight. Finally, the white powder underwent calcinations under an oxygen atmosphere at 550 degC for 6 h to yield canary-yellow products (catalyst).", "role": "user" }, { "content": "[{\"arguments\": [[\"Hydrogen peroxide\", \"Recipe_Precursor\"]], \"trigger\": \"purchased\"}, {\"arguments\": [[\"hydrazine\", \"Recipe_Precursor\"], [\"cyclohexane\", \"Recipe_Precursor\"], [\"acetonitrile\", \"Recipe_Precursor\"], [\"cetyltrimethylammonium bromide\", \"Recipe_Precursor\"], [\"Ammonium metatungstate, hydrate\", \"Recipe_Precursor\"], [\"anhydrous cupric chloride\", \"Recipe_Precursor\"], [\"ammonium hydroxide\", \"Recipe_Precursor\"]], \"trigger\": \"purchased\"}, {\"arguments\": [[\"chemicals\", \"Participant_Material\"]], \"trigger\": \"used\"}, {\"arguments\": [[\"Cu(II)\", \"Recipe_Target\"]], \"trigger\": \"supported\"}, {\"arguments\": [[\"WO3\", \"Participant_Material\"], [\"CuCl2\", \"Recipe_Precursor\"], [\"(NH4)6H2W12O40*xH2O\", \"Recipe_Precursor\"]], \"trigger\": \"prepared\"}, {\"arguments\": [[\"CuCl2\", \"Recipe_Precursor\"], [\"(NH4)6H2W12O40*xH2O\", \"Recipe_Precursor\"]], \"trigger\": \"dissolved\"}, {\"arguments\": [[\"solution\", \"Participant_Material\"]], \"trigger\": \"made\"}, {\"arguments\": [[\"NH4OH\", \"Participant_Material\"]], \"trigger\": \"using\"}, {\"arguments\": [[\"solution\", \"Participant_Material\"]], \"trigger\": \"formed\"}, {\"arguments\": [[\"CTAB\", \"Recipe_Precursor\"], [\"solution\", \"Participant_Material\"]], \"trigger\": \"added\"}, {\"arguments\": [[\"solution\", \"Participant_Material\"]], \"trigger\": \"stirred\"}, {\"arguments\": [[\"hydrazine\", \"Recipe_Precursor\"]], \"trigger\": \"added\"}, {\"arguments\": [[\"reagents\", \"Participant_Material\"]], \"trigger\": \"added\"}, {\"arguments\": [[\"H2O\", \"Participant_Material\"], [\"Cu\", \"Participant_Material\"], [\"CTAB\", \"Participant_Material\"], [\"N2H4\", \"Participant_Material\"]], \"trigger\": \"maintaining\"}, {\"arguments\": [[\"solution\", \"Participant_Material\"]], \"trigger\": \"transferred\"}, {\"arguments\": [[\"products\", \"Participant_Material\"]], \"trigger\": \"collected\"}, {\"arguments\": [[\"ethanol\", \"Participant_Material\"], [\"water\", \"Participant_Material\"]], \"trigger\": \"washed\"}, {\"arguments\": [[\"ions\", \"Participant_Material\"]], \"trigger\": \"remove\"}, {\"arguments\": [[\"powder\", \"Participant_Material\"], [\"oxygen\", \"Atmospheric_Material\"]], \"trigger\": \"calcinations\"}, {\"arguments\": [[\"products\", \"Participant_Material\"]], \"trigger\": \"yield\"}]", "role": "assistant" } ]

[ { "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\nPrescription of antiepileptics and the risk of road traffic crash. Studies assessing the impact of epilepsy and its medication on the risk of road traffic crashes have shown inconsistent results. The aim in this study was to assess this risk using French databases. Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. Only antiepileptics prescribed predominantly in epilepsy were studied (phenobarbital, phenytoin, ethosuximide, valproic acid, vigabatrin, tiagabin, levitiracetam, zonisamide, and lacosamide). A case-control analysis comparing responsible and non-responsible drivers and a case-crossover analysis were performed. Drivers (72 685) involved in an injurious crash in France between July 2005 and May 2008, were included. Drivers exposed to prescribed antiepileptic medicines (n = 251) had an increased risk of being responsible for a crash (OR 1.74 [1.29-2.34]). The association was also significant for the most severe epileptic patients (n = 99; OR = 2.20 [1.31-3.69]). Case-crossover analysis found no association between crash risk and treatment prescription. Patients with prescription of antiepileptic drugs should be cautioned about their potential risk of road traffic crash. This risk is however more likely to be related to seizures than to the effect of antiepileptic medicines.", "role": "user" }, { "content": "{\"Chemical\": [\"tiagabin\", \"lacosamide\", \"valproic acid\", \"levitiracetam\", \"phenobarbital\", \"vigabatrin\", \"ethosuximide\", \"phenytoin\", \"zonisamide\"]}", "role": "assistant" } ]

[ { "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: in some Norwegian sheep farms using a newly developed faecal oocyst count reduction test (FOCRT) . The aim of the present study was to use a controlled efficacy trial to assess the efficacy of toltrazuril against a field isolate suspected of being resistant. METHODS: Twenty lambs, 17–22 days old and raised protected against exposure to coccidia, were infected with a field isolate of 100,000 Eimeria spp. oocysts. This isolate was obtained from a farm with a previously calculated drug efficacy of 56% (95% confidence interval: -433.9 to 96.6%). At day 7 post-infection, 10 of the lambs were orally treated with 20 mg/kg toltrazuril (Baycox Sheep vet., Bayer Animal Health), while the other 10 lambs (controls) were given physiological saline. Clinical examinations were conducted, and weight gains recorded. Daily faecal samples were scored for diarrhoea on a scale from 1 to 5, and oocyst excretion was determined using a modified McMaster technique. Oocysts were morphologically identified to species level. At 17–24 days post-infection, the lambs were euthanized and necropsied. RESULTS: The tested Eimeria isolate was resistant against toltrazuril, and resistance was seen in both pathogenic and non-pathogenic species. In addition, no significant differences in faecal score, growth, gross pathology or histological changes were identified between the two groups. The pathogenic E. ovinoidalis was the dominant species, and no significant difference in the individual prevalence of E. ovinoidalis post-treatment was found between treated (66.9%) and control lambs (61.9%). Other species identified included E. crandallis/weybridgensis, E. parva, E. marsica, E. faurei, E. pallida, E. ahsata and E. bakuensis. CONCLUSIONS: This study confirms toltrazuril resistance in ovine Eimeria spp. ; in addition, the data support the use of FOCRT as an appropriate tool for field evaluation of anticoccidial efficacy. Due to limited anticoccidial treatment alternatives, these findings may have important implications for the sheep industry, particularly in northern Europe. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13071-018-2976-4) contains supplementary material, which is available to authorized users. Text: Anticoccidial resistance (ACR), which develops mainly as a result of intensive long-term use of anticoccidial drugs, occurs widely in poultry production and has also been identified in Cystoisospora suis in piglets [1] [2] [3] [4] [5] . In addition, a field method for the evaluation of reduced anticoccidial efficacy (ACE) in ovine Eimeria spp., the , has recently been developed and indicated that the efficacy of toltrazuril is reduced in some Norwegian sheep flocks [6] . Infections with Eimeria spp. may impact both animal welfare and productivity in the sheep industry, and controlling the infection is important to minimise mortality and morbidity, and to ensure that lamb growth is not compromised [7] [8] [9] . Suggested strategies to control ruminant coccidiosis include pasture management, adequate nutrition, and hygienic measures [10, 11] . However, these measures are often difficult to implement in practice, and the main control approach is often metaphylaxis with anticoccidials [12] [13] [14] [15] . Metaphylactic administration of a single oral dose of toltrazuril in the prepatent period has been shown to be effective at reducing clinical signs and maintaining adequate lamb growth rates in different production systems [13, [15] [16] [17] [18] [19] . In contrast, treatment of clinical coccidiosis is considered inefficient due to the extensive intestinal damage already caused by the infection [20, 21] . Loss of sensitivity to toltrazuril, the only anticoccidial registered for use in sheep in the Nordic countries [22] [23] [24] , should therefore be a matter for serious concern for lamb production. The World Association for the Advancement of Veterinary Parasitology guidelines for evaluation of ACE in mammals [25] , states that there is a need for verified methods for evaluation of ACE. Field methods for assessment of drug efficacy, such as the FOCRT [6] and the faecal egg count reduction test used to evaluate anthelmintic efficacy [26] , give only an indication of reduced efficacy, and need verification through controlled efficacy trials (CET) [27, 28] . In addition, due to the variation in pathogenicity between ovine Eimeria spp., the differentiation of species should be considered separately [25] . The aim of the present study was to perform a CET in order to determine whether different species in a field isolate of ovine Eimeria spp. with suspected ACR, based on the FOCRT [6] , actually demonstrated resistance to toltrazuril. A total of 20 lambs from 8 ewes of the Norwegian White Sheep breed (\"Norsk kvit sau\") was included in the study, which was approved by the Norwegian Animal Research Authority (ID: 11657). The ewes were synchronised using Chronogest® CR and PMSG® (MSD Animal Health, Buckinghamshire, UK) and served by natural mating. Lambs were either snatched at birth (n = 16) or delivered by caesarean section (n = 4) over a period of 6 days, and thereafter reared artificially. Individual ear tags were used for identification. Directly after birth, all lambs were washed with Optima pH 4 soap (Optima Produkter AS, Norheimsund, Norway) and dried before being placed in boxes with expanded metal floors, in groups of four. Infrared heaters were used during the whole trial. An overview of the study groups, including lamb age, birth weight and gender can be found in Additional file 1: Table S1 . Lambs received ovine colostrum from ewes vaccinated against Clostridium spp. (Covexin-8, Zoetis) during the first 30 min of life, followed by colostrum from vaccinated cows (Covexin-8, Zoetis) during the next 24 h. To avoid cases of haemolytic anaemia, the cow-colostrum had previously been tested on naturally reared lambs. Lambs were then fed ad libitum with a commercial milk replacer (Denkamilk, Denkavit, Fiskå, Mølle, Stavanger), using an automatic feeding system (Holm & Laue, Godkalven, Figgjo, Norway). The lambs had ad libitum access to water, hay and commercial lamb-starter concentrate (FORMEL lam vår, Felleskjøpet, Norway). To ensure that transmission of Eimeria to the lambs via contaminated colostrum and hay could not occur, both were frozen at -75°C for a minimum of 24 h, prior to provision to the lambs. The field isolate of Eimeria spp. was obtained from one of the flocks (ID 35) participating in the recent FOCRT study [6] . According to the FOCRT results, toltrazuril had reduced efficacy against Eimeria in two flocks. However, neither of these flocks were available for the CET, due to geographical and practical reasons. Thus, treatment with toltrazuril in the selected flock had been found to have an efficacy of 56.0%, but the results were classified as inconclusive, due to the wide 95% confidence interval (CI) of -433.9 and 96.6% [6] . To obtain sufficient Eimeria oocysts of this mixed field isolate (named \"NMBU ID 35\") for the present study, faecal samples were obtained from 35 lambs in this flock 9 days after toltrazuril treatment (Baycox® Sheep vet., Bayer Animal Health, Oslo, Noray). Oocysts were isolated according to Jackson [29] with some modifications. Briefly, faeces were mixed 1:1 with water and filtered. The faecal mix filtrate was subsequently mixed 1:1 with saturated sugar-solution (density: 1.5 g/l) in a plastic container and left to float onto a glass slide. The slide was washed every second hour with deionized water for three consecutive days, and the washings collected. The washings were centrifuged at 2300× g for 20 min, the supernatant discarded and the sediment mixed 1:1 with deionized water in a glass flask with constant aeration. The oocysts in the flask were left to sporulate for 7 days at room temperature. Sporulated oocysts were stored for 18 days at 4°C. Based on morphology [30] , as seen by light microscopy at 400× magnification (see also Faecal samples section), and classification of 300 oocysts, the field isolate consisted of E. parva (32%), E. crandallis/ weybridgensis (25%), E. ovinoidalis (24%), E. faurei (9%), E. marsica (8%), E. pallida (1%), E. ahsata (< 1%) and E. bakuensis (< 1 %). All lambs were infected (day 0) at 17-22 days of age, using an oesophageal tube. A dose of approximately 100,000 sporulated oocysts, diluted in water to a total volume of 5 ml, was given to each of the 20 lambs. Then, two randomly selected (coin toss) lambs from each group of four were orally treated (day 7) with 0.4 ml/kg toltrazuril (Baycox® Sheep vet. 50 mg/ml, Bayer Animal Health) and the remaining lambs (controls) were given 0.4 ml/kg of 0.9% NaCl (B. Braun Medical AS, Vestskogen, Norway). Clinical examinations were performed daily throughout the trial. Rectal temperature was measured at days 0, 1, 2 and 7, and daily from day 14, and temperatures > 40.5°C\n\nwere considered as fever. The lambs were weighed once a week using a calibrated weight (Kruuse, Drøbak Norway) with 0.1 kg sensitivity, until 14 days post-infection, and thereafter three times a week. Two lambs (controls) were treated orally with trimethoprim/sulphamethoxasole (Bactrim, Roche, Etterstad, Norway) during the first three days of life due to suspected Escherichia coli-infection, from which both recovered within 48 h. Six lambs, two controls and four treated with toltrazuril, developed lameness due to interdigital abscessation, and Streptococcus aureus was detected in two lambs. Four lambs recovered without treatment, and two of the lambs recovered after treatment with benzylpenicillinprocaine (Penovet vet., Boehringer Ingelheim Vetmedica, Copenhagen, Denmark) administered intramuscularly for three days. On clinical examination, special attention was paid to clinical signs associated with Eimeria spp. infections, i.e. dehydration, pyrexia, weakness, anorexia and, in particular, the presence of diarrhoea. Severe haemorrhagic diarrhoea and dehydration in one lamb at day 17, led to euthanasia of that whole group of four lambs. At day 18, another lamb showed signs of haemorrhagic diarrhoea, and all lambs in this group were also euthanized. The remaining three groups were euthanized on days 21, 23, and 24. Blood samples were drawn from v. jugularis using vacuette tubes (plain and EDTA-treated; BD, Franklin Lakes, USA) at 48 ± 2 h after birth and at days 0, 7 and at euthanasia. Haematology was performed using the ADVIA 120 Haematology system (Bayer Diagnostics, Leverkusen, Germany). Dehydration was considered with a haematocrit (hct) of > 45.0% [31] . Whole blood tubes were centrifuged, and the serum removed and stored at -20°C until further analysis. Biochemical analysis was performed by ABX Pentra 400 (Horiba, Les Ulis, France), and included analysis of iron, total protein, albumin, urea, creatinine, gamma-glutamyl transferase, glutamate dehydrogenase and beta hydroxybutyric acid. Individual faecal samples from each of the lambs were obtained daily from day 10 of life until the end of the experiment. Visual scoring of faecal consistency was performed on a scale from one to five (1: normal, pelleted; 2: soft; 3: liquid; 4: watery; 5: watery with blood and/or intestinal tissue) [32] . A score ≥ 3 was considered as diarrhoea. Samples were collected using an in-house \"faecal spoon\" [6] and the faecal samples were put in zip-lock bags, which were vacuum packed (Fresh'n'easy, OBH Nordica, Sundbyberg, Sweden), stored at 4°C, and analysed within 37 days. The rate of oocyst excretion was determined using a modified McMaster technique with a theoretical sensitivity of 5 oocysts per gram (OPG) [6] . One hundred Eimeria oocysts from all samples ≥ 1000 OPG were examined by light microscopy at 400× magnification and identified to species level, using morphological criteria [30] . However, due to their morphological similarity, oocysts of E. crandallis and E. weybridgensis were not differentiated. Oocyst counts were analysed by the FOCRT [6] , which consists of a two-step procedure. First, timing of treatment and sampling was evaluated, followed by evaluation of treatment efficacy, by comparing post-treatment faecal samples from treated lambs with equivalent samples from untreated controls. Pre-treatment samples (sample 1) were obtained on day 7 (day of treatment), and post-treatment samples (sample 2) were obtained on days 14-18. The FOCRT was then run using the post-treatment oocyst counts for all five possible time intervals (7-11 days) between samples 1 and 2. Faecal samples obtained at euthanasia were analysed for rotavirus, coronavirus, Cryptosporidium spp. and general bacteriology. Additional testing for Cryptosporidium spp. was performed in diarrhoeic lambs at the time of infection (day 0, n = 10).\n\nInquiry: What test can detect reduced anticoccidial efficacy in the field?", "role": "user" }, { "content": "faecal oocyst count reduction test (FOCRT)", "role": "assistant" } ]

[ { "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\nThis paper introduces a novel framework for learning algorithms to solve online combinatorial optimization problems.\nTowards this goal, we introduce a number of key ideas from traditional algorithms and complexity theory.\nFirst, we draw a new connection between primal-dual methods and reinforcement learning.\nNext, we introduce the concept of adversarial distributions (universal and high-entropy training sets), which are distributions that encourage the learner to find algorithms that work well in the worst case.\nWe test our new ideas on a number of optimization problem such as the AdWords problem, the online knapsack problem, and the secretary problem.\nOur results indicate that the models have learned behaviours that are consistent with the traditional optimal algorithms for these problems.\nMachine learning has led to dramatic improvements in our capabilities to solve problems previously considered intractable.\nBesides the obvious empirical evidence of success, there has also been a strong parallel effort in the theory of ML which aims to explain why, when, and how ML techniques work.Our goal in this paper is to explore whether machine learning can be used to learn algorithms for classic combinatorial optimization problems.\nWe will define this question more specifically by connecting to three concepts from traditional algorithms and complexity theory.\nIn this work, we introduced several ideas from traditional algorithmic thinking to train neural networks to solve online optimization problems.\nIn the problems that we consider, our results show that RL was able to find key characteristics of the optimal \"pen-and-paper\" algorithms.\nHowever, in some instances (such as in the knapsack and secretary problem), we saw that some state augmentation was needed in order for the learner to more adequately recover the optimal algorithms.\nIn this work, we took a step towards that by having the RL environment encode that state in a form usable by the agent.\nIn future work, we plan to remove the state augmentation from the RL environment and force the agent to learn the state augmentation as part of the training process.\nFIG3 compares the agent's learned algorithm with the optimal algorithm in the binary setting.\nFIG3 plots the threshold for the agent's learned algorithm in the value setting with changing distributions.\nObserve that both have learned a threshold at around 1/e.", "role": "user" }, { "content": "By combining ideas from traditional algorithms design and reinforcement learning, we introduce a novel framework for learning algorithms that solve online combinatorial optimization problems.", "role": "assistant" } ]

[ { "content": "Given the following biomedical passages, answer the question succinctly. Ensure your response is precise and limited to the answer only.\n\nQuestion: Which transcription factor is considered as a master regulator of lysosomal genes?\n\nPassages: In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression\nInteraction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB\nDepletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes\nThe identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lysosome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease\nTFEB regulates lysosomal proteostasis\nHere, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs\nour findings identify TFEB as a specific regulator of lysosomal proteostasis\nthe transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism\nA lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.\nthe Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane\nthe lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR\nThese data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.\nWe showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes.\nIn this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression.\nIn particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy.\nHere, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane.\nHere, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs.\nHere we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α.\nTranscription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity.\nThese data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.\nWe found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system.\nThe transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes.\nIn particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy.\nWe showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes.\nIn this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression.\nWe recently discovered the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network and its master gene transcription factor EB (TFEB), which regulates lysosomal biogenesis and function.\nTranscription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied.\nIn contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core.\nHere, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane.\nWe showed that the mouse GRN gene has two possible coordinated lysosomal expression and regulation (CLEAR) sequences that bind to transcription factor EB (TFEB), a master regulator of lysosomal genes.\nIn this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression.\nWe observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF (micropthalmia-associated transcription factor) and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes.\nTranscription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity.\nHere, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs.\nTranscription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied.\nThese data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.\nIn particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy.", "role": "user" }, { "content": "Transcription factor EB (TFEB)", "role": "assistant" } ]

[ { "content": "Examine the given text from a research paper in the field of NLP. Your task is to identify the role of the citation within the context provided. Focus on understanding the intent behind the citation and classify it accordingly.\n\nSection Title:\nconclusion\n\nText Before Citation:\nAnother interesting extension is to broaden the definition of a &quot;word&quot; to include multi-word lexical units (Smadja, 1992). Promising features for classification include part of speech, frequency of co-occurrence, relative word position, and translational entropy (Melamed, 1997). Even better accuracy can be achieved with a more fine-grained link class structure.\n\nCitation Text:\nAnother interesting extension is to broaden the definition of a `` word '' to include multi-word lexical units ( Smadja , 1992 ) .\n\nText After Citation:\nIf such units can be identified a priori, their translations can be estimated without modifying the word-to-word model. In this manner, the model can account for a wider range of translation phenomena.", "role": "user" }, { "content": "FutureWork", "role": "assistant" } ]

[ { "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: How lamina-associated polypeptide 1 (LAP1) activates Torsin\nContent Overview:\nAbstract:\nLamina-associated polypeptide 1( LAP1) resides at the nuclear envelope and interacts with Torsins, poorly understood endoplasmic reticulum( ER)-localized AAA+ ATPases, through a conserved, perinuclear domain. We determined the crystal structure of the perinuclear domain of human LAP1. LAP1 possesses an atypical AAA+ fold. While LAP1 lacks canonical nucleotide binding motifs, its strictly conserved arginine 563 is positioned exactly where the arginine finger of canonical AAA+ ATPases is found. Based on modeling and electron microscopic analysis, we propose that LAP1 targets Torsin to the nuclear envelope by forming an alternating, heterohexameric( LAP1-Torsin) 3 ring, in which LAP1 acts as the Torsin activator. The experimental data show that mutation of arginine 563 in LAP1 reduces its ability to stimulate TorsinA ATPase hydrolysis. This knowledge may help scientists understand the etiology of DYT1 primary dystonia, a movement disorder caused by a single glutamate deletion in TorsinA.\nIntroduction:\nLamina-Associated Polypeptide 1( LAP1) and Luminal domain-Like LAP1( LULL1) are type II integral membrane proteins with ∼30 kDa luminal domains that share 62% identity. LAP1 localizes to the nuclear envelope( NE) via its lamin-interacting domain, whereas LULL1 is found throughout the endoplasmic reticulum( ER)( Senior and Gerace, 1988; Goodchild and Dauer, 2005). LAP1 and LULL1 associate with Torsins( Goodchild and Dauer, 2005; Naismith et al., 2009; Zhao et al., 2013), which are ER-resident members of the ATPases Associated with a variety of cellular Activities( AAA+ ATPases) superfamily( Iyer et al., 2004; Hanson and Whiteheart, 2005; Erzberger and Berger, 2006). AAA+ ATPases use ATP hydrolysis to undergo conformational changes and to exert mechanical force on a substrate. AAA+ ATPases are involved in many processes, including vesicle fusion and scission, protein folding/unfolding, complex assembly/disassembly, protein transport, and nucleic acid remodeling. Detailed mechanistic knowledge exists for a number of AAA+ ATPases, but not for Torsins. Torsins are found in all animals, but not in single-cell organisms and plants. Deletion of a single glutamate in TorsinA( humans have four Torsin orthologs: TorsinA, TorsinB, Torsin2A, and Torsin3A) at position 302/303 causes the movement disorder DYT1 primary dystonia( Ozelius et al., 1997; Breakefield et al., 2008). Mammalian TorsinA has been assigned to a variety of possible functions including nuclear envelope( NE) organization, synaptic vesicle transport and turnover, operation of the secretory pathway, protein degradation, cytoskeletal organization and transport via NE budding( Vander Heyden et al., 2009; Granata and Warner, 2010; Jokhi et al., 2013). While LAP1 and LULL1 were first considered as Torsin substrates( Naismith et al., 2009), they are now being proposed as possible activators of Torsin( Zhao et al., 2013). To better understand the function of LAP1 in relation to Torsin, we set out to determine its structure. Our data suggest that LAP1 and LULL1 can both form heterohexameric ring assemblies with Torsin, whereby Torsin is activated through an arginine finger at amino acid( aa) R563 of LAP1( R449 of LULL1). Thus LAP1 and LULL1 each have dual roles, namely the targeting and activation of Torsins.\nDiscussion:\nHere we provide structural evidence to explain how LAP1 and LULL1 function as activating proteins for Torsin. This confirms recent work which biochemically showed that LAP1 and LULL1 activate TorsinA( Zhao et al., 2013). A heterohexameric ring assembly for AAA+ ATPases is unusual, but not unprecedented( Gribun et al., 2008; Saffian et al., 2012). However, to our knowledge this is the first description of a heterohexameric assembly where a canonical AAA+ domain alternates with a nucleotide-free AAA+ like domain, which we now call AAA+ Activator domain. It is striking that LAP1 and LULL1 lack all canonical nucleotide-binding elements. This feature has undoubtedly complicated their detection by sequence-based methods. Using the LAP1 structure, we performed a reverse hidden Markov model search to possibly identify structurally similar proteins in various organisms using Backphyre( Kelley and Sternberg, 2009). Interestingly, the top hits that we find besides LAP1 homologs are the Torsins. This indicates that both proteins are possibly derived from a common ancestor. In Drosophila as well as in Caenorhabditis, we find LAP1 homologs that have so far escaped detection( Figure 1—figure supplement 1). Gratifyingly, for all species where so far an orphaned Torsin has been found, we now also find a LAP1/LULL1 homolog( for many species, it is difficult to distinguish between LAP1 and LULL1 based on sequence alone). This lends further support to our model suggesting that a heterohexameric LAP1-Torsin ring is the functionally relevant protein assembly. Our structure was obtained using a VHH raised against LAP1. We can only speculate as to why VHH-BS1 helped in crystallizing the protein. Perhaps VHH-BS1 fortuitously generates packing contacts important for crystal formation. We note that VHH-BS1 binds to the area immediately surrounding the arginine finger of LAP1, thereby interfering with TorsinA binding( Figure 1—figure supplement 3). Inclusion of VHH-BS1 might prevent cryptic and poorly ordered hexamerization of LAP1 at high protein concentrations and therefore favor a more ordered conformation conducive to crystallization. Interestingly, VHH-BS1 can compete with LAP1 for TorsinA binding in vitro( Figure 1—figure supplement 3). When expressed intracellularly, it might be a useful tool to further characterize TorsinA-LAP1 function in vivo. What are the substrate( s) of Torsin? Torsin acts in close proximity to the NE or the ER membrane, depending on whether it interacts with membrane-bound LAP1 or LULL1, respectively. Membrane proximity is further ensured by the N-terminal hydrophobic region within TorsinA( Vander Heyden et al., 2011). Using an ATP-trapped mutant, it was shown that TorsinA is involved in the exit of large ribonucleoprotein( mRNP) granules from the nucleus through a pathway akin to the nuclear egress of herpes-type viruses( Rose and Schlieker, 2012; Speese et al., 2012; Jokhi et al., 2013). A substrate-trap mutant of TorsinA localized to the neck of mRNP-filled vesicles that bud from the inner nuclear membrane( INM) into the perinuclear space( Jokhi et al., 2013), consistent with our model of LAP1-mediated activation of TorsinA close to the INM. We therefore speculate that the so far elusive Torsin substrates include proteins involved in membrane scission. This is akin to the action of the AAA+ ATPase Vps4 involved in the scission of narrow membrane necks mediated by ESCRT-III( endosomal sorting complexes required for transport) components( Hill and Babst, 2012; McCullough et al., 2013), but with an important difference: while Vps4 acts on the inside of the necks, Torsins presumably act on the outside. We further speculate that under more physiological conditions, that is, properly complexed with LAP1 or LULL1 and engaged with substrate, the ATPase activity of Torsin might be substantially higher than that reported under the in vitro conditions tested so far. Apart from the identification of Torsin substrate( s), understanding the catalytic mechanism of the Torsin-LAP1/LULL1 machinery is equally important. Because of the unusual heterohexameric architecture with only three active sites, we expect substantial differences between this system and those that are better understood. One important aspect will be to unravel the role of the highly conserved cysteines, both in LAP1/LULL1 and in Torsin. While both proteins have conserved disulfides, these do not account for all cysteines and suggest a possible redox mechanism, as has been discussed previously( Zhu et al., 2010, 2008). We note that in our model the most conserved cysteine C496 in LAP1 cannot engage in an intramolecular disulfide bridge, but is close to the nucleotide-binding site of the neighboring TorsinA. This remarkable conservation might indicate a role in a redox mechanism that is coupled to the catalytic cycle of Torsin-LAP1/LULL1. The lumen of the endoplasmic reticulum is a site rich in oxidoreductases that assist in protein folding and assembly. The catalytic function( s) of the Torsin-LAP1/LULL1 assemblies may have co-opted part of this machinery.", "role": "user" }, { "content": "Cells are filled with activity—proteins must be folded into intricate shapes and unfolded , complex molecules must be built and taken apart—and all this activity requires energy . Cells use a molecule called ATP as a source of energy , with the energy being released when enzymes called ATPases remove a phosphate group from the ATP molecule . There are many different ATPases , and when one of them does not work properly , the consequences can be severe . A single mutation in the gene for an ATPase called TorsinA , for example , can lead to a painful and severely disabling disorder called primary dystonia . However , scientists have yet to discover what the TorsinA enzyme does in cells and how mutated TorsinA causes primary dystonia . It is known that the TorsinA enzyme is found in the endoplasmic reticulum—a region of the cell where , among other things , proteins are folded and unfolded—and that it interacts with two membrane proteins , LAP1 and LULL1 . Also , TorsinA is a member of the AAA+ family of ATPases ( AAA+ is short for ATPases Associated with diverse cellular Activities ) , and these enzymes tend to combine with each other to form functional ring-shaped arrays . Now Sosa et al . have used a combination of X-ray crystallography , electron microscopy , computer modeling , and biochemistry to study the interactions between TorsinA and the two membrane proteins . This work revealed that , somewhat surprisingly , certain parts of the membrane proteins have structures that are similar to those of AAA+ ATPases . This allows the TorsinA enzymes and the membrane proteins to combine to form rings that contain three enzymes and three LAP1 proteins or three LULL1 proteins . Within these rings , the LAP1 and LULL1 proteins activate the TorsinA enzyme by supplying an amino acid called arginine to the neighboring TorsinA molecule . The amino acid is supplied to a site on the enzyme that can bind nucleotides ( which are the building blocks of DNA and RNA ) ; the LAP1 and LULL1 proteins themselves cannot bind nucleotides . The work of Sosa et al . may help scientists to better understand how TorsinA causes primary dystonia . One of the important next steps is to work out what molecules TorsinA acts on .", "role": "assistant" } ]

[ { "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:\nWe study network coordination problems, as captured by the setting of generalized network design (, STOC 2018), in the face of uncertainty resulting from partial information that the network users hold regarding the actions of their peers. This uncertainty is formalized using 's Bayesian ignorance framework (TCS 2012). While the approach of is purely combinatorial, the current paper takes into account computational considerations: Our main technical contribution is the development of (strongly) polynomial time algorithms for local decision making in the face of Bayesian uncertainty.\n\nCited Works Summary:\n[1]: In this paper, we study online algorithms when the input is not chosen adversarially, but consists of draws from some given probability distribution. While this model has been studied for online problems like paging and k-server, it is not known how to beat the Φ(log n) bound for online Steiner tree if at each time instant, the demand vertex is a uniformly random vertex from the graph. For the online Steiner tree problem, we show that if each demand vertex is an independent draw from some probability distribution π: V → [0, 1], a variant of the natural greedy algorithm achieves Eω[A(ω)] Eω[OPT (ω)] = O(1); moreover, this result can be extended to some other subadditive problems. Both assumptions that the input sequence consists of independent draws from π, and that π is known to the algorithm are both essential; we show (almost) logarithmic lower bounds if either assumption is violated. Moreover, we give preliminary results on extending the Steiner tree results above to the related \"expected ratio\" measure Eω[ω(ω) OPT (ω)]. Finally, we use these ideas to give an average-case analysis of the Universal TSP problem.", "role": "user" }, { "content": "In [1] , investigate online combinatorial optimization problems where the requests arriving online are drawn independently and identically from a known distribution. As an example, [1] study the online Steiner tree problem on an undirected graph @math . In this problem, at each step the algorithm receives a terminal that is drawn independently from a distribution over @math , and needs to maintain a subset of edges connecting all the terminals received so far.", "role": "assistant" } ]

[ { "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: surgical masks and N95 respirators should be saved for health care workers as they are more effective in preventing covid-19\n\nResearch Abstract:\nThe Coronavirus Disease 2019 (COVID-19) has swept the whole world with high mortality.\nSince droplet transmission is the main route of transmission, wearing a mask serves as a crucial preventive measure.\nHowever, the virus has spread quite quickly, causing severe mask shortage.\nFinding alternative materials for homemade masks while ensuring the significant performance indicators will help alleviate the shortage of masks.\nReferring to the national standard for the \"Surgical Mask\" of China, 17 materials to be selected for homemade masks were tested in four key indicators: pressure difference, particle filtration efficiency, bacterial filtration efficiency and resistance to surface wetting.\nEleven single-layer materials met the standard of pressure difference ([≤]49 Pa), of which 3 met the standard of resistance to surface wetting ([≥]3), 1 met the standard of particle filtration efficiency ([≥]30%), but none met the standard of bacterial filtration efficiency ([≥]95%).\nBased on the testing results of single-layer materials, fifteen combinations of paired materials were tested.\nThe results showed that three double-layer materials including double-layer medical non-woven fabric, medical non-woven fabric plus non-woven shopping bag, and medical non-woven fabric plus granular tea towel could meet all the standards of pressure difference, particle filtration efficiency, and resistance to surface wetting, and were close to the standard of the bacterial filtration efficiency.\nIn conclusion, if resources are severely lacking and medical masks cannot be obtained, homemade masks using available materials, based on the results of this study, can minimize the chance of infection to the maximum extent.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "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: P.S.Sastry. A survey of temporal data mining \nChapter Title: Frequent episodes \n1. Abstract of Cited Paper (BIB001): One basic goal in the analysis of time-series data is to find frequent interesting episodes, i.e, collections of events occurring frequently together in the input sequence. Most widely-known work decide the interestingness of an episode from a fixed user-specified window width or interval, that bounds the length of the subsequent sequential association rules. We present in this paper, a more intuitive definition that allows, in turn, interesting episodes to grow during the mining without any user-specified help. A convenient algorithm to efficiently discover the proposed unbounded episodes is also implemented. Experimental results confirm that our approach results useful and advantageous. \n2. Abstract of Cited Paper (BIB002): In this paper we consider the process of discovering frequent episodes in event sequences. The most computationally intensive part of this process is that of counting the frequencies of a set of candidate episodes. We present two new frequency counting algorithms for speeding up this part. These, referred to as non-overlapping and non-inteleaved frequency counts, are based on directly counting suitable subsets of the occurrences of an episode. Hence they are different from the frequency counts of Mannila et al [1], where they count the number of windows in which the episode occurs. Our new frequency counts offer a speed-up factor of 7 or more on real and synthetic datasets. We also show how the new frequency counts can be used when the events in episodes have time-durations as well. \n3. Abstract of Cited Paper (BIB003): We present a method for a reliable detection of \"unusual\" sets of episodes in the form of many pattern sequences, scanned simultaneously for an occurrence as a subsequence in a large event stream within a window of size w. We also investigate the important special case of all permutations of the same sequence, which models the situation where the order of events in an episode does not matter, e.g., when events correspond to purchased market basket items. In order to build a reliable monitoring system, we compare obtained measurements to a reference model which in our case is a probabilistic model (Bernoulli or Markov). We first present a precise analysis that leads to a construction of a threshold. The difficulties of carrying out a probabilistic analysis for an arbitrary set of patterns, stems from the possible simultaneous occurrence of many members of the set as subsequences in the same window, the fact that the different patterns typically do have common symbols or common subsequences or possibly common prefixes, and that they may have different lengths. We also report on extensive experimental results, carried out on the Wal-Mart transactions database, that show a remarkable agreement with our theoretical analysis. This paper is an extension of our previous work where we laid out foundation for the problem of the reliable detection of an \"unusual\" episodes, but did not consider more than one episode scanned simultaneously for an occurrence. \n4. Abstract of Cited Paper (BIB004): This paper establishes a formal connection between two common, but previously unconnected methods for analyzing data streams: discovering frequent episodes in a computer science framework and learning generative models in a statistics framework. We introduce a special class of discrete hidden Markov models (HMMs), called episode generating HMMs (EGHs), and associate each episode with a unique EGH. We prove that, given any two episodes, the EGH that is more likely to generate a given data sequence is the one associated with the more frequent episode. To be able to establish such a relationship, we define a new measure of frequency of an episode, based on what we call nonoverlapping occurrences of the episode in the data. An efficient algorithm is proposed for counting the frequencies for a set of episodes. Through extensive simulations, we show that our algorithm is both effective and more efficient than current methods for frequent episode discovery. We also show how the association between frequent episodes and EGHs can be exploited to assess the significance of frequent episodes discovered and illustrate empirically how this idea may be used to improve the efficiency of the frequent episode discovery.\n\nReview Chapter:", "role": "user" }, { "content": "A second class of approaches to discovering temporal patterns in sequential data is the frequent episode discovery framework (Mannila et al 1997) . In the sequential patterns framework, we are given a collection of sequences and the task is to discover (ordered) sequences of items (i. e. sequential patterns) that occur in sufficiently many of those sequences. In the frequent episodes framework, the data are given in a single long sequence and the task is to unearth temporal patterns (called episodes) that occur sufficiently often along that sequence. Mannila et al (1997) apply frequent episode discovery for analysing alarm streams in a telecommunication network. The status of such a network evolves dynamically with time. There are different kinds of alarms that are triggered by different states of the telecommunication network. Frequent episode mining can be used here as part of an alarm management system. The goal is to improve understanding of the relationships between different kinds of alarms, so that, e. g., it may be possible to foresee an impending network congestion, or it may help improve efficiency of the network management by providing some early warnings about which alarms often go off close to one another. We explain below the framework of frequent episode discovery. The data, referred to here as an event sequence, are denoted by (E 1 , t 1 ), (E 2 , t 2 ), . . . , where E i takes values from a finite set of event types E, and t i is an integer denoting the time stamp of the ith event. The sequence is ordered with respect to the time stamps so that, t i ≤ t i+1 for all i = 1, 2, . . . . The following is an example event sequence with 10 events in it: An episode α is defined by a triple (V α , ≤ α , g α ), where V α is a collection of nodes, ≤ α is a partial order on V α and g α : V α → E is a map that associates each node in the episode with an event type. Put in simpler terms, an episode is just a partially ordered set of event types. When the order among the event types of an episode is total, it is called a serial episode and when there is no order at all, the episode is called a parallel episode. For example, (A → B → C) is a 3-node serial episode. The arrows in our notation serve to emphasize the total order. In contrast, parallel episodes are somewhat similar to itemsets, and so, we can denote a 3-node parallel episode with event types A, B and C, as (ABC). Although, one can have episodes that are neither serial nor parallel, the episode discovery framework of Mannila et al (1997) is mainly concerned with only these two varieties of episodes. An episode is said to occur in an event sequence if there exist events in the sequence occurring with exactly the same order as that prescribed in the episode. For example, in the example event sequence (1), the events (A, 2), (B, 3) and (C, 8) constitute an occurrence of the serial episode (A → B → C) while the events (A, 7), (B, 3) and (C, 8) do not, because for this serial episode to occur, A must occur before B and C. Both these sets of events, however, are valid occurrences of the parallel episode (ABC), since there are no restrictions with regard to the order in which the events must occur for parallel episodes. Recall that in the case of sequential patterns, we defined the notion of when a sequence is contained in another. Similarly here there is the idea of subepisodes. Let α and β be two episodes. β is said to be a subepisode of α if all the event types in β appear in α as well, and if the partial order among the event types of β is the same as that for the corresponding event types in α. For example, (A → C) is a 2-node subepisode of the serial episode (A → B → C) while (B → A) is not a subepisode. In case of parallel episodes, this order constraint is not there, and so every subset of the event types of an episode correspond to a subepisode. Finally, in order to formulate a frequent episode discovery framework, we need to fix the notion of episode frequency. Once a frequency is defined for episodes (in an event sequence) the task is to efficiently discover all episodes that have frequency above some (user-specified) threshold. For efficiency purposes, one likes to use the basic idea of the Apriori algorithm and hence it is necessary to stipulate that the frequency is defined in such a way that the frequency of an episode is never larger than that of any of its subepisodes. This would ensure that an n-node episode is a candidate frequent episode only if all its (n − 1)-node subepisodes are frequent. Mannila et al (1997) define the frequency of an episode as the fraction of all fixed-width sliding windows over the data in which the episode occurs at least once. Note that if an episode occurs in a window then all its subepisodes occur in it as well. The user specifies the width of the sliding window. Now, given an event sequence, a window-width and a frequency threshold, the task is to discover all frequent episodes in the event sequence. Once the frequent episodes are known, it is possible to generate rules (that describe temporal correlations between events) along the lines described earlier. The rules obtained in this framework would have the \"subepisode implies episode\" form, and the confidence, as earlier, would be the appropriate ratio of episode frequencies. This kind of a temporal pattern mining formulation has many interesting and useful application possibilities. As was mentioned earlier, this framework was originally applied to analysing alarm streams in a telecommunication network (Mannila et al 1997) . Another application is the mining of data from assembly lines in manufacturing plants BIB003 . The data are an event sequence that describes the time-evolving status of the assembly line. At any given instant, the line is either running or it is halted due to some reason (like lunch break, electrical problem, hydraulic failure etc.). There are codes assigned for each of these situations and these codes are logged whenever there is a change in the status of the line. This sequence of time-stamped status codes constitutes the data for each line. The frequent episode discovery framework is used to unearth some temporal patterns that could help understanding hidden correlations between different fault conditions and hence improving the performance and throughputs of the assembly line. In manufacturing plants, sometimes it is known that one particular line performs significantly better than another (although no prior reason is attributable to this difference). Here, frequent episode discovery may actually facilitate the devising of some process improvements by studying the frequent episodes in one line and comparing them to those in the other. The frequent episode discovery framework has also been applied on many other kinds of data sets, like web navigation logs (Mannila et al 1997; BIB002 , and Wal-Mart sales data BIB004 etc. The process of frequent episode discovery is an Apriori-style level-wise algorithm that starts with discovering frequent 1-node episodes. These are then combined to form candidate 2-node episodes and then by counting their frequencies, 2-node frequent episodes are obtained. This process is continued till frequent episodes of all lengths are found. Like in the Apriori algorithm, the candidate generation step here declares an episode as a candidate only if all its subepisodes have already been found frequent. This kind of a construction of bigger episodes from smaller ones is possible because the definition of episode frequency guarantees that subepisodes are at least as frequent as the episode. Starting with the same set of frequent 1-node episodes, the algorithms for candidate generation differ slightly for the two cases of parallel and serial episodes (due to the extra total order constraint imposed in the latter case). The difference between the two frequency counting algorithms (for parallel and serial episodes) is more pronounced. Counting frequencies of parallel episodes is comparatively straightforward. As mentioned earlier, parallel episodes are like itemsets and so counting the number of sliding windows in which they occur is much like computing the support of an itemset over a list of customer transactions. An O((n + l 2 )k) algorithm is presented by (Mannila et al (1997) for computing the frequencies of a set of k, l-node parallel episodes in an n-length event sequence. Counting serial episodes, on the other hand, is a bit more involved. This is because, unlike for parallel episodes, we need finite state automata to recognize serial episodes. More specifically, an appropriate l-state automaton can be used to recognize occurrences of an l-node serial episode. The automaton corresponding to an episode accepts that episode and rejects all other input. For example, for the episode (A → B → C), there would be a 3-state automaton that transits to its first state on seeing an event of type A and then waits for an event of type B to transit to its next state and so on. When this automaton transits to its final state, the episode is recognized (to have occurred once) in the event sequence. We need such automata for each episode α whose frequency is being counted. In general, while traversing an event sequence, at any given time, there may be any number of partial occurrences of a given episode and hence we may need any number of different instances of the automata corresponding to this episode to be active if we have to count all occurrences of the episode. Mannila et al (1997) , present an algorithm which needs only l instances of the automata (for each l-node episode) to be able to obtain the frequency of the episode. It is noted here that such an automata-based counting scheme is particularly attractive since it facilitates the frequency counting of not one but an entire set of serial episodes in one pass through the data. For a set of k l-node serial episodes the algorithm has O(lk) space complexity. The corresponding time complexity is given by O(nlk) , where n is, as earlier, the length of the event stream being mined. The episode discovery framework described so far employs the windows-based frequency measure for episodes (which was proposed by Mannila et al 1997) . However, there can be other ways to define episode frequency. One such alternative is proposed by Mannila et al (1997) itself and is based on counting what are known as minimal occurrences of episodes. A minimal occurrence of an episode is defined as a window (or contiguous slice) of the input sequence in which the episode occurs, and further, no proper sub-window of this window contains an occurrence of the episode. The algorithm for counting minimal occurrences trades space efficiency for time efficiency when compared to the windows-based counting algorithm. In addition, since the algorithm locates and directly counts occurrences (as against counting the number of windows in which episodes occur), it facilitates the discovery of patterns with extra constraints (like being able to discover rules of the form \"if A and B occur within 10 seconds of one another, C follows within another 20 seconds\"). Another frequency measure was proposed in BIB002 where the user chooses the maximum inter-node distance allowed (instead of the window width which was needed earlier) and the algorithm automatically adjusts the window width based on the length of the episodes being counted. In BIB003 BIB005 , two new frequency counts (referred to as the non-overlapped occurrence count and the non-interleaved occurrence count) are proposed based on directly counting some suitable subset of occurrences of episodes. These two counts (which are also automatabased counting schemes) have the same space complexity as the windows-based count of Mannila et al (1997) (i. e. l automata per episode for l-node episodes) but exhibit a significant advantage in terms of run-time efficiency. Moreover, the non-overlapped occurrences count is also theoretically elegant since it facilitates a connection between frequent episode discovery process and HMM learning BIB005 . We will return to this aspect later in Sec. 5.. Graph-theoretic approaches have also been explored to locate episode occurrences in a sequence (Baeza-Yates 1991; BIB001 . These algorithms, however, are more suited for search and retrieve applications rather than for discovery of all frequent episodes. The central idea here is to employ a preprocessing step to build a finite automaton called the DASG (Directed Acyclic Subsequence Graph), which accepts a string if and only if it is a subsequence of the given input sequence. It is possible to build this DASG for a sequence of length n in O(nσ ) time, where σ is the size of the alphabet. Once the DASG is constructed, an episode of length l can be located in the sequence in linear, i. e. O(l), time.", "role": "assistant" } ]

[ { "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:\nImmunofluorescenceandimmunohistochemistry", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "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\nSomatic von Hippel-Lindau mutation in clear cell papillary cystadenoma of the epididymis. Papillary cystadenoma of the epididymis is an uncommon benign lesion that may occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Neither immunohistochemical studies nor molecular genetic analyses of the VHL gene have been reported previously for this lesion. The authors describe two cases of clear cell papillary cystadenoma of the epididymis, both of which were initially confused with metastatic renal cell carcinoma. Both lesions showed positive immunohistochemical staining for low and intermediate molecular weight keratins (Cam 5. 2 and AE1/AE3), EMA, vimentin, alpha 1-antitrypsin, and alpha 1-antichymotrypsin. Each was negative for CEA. Because clear cell papillary cystadenoma is similar to renal cell carcinoma histologically, and because both occur as components of the von Hippel-Lindau disease complex, the authors analyzed both cases for the presence of mutations in the VHL gene. A somatic VHL gene mutation was detected in one of the two tumors by polymerase chain reaction followed by single-strand conformation polymorphism analysis. Direct sequencing revealed a cytosine to thymine transition at nucleotide 694, resulting in the replacement of an arginine with a stop codon after the sixth amino acid of exon 3. As the VHL gene is believed to function as a tumor suppressor gene, VHL gene mutations may play a role in the initiation of tumorigenesis in sporadic cystadenomas of the epididymis.", "role": "user" }, { "content": "{\"Disease\": [\"metastatic renal cell carcinoma\", \"papillary cystadenoma of the epididymis\", \"renal cell carcinoma\", \"VHL\", \"papillary cystadenoma\", \"cystadenomas of the epididymis\", \"Papillary cystadenoma of the epididymis\", \"von Hippel-Lindau\", \"tumor\", \"von Hippel-Lindau (VHL) disease\", \"tumors\", \"von Hippel-Lindau disease\"]}", "role": "assistant" } ]

[ { "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\nTargeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. The cAMP signaling system can trigger precise physiological cellular responses that depend on the fidelity of many protein-protein interactions, which act to bring together signaling intermediates at defined locations within cells. In the heart, cAMP participates in the fine control of excitation-contraction coupling, hence, any disregulation of this signaling cascade can lead to cardiac disease. Due to the ubiquitous nature of the cAMP pathway, general inhibitors of cAMP signaling proteins such as PKA, EPAC and PDEs would act non-specifically and universally, increasing the likelihood of serious 'off target' effects. Recent advances in the discovery of peptides and small molecules that disrupt the protein-protein interactions that underpin cellular targeting of cAMP signaling proteins are described and discussed.", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "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: The code is open source and can be used to train GANs on common datasets.\n\nKeywords: gans\n\nDataset Information:\nMulti-Modal CelebA-HQ: Multi-Modal-CelebA-HQ is a large-scale face image dataset that has 30,000 high-resolution face images selected from the CelebA dataset by following CelebA-HQ. Each image has high-quality segmentation mask, sketch, descriptive text, and image with transparent background.\nJuICe: JuICe is a corpus of 1.5 million examples with a curated test set of 3.7K instances based on online programming assignments. Compared with existing contextual code generation datasets, JuICe provides refined human-curated data, open-domain code, and an order of magnitude more training data.\nTableBank: To address the need for a standard open domain table benchmark dataset, the author propose a novel weak supervision approach to automatically create the TableBank, which is orders of magnitude larger than existing human labeled datasets for table analysis. Distinct from traditional weakly supervised training set, our approach can obtain not only large scale but also high quality training data.\nCelebA: CelebFaces Attributes dataset contains 202,599 face images of the size 178×218 from 10,177 celebrities, each annotated with 40 binary labels indicating facial attributes like hair color, gender and age.\n\nAvailable Datasets: A: Multi-Modal CelebA-HQ B: JuICe C: TableBank D: CelebA", "role": "user" }, { "content": "CelebA", "role": "assistant" } ]

[ { "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:\nMost of the works on planning and learning, e.g., planning by (model based) reinforcement learning, are based on two main assumptions: (i) the set of states of the planning domain is fixed; (ii) the mapping between the observations from the real word and the states is implicitly assumed or learned offline, and it is not part of the planning domain. Consequently, the focus is on learning the transitions between states. In this paper, we drop such assumptions. We provide a formal framework in which (i) the agent can learn dynamically new states of the planning domain; (ii) the mapping between abstract states and the perception from the real world, represented by continuous variables, is part of the planning domain; (iii) such mapping is learned and updated along the \"life\" of the agent. We define an algorithm that interleaves planning, acting, and learning, and allows the agent to update the planning domain depending on how much it trusts the model w.r.t. the new experiences learned by executing actions. We define a measure of coherence between the planning domain and the real world as perceived by the agent. We test our approach showing that the agent learns increasingly coherent models, and that the system can scale to deal with models with an order of @math states.\n\nCited Works Summary:\n[1]: Current domain-independent, classical planners require symbolic models of the problem domain and instance as input, resulting in a knowledge acquisition bottleneck. Meanwhile, although deep learning has achieved significant success in many fields, the knowledge is encoded in a subsymbolic representation which is incompatible with symbolic systems such as planners. We propose LatPlan, an unsupervised architecture combining deep learning and classical planning. Given only an unlabeled set of image pairs showing a subset of transitions allowed in the environment (training inputs), and a pair of images representing the initial and the goal states (planning inputs), LatPlan finds a plan to the goal state in a symbolic latent space and returns a visualized plan execution. The contribution of this paper is twofold: (1) State Autoencoder, which finds a propositional state representation of the environment using a Variational Autoencoder. It generates a discrete latent vector from the images, based on which a PDDL model can be constructed and then solved by an off-the-shelf planner. (2) Action Autoencoder Discriminator, a neural architecture which jointly finds the action symbols and the implicit action models (preconditions effects), and provides a successor function for the implicit graph search. We evaluate LatPlan using image-based versions of 3 planning domains: 8-puzzle, Towers of Hanoi and LightsOut.\n\n[2]: In the model-based policy search approach to reinforcement learning (RL), policies are found using a model (or \"simulator\") of the Markov decision process. However, for high-dimensional continuous-state tasks, it can be extremely difficult to build an accurate model, and thus often the algorithm returns a policy that works in simulation but not in real-life. The other extreme, model-free RL, tends to require infeasibly large numbers of real-life trials. In this paper, we present a hybrid algorithm that requires only an approximate model, and only a small number of real-life trials. The key idea is to successively \"ground\" the policy evaluations using real-life trials, but to rely on the approximate model to suggest local changes. Our theoretical results show that this algorithm achieves near-optimal performance in the real system, even when the model is only approximate. Empirical results also demonstrate that---when given only a crude model and a small number of real-life trials---our algorithm can obtain near-optimal performance in the real system.\n\n[3]: In recent years, deep generative models have been shown to 'imagine' convincing high-dimensional observations such as images, audio, and even video, learning directly from raw data. In this work, we ask how to imagine goal-directed visual plans -- a plausible sequence of observations that transition a dynamical system from its current configuration to a desired goal state, which can later be used as a reference trajectory for control. We focus on systems with high-dimensional observations, such as images, and propose an approach that naturally combines representation learning and planning. Our framework learns a generative model of sequential observations, where the generative process is induced by a transition in a low-dimensional planning model, and an additional noise. By maximizing the mutual information between the generated observations and the transition in the planning model, we obtain a low-dimensional representation that best explains the causal nature of the data. We structure the planning model to be compatible with efficient planning algorithms, and we propose several such models based on either discrete or continuous states. Finally, to generate a visual plan, we project the current and goal observations onto their respective states in the planning model, plan a trajectory, and then use the generative model to transform the trajectory to a sequence of observations. We demonstrate our method on imagining plausible visual plans of rope manipulation.", "role": "user" }, { "content": "A complementary approach is pursued in works that plan directly in a continuous space, see, e.g., [2] [1] [3] . In this way there is no need to define a mapping such as the perception function, since there is no abstract discrete model of the world. Such approaches are very suited to address some tasks, e.g., moving a robot arm to a desired position or performing some manipulations. However, we believe that, in several situations, it is conceptually appropriate and practically efficient to perform planning in an abstract discrete state space.", "role": "assistant" } ]

[ { "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: Learning Relational Dependency Networks for Relation Extraction\n\nWe consider the task of KBP slot filling -- extracting relation information from newswire documents for knowledge base construction. We present our pipeline, which employs Relational Dependency Networks (RDNs) to learn linguistic patterns for relation extraction. Additionally, we demonstrate how several components such as weak supervision, word2vec features, joint learning and the use of human advice, can be incorporated in this relational framework. We evaluate the different components in the benchmark KBP 2015 task and show that RDNs effectively model a diverse set of features and perform competitively with current state-of-the-art relation extraction.\n\nIntroduction\nThe problem of knowledge base population (KBP) – constructing a knowledge base (KB) of facts gleaned from a large corpus of unstructured data – poses several challenges for the NLP community. Commonly, this relation extraction task is decomposed into two subtasks – entity linking, in which entities are linked to already identified identities within the document or to entities in the existing KB, and slot filling, which identifies certain attributes about a target entity.\nWe present our work-in-progress for KBP slot filling based on our probabilistic logic formalisms and present the different components of the system. Specifically, we employ Relational Dependency Networks BIBREF0 , a formalism that has been successfully used for joint learning and inference from stochastic, noisy, relational data. We consider our RDN system against the current state-of-the-art for KBP to demonstrate the effectiveness of our probabilistic relational framework.\nAdditionally, we show how RDNs can effectively incorporate many popular approaches in relation extraction such as joint learning, weak supervision, word2vec features, and human advice, among others. We provide a comprehensive comparison of settings such as joint learning vs learning of individual relations, use of weak supervision vs gold standard labels, using expert advice vs only learning from data, etc. These questions are extremely interesting from a general machine learning perspective, but also critical to the NLP community. As we show empirically, some of the results such as human advice being useful in many relations and joint learning being beneficial in the cases where the relations are correlated among themselves are on the expected lines. However, some surprising observations include the fact that weak supervision is not as useful as expected and word2vec features are not as predictive as the other domain-specific features.\nWe first present the proposed pipeline with all the different components of the learning system. Next we present the set of 14 relations that we learn on before presenting the experimental results. We finally discuss the results of these comparisons before concluding by presenting directions for future research.\n\nProposed Pipeline\nWe present the different aspects of our pipeline, depicted in Figure FIGREF1 . We will first describe our approach to generating features and training examples from the KBP corpus, before describing the core of our framework – the RDN Boost algorithm.\n\nFeature Generation\nGiven a training corpus of raw text documents, our learning algorithm first converts these documents into a set of facts (i.e., features) that are encoded in first order logic (FOL). Raw text is processed using the Stanford CoreNLP Toolkit BIBREF1 to extract parts-of-speech, word lemmas, etc. as well as generate parse trees, dependency graphs and named-entity recognition information. The full set of extracted features is listed in Table TABREF3 . These are then converted into features in prolog (i.e., FOL) format and are given as input to the system.\nIn addition to the structured features from the output of Stanford toolkit, we also use deeper features based on word2vec BIBREF2 as input to our learning system. Standard NLP features tend to treat words as individual objects, ignoring links between words that occur with similar meanings or, importantly, similar contexts (e.g., city-country pairs such as Paris – France and Rome – Italy occur in similar contexts). word2vec provide a continuous-space vector embedding of words that, in practice, capture many of these relationships BIBREF2 , BIBREF3 . We use word vectors from Stanford and Google along with a few specific words that, experts believe, are related to the relations learned. For example, we include words such as “father” and “mother” (inspired by the INLINEFORM0 relation) or “devout”,“convert”, and “follow” ( INLINEFORM1 relation). We generated features from word vectors by finding words with high similarity in the embedded space. That is, we used word vectors by considering relations of the following form: INLINEFORM2 , where INLINEFORM3 is the cosine similarity score between the words. Only the top cosine similarity scores for a word are utilized.\n\nLearning Relational Dependency Networks\nPrevious research BIBREF11 has demonstrated that joint inferences of the relations are more effective than considering each relation individually. Consequently, we have considered a formalism that has been successfully used for joint learning and inference from stochastic, noisy, relational data called Relational Dependency Networks (RDNs) BIBREF0 , BIBREF12 . RDNs extend dependency networks (DN) BIBREF13 to the relational setting. The key idea in a DN is to approximate the joint distribution over a set of random variables as a product of their marginal distributions, i.e., INLINEFORM0 INLINEFORM1 INLINEFORM2 . It has been shown that employing Gibbs sampling in the presence of a large amount of data allows this approximation to be particularly effective. Note that, one does not have to explicitly check for acyclicity making these DNs particularly easy to be learned.\nIn an RDN, typically, each distribution is represented by a relational probability tree (RPT) BIBREF14 . However, following previous work BIBREF12 , we replace the RPT of each distribution with a set of relational regression trees BIBREF15 built in a sequential manner i.e., replace a single tree with a set of gradient boosted trees. This approach has been shown to have state-of-the-art results in learning RDNs and we adapted boosting to learn for relation extraction. Since this method requires negative examples, we created negative examples by considering all possible combinations of entities that are not present in positive example set and sampled twice as many negatives as positive examples.\n\nIncorporating Human Advice\nWhile most relational learning methods restrict the human to merely annotating the data, we go beyond and request the human for advice. The intuition is that we as humans read certain patterns and use them to deduce the nature of the relation between two entities present in the text. The goal of our work is to capture such mental patterns of the humans as advice to the learning algorithm. We modified the work of Odom et al. odomAIME15,odomAAAI15 to learn RDNs in the presence of advice. The key idea is to explicitly represent advice in calculating gradients. This allows the system to trade-off between data and advice throughout the learning phase, rather than only consider advice in initial iterations. Advice, in particular, become influential in the presence of noisy or less amout of data. A few sample advice rules in English (these are converted to first-order logic format and given as input to our algorithm) are presented in Table TABREF11 . Note that some of the rules are “soft\" rules in that they are not true in many situations. Odom et al. odomAAAI15 weigh the effect of the rules against the data and hence allow for partially correct rules.\n\nJoint learning\nTo address our next question, we assessed our pipeline when learning relations independently (i.e., individually) versus learning relations jointly within the RDN, displayed in Table TABREF22 . Recall and F1 are omitted for conciseness – the conclusions are the same across all metrics. Joint learning appears to help in about half of the relations (8/14). Particularly, in person category, joint learning with gold standard outperforms their individual learning counterparts. This is due to the fact that some relations such as parents, spouse, siblings etc. are inter-related and learning them jointly indeed improves performance. Hence Q2 can be answered affirmatively for half the relations.\n\nAdvice\nTable TABREF26 shows the results of experiments that test the use of advice within the joint learning setting. The use of advice improves or matches the performance of using only joint learning. The key impact of advice can be mostly seen in the improvement of recall in several relations. This clearly shows that using human advice patterns allows us to extract more relations effectively making up for noisy or less number of training examples. This is in-line with previously published machine learning literature BIBREF17 , BIBREF18 , BIBREF19 , BIBREF20 in that humans can be more than mere labelers by providing useful advice to learning algorithms that can improve their performance. Thus Q4 can be answered affirmatively.\n\nRDN Boost vs Relation Factory\nRelation factory (RF) BIBREF16 is an efficient, open source system for performing relation extraction based on distantly supervised classifiers. It was the top system in the TAC KBP 2013 competition BIBREF21 and thus serves as a suitable baseline for our method. RF is very conservative in its responses, making it very difficult to adjust the precision levels. To be most generous to RF, we present recall for all returned results (i.e., score INLINEFORM0 ). The AUC ROC, recall, and F1 scores of our system against RF are presented in Table TABREF28 .\nOur system performs comparably, and often better than the state-of-the-art Relation Factory system. In particular, our method outperforms Relation Factory in AUC ROC across all relations. Recall provides a more mixed picture with both approaches showing some improvements – RDN outperforms in 6 relations while Relation Factory does so in 8. Note that in the instances where RDN provides superior recall, it does so with dramatic improvements (RF often returns 0 positives in these relations). F1 also shows RDN's superior performance, outperforming RF in most relations. Thus, the conclusion for Q5 is that our RDN framework performas comparably, if not better, across all metrics against the state-of-the-art.\n\nConclusion\nWe presented our fully relational system utilizing Relational Dependency Networks for the Knowledge Base Population task. We demonstrated RDN's ability to effectively learn the relation extraction task, performing comparably (and often better) than the state-of-art Relation Factory system. Furthermore, we demonstrated the ability of RDNs to incorporate various concepts in a relational framework, including word2vec, human advice, joint learning, and weak supervision. Some surprising results are that weak supervision and word2vec did not significantly improve performance. However, advice is extremely useful thus validating the long-standing results inside the Artificial Intelligence community for the relation extraction task as well. Possible future directions include considering a larger number of relations, deeper features and finally, comparisons with more systems. We believe further work on developing word2vec features and utilizing more weak supervision examples may reveal further insights into how to effectively utilize such features in RDNs.\n\nFig. 1. Pipeline Full RDN relation extraction pipeline\n\nTable 1. Standard NLP Features Features derived from the training corpus used by our learning system. POS - part of speech. NE - Named Entity. DPR - root of dependency path tree.\n\nTable 2. Rules for KB Weak Supervision A sample of knowledge-based rules for weak supervision. The first value defines a weight, or confidence in the accuracy of the rule. The target relation appears at the end of each clause. “PER”, “ORG”, “NUM” represent entities that are persons, organizations, and numbers, respectively.\n\nTable 3. Advice Rules Sample advice rules used for relation extraction. We employed a total of 72 such rules for our 14 relations.\n\nFig. 2. Example regression tree for the siblings relation. This tree states that the weight for the relation being true is higher if either “husband” or “wife” appear between the entities.\n\nTable 6. Joint Learning Results comparing relation models learned individually (IL) and jointly (JL).\n\nTable 8. Advice Results comparing models trained without (-Adv) and with advice (+Adv).\n\nTable 9. RelationFactory (RF) vs RDN Values in bold indicate superiour performance against the alternative approach.\n\nInquiry: What do they learn jointly?", "role": "user" }, { "content": "{\"answer\": [\"relations\"], \"evidence\": [\"To address our next question, we assessed our pipeline when learning relations independently (i.e., individually) versus learning relations jointly within the RDN, displayed in Table TABREF22 . Recall and F1 are omitted for conciseness \\u2013 the conclusions are the same across all metrics. Joint learning appears to help in about half of the relations (8/14). Particularly, in person category, joint learning with gold standard outperforms their individual learning counterparts. This is due to the fact that some relations such as parents, spouse, siblings etc. are inter-related and learning them jointly indeed improves performance. Hence Q2 can be answered affirmatively for half the relations.\"]}", "role": "assistant" } ]

[ { "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 currently isn't a vaccine against developing COVID-19. Antibiotics are also ineffective because COVID-19 is a viral infection and not bacterial.\n\nResearch Abstract:\nRemdesivir is one of the most promising drugs to treat COVID-19 based on the following facts: remdesivir has a broad-spectrum antiviral mechanism of action; it demonstrated in vitro activity against SARS-CoV-2 and in vivo efficacy in animal models against the similar coronavirus MERS-CoV; its safety profile has been tested in Ebola patients and in compassionate use in COVID-19 patients.\nCurrently, remdesivir is being investigated in ten randomized controlled trials against COVID-19.\nThe dose regimen of remdesivir is an IV loading dose of 200 mg on day 1 followed by daily IV maintenance doses of 100 mg for 5-9 days.\nBased on our data analysis, however, remdesivir with IV administration alone is unlikely to achieve excellent clinical efficacy.\nThis analysis is based on the following observations: plasma exposures of remdesivir and its active metabolite are unlikely to be correlated with its clinical efficacy; remdesivir and its active metabolites are unlikely to be adequate in the lung to kill the SARS-CoV-2 virus.\nEven if remdesivir demonstrates benefits in the current randomized controlled trials, its efficacy may be limited.\nWe suggest that a combination of an IV and pulmonary delivery dose regimen should be studied immediately to realize a potentially more effective antiviral therapy against COVID-19.\nGraphical abstract.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "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 nature of placebo response in clinical studies of major depressive disorder . OBJECTIVE To review factors influencing placebo response and clinical trial outcome in depression , and suggest ways to optimize trial success in mood disorders . DATA SOURCES PubMed searches were conducted by cross-referencing the terms depression , depressive with placebo , clinical trial , and clinical trials for studies published in English between 1970 and September 2013 . STUDY SELECTION Relevant abstracts were identified in PubMed , including clinical trials , quantitative studies , and qualitative research . We obtained and reviewed relevant articles and utilized their information to synthesize the present review . DATA EXTRACTION Included articles were grouped in the following areas of relevance : ( 1 ) biological validity of illness , ( 2 ) baseline severity of illness , ( 3 ) chronicity of the index episode of depression , ( 4 ) age of participants , ( 5 ) medical and psychiatric comorbidity , ( 6 ) probability of receiving placebo , ( 7 ) use of prospective treatment phases ( lead-in ) ( 8 ) dosing schedule , ( 9 ) trial duration , ( 10 ) frequency of follow-up assessments , and ( 11 ) study outcome measure . RESULTS Several key elements emerge as critical to the ultimate success of a clinical trial , including the probability of receiving placebo , study duration , dosing schedule , visit frequency , the use of blinded lead-in phases , the use of centralized raters , illness severity and duration , and comorbid anxiety . CONCLUSIONS Our increasing understanding of the placebo response in clinical trials of major depressive disorder lends to a , gradually , more predictable phenomenon and , hopefully , to one that becomes lesser in magnitude and variability . Several elements have emerged that seem to play a critical role in trial success , gradually reshaping the design of clinical , translational , as well as mechanistic studies in depression .", "role": "user" }, { "content": "{\"Intervention\": [\"receiving placebo\", \"placebo\"], \"Outcome\": [\"visit frequency\", \"the use of centralized raters\", \"probability of receiving placebo\", \"study duration\", \"dosing schedule\", \"comorbid anxiety\", \"the use of blinded lead-in phases\", \"illness severity and duration\"], \"Participant\": []}", "role": "assistant" } ]

[ { "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:\nHyperextension injuries of the PIP finger joint. Comparison of early motion and immobilization.\nReport Abstract 1:\nIn a prospective study of traumatic lesions of the volar fibrocartilage of the PIP joint, 56 patients were randomized to treatment by immobilization for 3 weeks and 56 patients, to purely analgetic treatment without immobilization. Seventy-eight patients were reexamined 6 months later and 77 patients, in a follow-up study 2-3 years after the injury. No difference was found between the two groups with respect to subjective complaints or objective signs.\n\n\nReport Title 2:\n[Hyperextension injuries of the volar fibrocartilage in the proximal interphalangeal joints of the fingers].\nReport Abstract 2:\nnan", "role": "user" }, { "content": "There is insufficient evidence from trials testing the need for, and the extent and duration of, immobilisation to inform on the key conservative management decisions for treating hyperextension injuries of the proximal interphalangeal joints.", "role": "assistant" } ]

[ { "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:\nPGC-1alpha-/-MiceExhibitanAbnormalSkeletalMuscleFunctionalPhenotype", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "Review the following segment from a research document in AI. Answer the subsequent query based solely on the provided information. Limit your response to the answer itself.\n\nResearch Segment: Domain Classification Loss. For a given input image x and a target domain label c, our goal is to translate x into an output image y, which is properly classified to the target domain c. To achieve this condition, we add an auxiliary classifier on top of D and impose the domain classification loss when optimizing both D and G. That is, we decompose the objective into two terms: a domain classification loss of real images used to optimize D, and a domain classification loss of fake images used to optimize G. In detail, the former is defined as\\mathcal{L}_{cls}^{r}={\\mathbb{E}}_{x,c^{\\prime}}[-\\log{{D}_{cls}(c^{\\prime}|x)}],(2)where the term {D}_{cls}(c^{\\prime}|x) represents a probability distribution over domain labels computed by D. By minimizing this objective, D learns to classify a real image x to its corresponding original domain c^{\\prime}. We assume that the input image and domain label pair (x,c^{\\prime}) is given by the training data. On the other hand, the loss function for the domain classification of fake images is defined as\\mathcal{L}_{cls}^{f}={\\mathbb{E}}_{x,c}[-\\log{{D}_{cls}(c|G(x,c))}].(3)In other words, G tries to minimize this objective to generate images that can be classified as the target domain c. \n\nInquiry: Why do they divide domain classification loss in two terms for real image and fake image, respectively?", "role": "user" }, { "content": "to translate x into an output image y, which is properly classified to the target domain c, authors divided classification loss in two terms.", "role": "assistant" } ]

[ { "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: METHODS: It was a surveillance system-based study, for which data from a total of 23,646 suspected patients in Riyadh and Al Qassim regions were analyzed from January 2017 until December 2017 to estimate the prevalence of MERS-CoV among suspected cases and to determine potential demographic risk factors related to the confirmation of the diagnosis. RESULTS: Of 23,646 suspected cases, 119 (0.5%) were confirmed by laboratory results. These confirmed cases (67.2% of which were males) had a mean age of 43.23 years (SD ± 22.8). Around 42.2% of the confirmed cases were aged between 41 and 60 years and about 47% of confirmed cases had their suspected specimen tested in the summer. The study identified three significant and independent predictors for confirmation of the disease: an age between 41 and 60 years, male gender, and summer season admission. CONCLUSION: The study provides evidence that the MERS-CoV epidemic in the subject regions has specific characteristics that might help future plans for the prevention and management of such a contagious disease. Future studies should aim to confirm such findings in other regions of Saudi Arabia as well and explore potential preventable risk factors. Text: A respiratory viral disease caused by the Middle East Respiratory Syndrome CoronaVirus (MERS-CoV) was first isolated in 2012, in a 60-year-old man who died in Jeddah, KSA due to severe acute pneumonia and multiple organ failure [1] . Since then, 27 countries have reported the presence of this virus, including the 12 countries of the Eastern Mediterranean region. Several outbreaks have occurred in multiple countries including Saudi Arabia, the United Arab Emirates and the Republic of Korea [2] . Recent fatality rate (CFR) of 21% [5, 6] . Very limited evidence is available for exploring the epidemiology of this virus among the pediatric population [7] . e literature shows that MERS-CoV infects males more than females [8, 9] . e casefatality rate of men (52%) is higher than that of women (23%) [10] . Males with a history of serious medical conditions are highly susceptible to this infection. Moreover, the mean age of infection in adults is 60 years [10] . e mode of transmission is not entirely understood yet [2] ; however, human-to-human [11] and zoonotic sources of transmission [12] have been documented in many studies. Dromedary camels are the major animal source of MERS-CoV transmission to humans. Interhuman transmission of the virus did not occur easily, but it is seen mainly in patients' families and healthcare settings [2] . Clinical pictures of this infection varied from asymptomatic to mild respiratory symptoms to severe respiratory distress and death [2] . Severe ailment can often cause respiratory catastrophes that need mechanical ventilation and support in ICUs across different healthcare settings [4] . Studies have suggested an incubation period of 16 days with a mean of 5-6 days [12, 13] , while the median time until death is 11-13 days (range 5-27 days) among severely ill patients [13] . e gold standard test for the detection of this virus is real-time reverse-transcription polymerase chain reaction (rRT-PCR) assays [14] . ere is no specific treatment for MERS-CoV. Like most viral infections, the treatment options are supportive and symptomatic [2] . At present, no vaccine exists for preventing the infections of MERS-CoV. e CDC indicated that preventative actions should be taken for any type of respiratory illness [4] . Such actions include washing hands with water and soap for around 20 seconds or using hand sanitizers with alcohol if no water is available. One must cover their nose and mouth during instances of sneezing and coughing with a tissue and avoid touching the mouth, nose, or eyes with their hands until washed properly. Repeatedly touched surfaces, such as door knobs, should be disinfected and cleaned regularly. Intimate personal contact, e.g., kissing, and sharing cups or eating utensils must also be avoided [15] . Many studies have been conducted in recent years in Saudi Arabia to combat this deadly disease. A large multicentre study showed that it is nearly impossible to differentiate between patients of MERS-CoV and non-MERS-CoV just on the basis of clinical presentation [16] . Another cohort study, which was hospital-based (17 cases vs. 82 controls), found that there were statistically significant differences in terms of gender, clinical, and radiographic presentations [17] . Similarly, two more single-centre case control studies reported that the presenting symptoms of MERS-CoV infection were not specific [18, 19] . Physicians and public health practitioners need to identify suspected cases which have higher chances of diagnosis as confirmed cases prior to laboratory testing (which usually takes between 12 and 24 hours). Identification of a confirmed case is necessary to implement preventive strategies to combat the spread of the disease to family members and hospital healthcare workers [20] . Mild symptomatic cases, which result in a positive PCR, may be isolated at home. Severe to moderate cases should be admitted to and isolated in a hospital until they improve and then be discharged for isolation at home for an extended period. Both mild and severe cases are retested after 7 days, and the test is subsequently repeated after every 3 days until a negative result is obtained [20] . Identifying suspected cases which may have higher chances of getting diagnosed as a confirmed case and implementing strict procedures on them might offer the best solution. e challenge is to flag these patients by some demographic markers, as the clinical presentation of MERS-CoV infected patients were non-specific. erefore, we aimed to identify some demographic markers specific to confirmed cases of MERS-CoV. e nature of these markers has not been investigated in Saudi Arabia, and hence this study aims to identify them. A cross-sectional study was conducted at the regional laboratory and blood bank, located at Shumaisi Hospital in Riyadh, KSA. e laboratory has received the Central Blood Banks and Reference Laboratories Accreditation Program Saudi Central Board for Accreditation of Healthcare Institution (CBAHI) 2018 [21] . Technique. Data were collected during the period of January 2017 to December 2017. All patients in Riyadh and Al-Qassim regions who had their samples tested at Riyadh regional lab during the study period were considered as suspected cases. e study had two aims: descriptive and analytical. For the descriptive aim, we estimated the prevalence of MERS-CoV. For the analytical aim, a binary logistic regression model was developed. In this model, we included the risk factors of gender, age, seasons, nationality, healthcare status (yes/no), hospitals, and area of residence. Data were cross-checked with a labcomputerized database. Further data were collected on demographic characteristics (age and sex), underlying nationality, and health care status. We collected data from 25,400 cases, of which 23,646 suspected cases of MERS-CoV were included in the final analysis. Data were cleaned, entered, stored, and managed with an excel database and IBM SPSS Version 25. e statistical analyses consisted of descriptive counts and percentages. For those continuously scaled items, nonparametric statistics (medians, interquartile ranges, minimum, and maximum) were used to describe the distribution. A logistic regression analysis was used to identify predictors of confirmation of infection within the suspected cases groups. At first, univariate analyses were conducted to estimate the unadjusted contribution and to determine the significant risk factors. is was followed by a multivariate logistic regression analysis to estimate the independent contribution of each covariate. To determine significant factors, a p value below 0.05 and a 95% confidence interval were considered. A confirmed case is defined as a suspected case with laboratory confirmation of MERS-CoV infection [20] . A total of 23,646 of MERS-CoV suspected cases were included in this study, of which 52.3% were males (n � 12376) and 47.7% were females (n � 11270). e age of individuals with suspected cases ranged between 0 to 92 years with a mean age of 43. 23 e adjusted odds of MERS-CoV remained significant among different age groups; the odds of patients aged between 20-40 years increased threefold (A.OR: 3.11, 95% CI: 1.104-8.76, P value � 0.032), whereas in the age group of 41-60 years, it increased further to a risk that was six times higher \n\nis cross-sectional study about the epidemiological analysis of MERS-CoV infection laboratory-based data was conducted in Riyadh over a one-year period (2017). A total of 23,646 suspected cases were included in the results. Of the total suspected cases, 119 cases had been confirmed via laboratory results. All the confirmed cases are reported to MOH through HESN (health electronic surveillance networks) and to the World Health Organization (WHO) through the International Health Regulations (IHR), National Focal Point of Saudi Arabia. We found that MERS-CoV infection was found significantly in people aged between 41 and 60 years and was reported most commonly during the summer season. e odds of infection among males were found to be twice as high as that of females with suspected cases. During the study period, i.e., the year 2017, only 119 confirmed cases were reported, which means that the number of MERS-CoV infection cases has decreased in Riyadh and Al-Qassim regions in comparison to that of the last three years. From 2015 to 2016, there was a 25.4% decrease, whereas from 2016 to 2017, it decreased by 48.7%, which translates into a 50% decrease between the two periods. is also complements the findings reported by of Da'ar and Ahmed in their paper [23] . e predominance of infection in males was also observed in another study pwefromed in KSA (2015), which reported the percentage of confirmed cases among males to be 66%, compared with 34% among females [24] . It is worth mentioning that Saudi Arabia defines age categories differently from the WHO (children: 0-14, adult: otherwise) [20] . However, unlike the classification used in Saudi Arabia, we have followed the WHO categorization of age to differentiate between children/adolescents (0 to 19 years) and adults (20 years and older) as indicated in WHO reports for age-standardized population and in infectious diseases [25] . is categorization was also followed by Aly and his collaborators in their recent paper published in 2017 [14] . Adults were further subcategorized into three groups according to the age distribution of the study population using the following two cutoff points (age of 41 and age of 60) [14] . ese data agreed with a previous surveillance study, which stated that the majority of confirmed cases of MERS-CoV were reported among people aged 40 and above [24] . In 2016, only 9 of 552 cases (1.6%) of MERS-CoV infection were found among pediatric patients. Moreover, the study which was conducted in King Fahad Medical City in Riyadh (KFMC) between January 2012 and December 2013 did not report any MERS-CoV cases among children [26] . e study which was conducted across the Gulf countries for four years by Mahmoud Aly et al. between 2012 and 2016 suggests that the prevalence and distribution of MERS-CoV were the highest-risk in elderly aged 60 years or above [14] . Similar to our results, this study also reported the highest number of confirmed cases during the summer season [14] . Among confirmed cases, only 25.2% were healthcare workers, whereas around 75% were non-healthcare workers. is is in agreement with the study done by Ahmad to estimate the survival rate in MERS-CoV globally prior to 26 January 2017; 86.9% were not health-care workers compared with 13.1% confirmed cases of healthcare workers [27] . Similarly, other studies also reported a lower prevalence in healthcare workers [28] [29] [30] . Our data reported a higher prevalence of infection among Saudi nationals as compared with non-Saudi. Another study also showed similar results but with a much higher percentage among Saudis, which may be due to the fact that it included Saudis from all regions [29] . ere is no finding basis for comparison as such, because our study was focused on the Riyadh and Al Qassim regions only. In our study, we detected a low prevalence (0.5%). e low positive predictive value of our lab results is not related to the low sensitivity and specificity of the lab assay. e estimated analytical sensitivity and specificity of the Real Star kit from Altona was reported to be 100% with no cross reactivity with other respiratory pathogens [31] . Moreover, this low predictive value in the lab results is related to the high burden of false positive cases referred to the lab. In fact, this research is just the starting point to shed the light on more factors that might help in putting more descriptive criteria to lower the financial and human resources burden. To the best of our knowledge, no one has developed a logistic regression that focuses on demographic risk factors such as sex, age, and seasons prior to our study. However, it is worth mentioning that Ahmed et al. developed a risk prediction model that encompasses risk factors such as chest pain, leukopenia, and elevated aspartate aminotransferase (AST) [21] . However, further investigations are needed to confirm our findings. One of the major strengths of our study is that it is a comprehensive regional study which included all the suspected cases of MERS-CoV in the Riyadh and Al-Qassim regions. Secondly, the external validity of our study is also expected to be high, as it covers the two regions completely, meaning that the records of all suspected cases in these two main regions in Saudi Arabia were included. irdly, the quality of the data is considered to be high, given that the contagious and life-threatening nature of this disease has led to strict obedience to rules which are enforced in a timely manner, thus ensuring accurate reporting of suspected cases. In addition to this, quality assurance policies are implemented at HESN in order to maintain the highest level of validity and reliability of the data collection process. e variables available for suspected cases were limited to demographics, which limited the scope of our research, but they provided valuable information to form a basis for future studies of a broader scope. Variables such as primary/secondary infections are vital pieces of information, but due the limitation of the data available, we could not determine their effects. According to our knowledge, this is one of the few studies that have specifically investigated MERS-CoV risk factors in the Riyadh and Al-Qassim areas (two major regions in KSA). Given that all suspected and confirmed cases were included in this study, we assume that our results are generalizable for both the regions with confidence.\n\nInquiry: What age group had the most MERS-COV infections?", "role": "user" }, { "content": "majority of confirmed cases of MERS-CoV were reported among people aged 40 and above", "role": "assistant" } ]

[ { "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\nCompared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists.\nThe potent histamine H(1)-receptor antagonist cetirizine (Zyrtec) is a racemic mixture of levocetirizine (now available under the trademark Xyzal and dextrocetirizine. In this Commentary, we examine some biological properties of cetirizine and levocetirizine, namely enantioselectivity in pharmacological activity and pharmacokinetic properties, with emphasis on the possibility of racemization, the compared behavior of the two enantiomers, and the potential for interactions with other drugs. Recent data demonstrate that the antihistaminergic activity of the racemate is primarily due to levocetirizine. Levocetirizine is rapidly and extensively absorbed, poorly metabolized, and not subject to racemization. Its pharmacokinetic characteristics are comparable after administration alone or in the racemate. Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 L kg(-1) vs. 0.60 L kg(-1)). Moreover, the non-renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min(-1) vs. 29.2 mL min(-1)). Our conclusion is that levocetirizine is indeed the eutomer of cetirizine. The evidence reviewed here confirms preclinical findings and offers a rationale for the chiral switch from the racemate to levocetirizine.", "role": "user" }, { "content": "{\"Chemical\": [\"histamine\", \"Levocetirizine\", \"cetirizine\", \"Zyrtec\", \"levocetirizine\", \"dextrocetirizine\", \"Xyzal\"], \"Protein\": [\"histamine H(1)-receptor\", \"histamine H1-receptor\"]}", "role": "assistant" } ]

[ { "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 Community Question Answering (CQA) websites can be claimed as the most major venues for knowledge sharing, and the most effective way of exchanging knowledge at present. Considering that massive amount of users are participating online and generating huge amount data, management of knowledge here systematically can be challenging. Expert recommendation is one of the major challenges, as it highlights users in CQA with potential expertise, which may help match unresolved questions with existing high quality answers while at the same time may help external services like human resource systems as another reference to evaluate their candidates. In this paper, we in this work we propose to exploring experts in CQA websites. We take advantage of recent distributed word representation technology to help summarize text chunks, and in a semantic view exploiting the relationships between natural language phrases to extract latent knowledge domains. By domains, the users’ expertise is determined on their historical performance, and a rank can be compute to given recommendation accordingly. In particular, Stack Overflow is chosen as our dataset to test and evaluate our work, where inclusive experiment shows our competence.\n\nCited Works Summary:\n[1]: Community Question Answering (CQA) sites are becoming an increasingly important source of information where users can share knowledge on various topics. Although these sites provide opportunities for users to seek for help or provide answers, they also bring new challenges. One of the challenges is most new questions posted everyday cannot be routed to the appropriate users who can answer them in CQA. That is to say, experts cannot receive questions that match their expertise. Therefore new questions cannot be answered in time. In this paper, we propose an approach which based on distributed representations of words to predict the best answerer for a new question on CQA sites. Our approach considers both user activity and user authority. The user activity and user authority are based on the previous questions answered by the user. We have applied our model on the dataset downloaded from StackOverflow, one of the biggest CQA sites. The results show that our approach performs better than the TF-IDF and Language Model based methods.\n\n[2]: The rapidly increasing popularity of community-based Question Answering (cQA) services, e.g. Yahoo! Answers, Baidu Zhidao, etc. have attracted great attention from both academia and industry. Besides the basic problems, like question searching and answer finding, it should be noted that the low participation rate of users in cQA service is the crucial problem which limits its development potential. In this paper, we focus on addressing this problem by recommending answer providers, in which a question is given as a query and a ranked list of users is returned according to the likelihood of answering the question. Based on the intuitive idea for recommendation, we try to introduce topic-level model to improve heuristic term-level methods, which are treated as the baselines. The proposed approach consists of two steps: (1) discovering latent topics in the content of questions and answers as well as latent interests of users to build user profiles; (2) recommending question answerers for new arrival questions based on latent topics and term-level model. Specifically, we develop a general generative model for questions and answers in cQA, which is then altered to obtain a novel computationally tractable Bayesian network model. Experiments are carried out on a real-world data crawled from Yahoo! Answers during Jun 12 2007 to Aug 04 2007, which consists of 118510 questions, 772962 answers and 150324 users. The experimental results reveal significant improvements over the baseline methods and validate the positive influence of topic-level information.", "role": "user" }, { "content": "User performance is usually the only element considered in past works for picking answerers to questions. Yet, better results can be achieved in our perspective, where the textual is also our concern, as it contains substantial relevance information and recent language processing technology enabled this. [1] classify users according to the similarities between their topics and questions for a better recommendation. However, user tags and uses user authority are selected as metrics, where tags in some cases may not be trust. [2] also come up with a topic-based method, and their general idea is to either investigate the answers to questions that are similar to unsolved one, or study user's history to determine his her expertise.", "role": "assistant" } ]

[ { "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:\nWesternblotswerecarriedoutUsingECL(PIERCE)asdescribedpreviously[1].", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "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:\nEffect of preoperative abstinence on poor postoperative outcome in alcohol misusers: randomised controlled trial.\nReport Abstract 1:\nTo evaluate the influence of preoperative abstinence on postoperative outcome in alcohol misusers with no symptoms who were drinking the equivalent of at least 60 g ethanol/day.\n Randomised controlled trial. Setting: Copenhagen, Denmark.\n 42 alcoholic patients without liver disease admitted for elective colorectal surgery.\n Withdrawal from alcohol consumption for 1 month before operation (disulfiram controlled) compared with continuous drinking.\n Postoperative complications requiring treatment within the first month after surgery. Perioperative immunosuppression measured by delayed type hypersensitivity; myocardial ischaemia and arrhythmias measured by Holter tape recording; episodes of hypoxaemia measured by pulse oximetry. Response to stress during the operation were assessed by heart rate, blood pressure, serum concentration of cortisol, and plasma concentrations of glucose, interleukin 6, and catecholamines.\n The intervention group developed significantly fewer postoperative complications than the continuous drinkers (31% v 74%, P=0.02). Delayed type hypersensitivity responses were better in the intervention group before (37 mm2 v 12 mm2, P=0.04), but not after surgery (3 mm2 v 3 mm2). Development of postoperative myocardial ischaemia (23% v 85%) and arrhythmias (33% v 86%) on the second postoperative day as well as nightly hypoxaemic episodes (4 v 18 on the second postoperative night) occurred significantly less often in the intervention group. Surgical stress responses were lower in the intervention group (P</=0.05).\n One month of preoperative abstinence reduces postoperative morbidity in alcohol abusers. The mechanism is probably reduced preclinical organ dysfunction and reduction of the exaggerated response to surgical stress.", "role": "user" }, { "content": "Based on the finding of two studies, it appears that intensive preoperative alcohol cessation interventions, including pharmacological strategies for relapse prophylaxis and withdrawal symptoms, may significantly reduce postoperative complication rates. No effect was found on mortality rates and length of stay.\nThe effect of preoperative alcohol cessation intervention should be further explored in an effort to reduce the adverse effect of alcohol use on surgical outcomes. The number needed to screen to identify eligible patients for alcohol intervention studies in surgical settings seems to be extremely high. This may indicate that these studies are difficult to perform. Nevertheless, timing, duration and intensity of alcohol cessation interventions need to be subject to further investigation.", "role": "assistant" } ]

[ { "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\nTreatment of gastrointestinal cancer : the Southeastern Cancer Study Group experience , 1979 to 1983 . The treatment of gastrointestinal cancer was studied in 20 phase I , II , and III clinical trials from 1979 to 1983 at 30 member institutions of the Southeastern Cancer Study Group ( SECSG ) . These studies used both new and commercially available drugs , as well as surgery and/or radiation therapy in 1,087 patients . No significant benefit was seen from 18 agents , and one agent is still under evaluation . Unfortunately , no recommendations can be drawn from these studies that would alter presently accepted methods of management . Adenocarcinoma of the gastrointestinal tract remains a major challenge to tumor biologists and clinical oncologists because it is generally resistant to chemotherapy and radiation therapy , yet common enough to represent a vital public health concern in America .", "role": "user" }, { "content": "{\"Intervention\": [\"18 agents\", \"surgery\", \"radiation therapy\", \"chemotherapy\", \"new and commercially available drugs\"], \"Outcome\": [\"gastrointestinal cancer\"], \"Participant\": []}", "role": "assistant" } ]

[ { "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: Pre-Translation for Neural Machine Translation\n\nRecently, the development of neural machine translation (NMT) has significantly improved the translation quality of automatic machine translation. While most sentences are more accurate and fluent than translations by statistical machine translation (SMT)-based systems, in some cases, the NMT system produces translations that have a completely different meaning. This is especially the case when rare words occur. When using statistical machine translation, it has already been shown that significant gains can be achieved by simplifying the input in a preprocessing step. A commonly used example is the pre-reordering approach. In this work, we used phrase-based machine translation to pre-translate the input into the target language. Then a neural machine translation system generates the final hypothesis using the pre-translation. Thereby, we use either only the output of the phrase-based machine translation (PBMT) system or a combination of the PBMT output and the source sentence. We evaluate the technique on the English to German translation task. Using this approach we are able to outperform the PBMT system as well as the baseline neural MT system by up to 2 BLEU points. We analyzed the influence of the quality of the initial system on the final result.\n\nIntroduction\nIn the last years, statistical machine translation (SMT) system generated state-of-the-art performance for most language pairs. Recently, systems using neural machine translation (NMT) were able to outperform SMT systems in several evaluations. These models are able to generate more fluent and accurate translation for most of sentences.\nNeural machine translation systems provide the output with high fluency. A weakness of NMT systems, however, is that they sometimes lose the original meaning of the source words during translation. One example from the first conference on machine translation (WMT16) test set is the segment in Table TABREF1 .\nThe English word goalie is not translated to the correct German word Torwart, but to the German word Gott, which means god. One problem could be that we need to limit the vocabulary size in order to train the model efficiently. We used Byte Pair Encoding (BPE) BIBREF0 to represent the text using a fixed size vocabulary. In our case the word goali is splitted into three parts go, al and ie. Then it is more difficult to transport the meaning to the translation.\nIn contrast to this, in phrase-based machine translation (PBMT), we do not need to limit the vocabulary and are often able to translate words even if we have seen them only very rarely in the training. In the example mentioned before, for instance, the PBMT system had no problems translating the expression correctly.\nOn the other hand, official evaluation campaigns BIBREF1 have shown that NMT system often create grammatically correct sentence and are able to model the morphologically agreement much better in German.\nThe goal of this work is to combine the advantages of neural and phrase-based machine translation systems. Handling of rare words is an essential aspect to consider when it comes to real-world applications. The pre-translation framework provides a straightforward way to support such applications. In our approach, we will first translate the input using a PBMT system, which can handle the rare words well. In a second step, we will generate the final translation using an NMT system. This NMT system is able to generate a more fluent and grammatically correct translation. Since the rare words are already handled by the PBMT system, there should be less problems to generate the translation of these words. Using this approach naturally introduces a necessity to handle the potential errors by the PBMT systems.\nThe remaining of the paper is structured as follows: In the next section we will review the related work. In Section SECREF3 , we will briefly review the phrase-based and neural approach to machine translation. Section SECREF4 will introduce the approach presented in this paper to pre-translate the input using a PBMT system. In the following section, we will evaluate the approach and analyze the errors. Finally, we will finish with a conclusion.\n\nPipeline\nIn our first attempt, we combined the phrase-based MT and the neural MT in one pipeline as shown in Figure FIGREF3 . The input is first processed by the phrase-based machine translation system from the input language INLINEFORM0 to the target language INLINEFORM1 . Since the machine translation system is not perfect, the output of the system may not be correct translation containing errors possibly. Therefore, we will call the output language of the PBMT system INLINEFORM2 .\nIn a second step, we will train a neural monolingual translation system, that translates from the output of the PBMT system INLINEFORM0 to a better target sentence INLINEFORM1 .\n\nMixed Input\nOne drawback of the pipelined approach is that the PBMT system might introduce some errors in the translation that the NMT can not recover from. For example, it is possible that some information from the source sentence gets lost, since the word is entirely deleted during the translation of the PBMT system.\nWe try to overcome this problem by building an NMT system that does not only take the output of the PBMT system, but also the original source sentence. One advantage of NMT system is that we can easily encode different input information. The architecture of our system is shown in Figure FIGREF3 .\nThe implementation of the mixed input for the NMT system is straight forward. Given the source input INLINEFORM0 and the output of the PBMT system INLINEFORM1 , we generated the input for the NMT system. First, we ensured a non-overlapping vocabulary of INLINEFORM2 and INLINEFORM3 by marking each token in INLINEFORM4 by a character and INLINEFORM5 by different ones. Then both input sequences are concatenated to the input INLINEFORM6 of the NMT system.\nUsing this representation, the NMT can learn to focus on source word INLINEFORM0 and words INLINEFORM1 when generating a word INLINEFORM2 .\n\nTraining\nIn both cases, we can no longer train the NMT system on the source language and target language data, but on the output of the PBMT system and the target language data. Therefore, we need to generate translations of the whole parallel training data using the PBMT system.\nDue to its ability to use very long phrases, a PBMT system normally performs significantly better on the training data than on unseen test data. This of course will harm the performance of our approach, because the NMT system will underestimate the number of improvements it has to perform on the test data.\nIn order to limit this effect, we did not use the whole phrase tables when translating the training data. If a phrase pair only occurs once, we cannot learn it from a different sentence pair. Following BIBREF9 , we removed all phrase pairs that occur only once for the translation of the corpus.\n\nExperiments\nWe analyze the approach on the English to German news translation task of the Conference on Statistical Machine Translation (WMT). First, we will describe the system and analyze the translation quality measured in BLEU. Afterwards, we will analyze the performance depending on the frequency of the words and finally show some example translations.\n\nSystem description\nFor the pre-translation, we used a PBMT system. In order to analyze the influence of the quality of the PBMT system, we use two different systems, a baseline system and a system with advanced models. The systems were trained on all parallel data available for the WMT 2016. The news commentary corpus, the European parliament proceedings and the common crawl corpus sum up to 3.7M sentences and around 90M words.\nIn the baseline system, we use three language models, a word-based, a bilingual BIBREF17 and a cluster based language model, using 100 automatically generated clusters using MKCLS BIBREF18 .\nThe advanced system use pre-reodering BIBREF19 and lexicalized reordering. In addition, it uses a discriminative word lexicon BIBREF9 and a language model trained on the large monolingual data.\nBoth systems were optimized on the tst2014 using Minimum error rate training BIBREF20 . A detailed description of the systems can be found in BIBREF21 .\nThe neural machine translation was trained using Nematus. For the NMT system as well as for the PreMT system, we used the default configuration. In order to limit the vocabulary size, we use BPE as described in BIBREF0 with 40K operations. We run the NMT system for 420K iterations and stored a model every 30K iterations. We selected the model that performed best on the development data. For the ensemble system we took the last four models. We did not perform an additional fine-tuning.\nThe PreMT system was trained on translations of the PBMT system of the corpus and the target side of the corpus. For this translation, we only used the baseline PBMT system.\n\nEnglish - German Machine Translation\nThe results of all systems are summarized in Table TABREF13 . It has to be noted, that the first set, tst2014, has been used as development data for the PBMT system and as validation set for the NMT-based systems.\nUsing the neural MT system, we reach a BLEU score of 23.34 and 27.65 on tst2015 and tst2016. Using an ensemble system, we can improve the performance to 24.03 and 28.89 respectively. The baseline PBMT system performs 1.5 to 1.2 BLEU points worse than the single NMT system. Using the PBMT system with advanced models, we get the same performance on the tst2015 and 0.5 BLEU points better on tst2016 compared to the NMT system.\nFirst, we build a PreMT system using the pipeline method as described in Section SECREF6 . The system reaches a BLEU score of 22.04 and 26.75 on both test sets. While the PreMT can improve of the baseline PBMT system, the performance is worse than the pure NMT system. So the first approach to combine neural and statistical machine translation is not able the combine the strength of both system. In contrast, the NMT system seems to be not able to recover from the errors done by the SMT-based system.\nIn a second experiment, we use the advanced PBMT system to generate the translation of the test data. We did not use it to generate a new training corpus, since the translation is computationally very expensive. So the PreMT system stays the same, being trained on the translation of the baseline PBMT. However, it is getting better quality translation in testing. This also leads to an improvement of 0.9 BLEU points on both test sets. Although it is smaller then the difference between the two initial phrase-based translation systems of around 1.5 BLUE points, we are able to improve the translation quality by using a better pre-translation system. It is interesting to see that we can improve the quality of the PreMT system, but improving one component (SMT Pre-Translation), even if we do it only in evaluation and not in training. But the system does not improve over the pure NMT system and even the post editing of the NMT system lowers the performance compared to the initial PBMT system used for pre-translation.\nAfter evaluating the pipelined system, we performed experiments using the mixed input system. This leads to an improvement in translation quality. Using the baseline PBMT system for per-translation, we perform 0.8 BLEU points better than the purely NMT system on tst2015 and 0.4 BLEU point better on tst2016. It also showed better performance than both PBMT systems on tst2015 and comparable performance with the advanced PBMT on tst2016. So by looking at the original input and the pre-translation, the NMT system is able to recover some of the errors done by the PBMT system and also to prevent errors the NMT does if it is directly translating the source sentence.\nUsing the advanced PBMT system for input, we can get additional gains of 0.3 and 1.6 BLEU points The system even outperforms the ensemble system on tst2016. The experiments showed that deploying a pre-translation PBMT system with a better quality improves the NMT quality in the mixed input scheme, even when it is used only in testing, not in training.\nBy using an ensemble of four model, we improve the model by one BLEU point on both test sets, leading to the best results of 25.35 and 30.67 BLEU points. This is 1.3 and 1.8 BLEU points better than the pure NMT ensemble system.\n\nSystem Comparison\nAfter evaluating the approach, we further analyze the different techniques for machine translation. For this, we compared the single NMT system, the advanced PBMT system and the mixed system using the advanced PBMT system as input.\nOut initial idea was that PBMT systems are better for translating rare words, while the NMT is generating more fluent translation. To confirm this assumption, we edited the output of all system. For all analyzed systems, we replaced all target words, which occur in the training data less than INLINEFORM0 times, by the UNK token. For large INLINEFORM1 , we have therefore only the most frequent words in the reference, while for lower INLINEFORM2 more and more words are used.\nThe results for INLINEFORM0 are shown in Figure FIGREF15 . Of course, with lower INLINEFORM1 we will have fewer UNK tokens in the output. Therefore, we normalized the BLEU scores by the performance of the PreMT system.\nWe can see in the figure, that when INLINEFORM0 , where only the common words are used, we perform best using the NMT system. The PreMT system performs similar and the PBMT system performs clearly worse. If we now decrease INLINEFORM1 , more and more less frequent words will be considered in the evaluation of the translation quality. Although the absolute BLEU scores raise for all systems, on these less frequent words the PBMT performs better than the NMT system and therefore, finally it even achieves a better performance.\nIn contrast to this, the PreMT is able to benefit from the pre-translation of the PBMT system and therefore stays better than the PBMT system.\n\nConclusion\nIn this paper, we presented a technique to combine phrase-based and neural machine translation. Motivated by success in statistical machine translation, we used phrase-based machine translation to pre-translate the input and then we generate the final translation using neural machine translation.\nWhile a simple serial combination of both models could not generate better translation than the neural machine translation system, we are able to improve over neural machine translation using a mixed input. By simple concatenation of the phrase-based translation and the original source as input for the neural machine translation, we can increase the machine translation quality measured in BLEU. The single pre-translated system could even outperform the ensemble NMT system. For the ensemble system, the PreMT system could outperform the NMT system by up to 1.8 BLEU points.\nUsing the combined approach, we can generate more fluent translation typical for the NMT system, but also translate rare words. These are often more easily translated by PBMT. Furthermore, we are able to improve the overall system performance by improving the individual components.\n\nFigure 1: Pre-translation methods\n\nFigure 2: Compare BLEU score by word frequency\n\nInquiry: Which NMT architecture do they use?", "role": "user" }, { "content": "{\"answer\": [\"trained using Nematus\", \"default configuration\"], \"evidence\": [\"The neural machine translation was trained using Nematus. For the NMT system as well as for the PreMT system, we used the default configuration. In order to limit the vocabulary size, we use BPE as described in BIBREF0 with 40K operations. We run the NMT system for 420K iterations and stored a model every 30K iterations. We selected the model that performed best on the development data. For the ensemble system we took the last four models. We did not perform an additional fine-tuning.\"]}", "role": "assistant" } ]

[ { "content": "Write an abstract for the research paper below. Your response should only include the abstract and no additional text.\n\nArticle text:\nfield theories defined on a nc geometry are highly fashionable , in particular because they arise from a low energy limit of string theory @xcite\n. a nc space may be defined by the non commutativity of some of its coordinates @xmath2 = i\\theta_{\\mu\\nu } \\,\\overset{\\text{2d}}{=}\\ , i \\theta \\epsilon_{\\mu \\nu}\\,.\\ ] ] for a review of nc field theories , see ref .\nthe extension of actions of commutative field theories to their nc counterparts can be realized by replacing all products between fields by the _ star product _ @xmath3 in the nc @xmath0 model this replacement leads to the action @xmath4\\,,\\nonumber\\ ] ] where only the interaction term requires the star product . in perturbation\ntheory the one loop contribution to the 1 pi two point function splits into two parts coming from the planar and the non planar graphs .\nthe planar terms are proportional to their ( uv divergent ) commutative counterparts @xcite . in the case of the non planar graphs the momentum cut off\n@xmath5 is replaced by an effective cut off @xmath6 @xcite , @xmath7 where @xmath8 denotes the incoming momentum .\nthe cut off @xmath5 may be safely send to infinity , leading to a uv finite contribution .\nhowever , the uv divergences reappear as ir divergences in the limit @xmath9 .\nthis mixing of uv and ir effects still causes serious problems in a perturbative treatment of nc field theories beyond one loop .\nwe studied the mixing of divergences non perturbatively in the 3d model , with a commutative time direction .\n, see refs .\n@xcite . ] to avoid the ( cpu ) time consuming lattice version of the star product , we mapped the system on a dimensionally reduced model @xcite . here the scalar fields @xmath10 defined on a @xmath11 lattice are mapped on @xmath12 hermitian matrices @xmath13 .\ntheir action reads @xmath14&\\hspace{-.5cm}=\\vspace{-.1cm}n\\textrm{tr}\\sum_{t=1}^{t } \\biggl [ \\frac{1}{2}\\sum_\\mu\\left(\\gamma_\\mu\\hat{\\phi}(t)\\ , \\gamma_\\mu^\\dagger\\!-\\hat{\\phi}(t)\\right)^2\\\\ & \\hspace{-.5cm}+\\frac{1}{2}\\left(\\hat{\\phi}(t\\!+\\!1)-\\hat{\\phi}(t)\\right)^2\\!\\!+ \\!\\frac{m^2}{2}\\hat{\\phi}^2(t)+\\frac{\\lambda}{4}\\hat{\\phi}^4(t ) \\biggl]\\nonumber\\,,\\end{aligned}\\ ] ] where the twist \neaters @xmath15 are defined by @xmath16 this implies @xmath17 , where @xmath18 is the lattice spacing . for this action we studied the phase diagram and the dispersion relation .\nbased on the momentum dependent order parameter @xmath19 , with is the spatial fourier transform of @xmath10 . ]\n@xmath20 we studied the phase diagram in the @xmath21@xmath22 plane .\nour results for various values of @xmath23 are shown in fig .\n[ fig : phase ] . model .\nthe connected symbols show the separation line between disordered and ordered regime , and the vertical lines mark the transition region between uniformly ordered and striped phase . _ _ ] we identify a clear separation line ( connected symbols ) between the disordered phase and the ordered regime .\nthe ordered regime splits into a uniformly ordered phase and a striped phase , where the transition region is marked by two vertical lines for each value of @xmath24 . to illustrate the striped phase we present in fig .\n[ fig : snapshot ] snapshots of single configurations , which represent the ground state in this phase in the @xmath25@xmath26 plane at fixed time @xmath27 at a certain time @xmath27 , for @xmath28.__,title=\"fig : \" ] at a certain time @xmath27 , for @xmath28.__,title=\"fig : \" ] for @xmath29 at @xmath30 and @xmath31 .\nthe dotted areas indicate @xmath32 and in the blank areas @xmath33 is negative . here\nwe show configurations with two diagonal stripes resp .\nfour stripes parallel to the @xmath25 axis . at smaller values of the coupling @xmath21 or smaller system size\n@xmath24 we also find two stripes parallel to one of the axis @xcite .\nthese results agree qualitatively with the conjecture by gubser and sondhi , who predicted the occurrence of a striped phase @xcite . to complete the agreement the striped phase has to survive the continuum limit , where the number of stripes should diverge , such that the width of the stripes remains finite .\nthe star product breaks explicitly the lorentz symmetry , which leads to a deformation of the standard dispersion relation .\nthe one loop result for this relation reads @xcite @xmath34 where @xmath6 is defined in eq .\n( [ eq : eff - cutoff ] ) .\nthe deformation causes a shift in the energy minimum from @xmath35 to non \nzero momenta .\nwe investigated numerically the energy \nmomentum relation in the disordered phase .\nthe energy @xmath36 can be computed from the correlator @xmath37 where the physical momenta are given by @xmath38 .\nthis correlator behaves like a cosh @xmath39 and the study of its decay allows to extract the energy . in fig .\n[ fig : disp1 ] ( on top ) the system is close to the uniformly ordered phase transition . here the square of the energy is linear in @xmath40 as in a lorentz invariant theory .\nclose to the striped phase ( fig .\n[ fig : disp1 ] below ) the situation is changed .\nwe see a clear deviation from lorentz symmetry .\nthe minimum of the energy is now at the lowest non zero ( lattice ) momentum and thus there will be two stripes parallel to the axes in the non uniform phase . in fig .\n[ fig : disp2 ] the results at very large coupling @xmath21 , far outside the phase diagram in fig .\n[ fig : phase ] , are shown .\nnow the energy minimum is shifted to larger momenta , leading to the more complicated patterns in the striped phase as in fig .\n[ fig : snapshot ] . in figs .\n[ fig : disp1 ] and [ fig : disp2 ] the solid lines are fits to the one loop result for the energy in eq .\n( [ eq : deformation ] ) . .\nclose to the uniform phase at @xmath41 ( on top ) and close to the striped phase at @xmath42 ( below).__,title=\"fig : \" ] + .\nclose to the uniform phase at @xmath41 ( on top ) and close to the striped phase at @xmath42 ( below).__,title=\"fig : \" ]\nwe studied numerically the effects of uv / ir mixing in the 3d nc @xmath0 model . for the phase diagram we found that the ordered regime is split into an ising type phase for small coupling @xmath21 and a striped phase for larger coupling .\nthe patterns in the striped phase become more complex when @xmath21 or the system size @xmath24 is increased .\nthese results are in qualitative agreement with the conjecture of gubser and sondhi , if this type of stripes survives the large @xmath24 limit . the energy momentum relation behaves as predicted from one loop perturbation theory .\nthis is a remarkable result , since due to the uv / ir mixing there could be strong effects from higher order calculations .\nour results imply that such effects do not change the results qualitatively\n. however , for final conclusions one has to perform the continuum limit @xcite .", "role": "user" }, { "content": "the uv / ir mixing in the @xmath0 model on a non - commutative ( nc ) space leads to new predictions in perturbation theory , including hartree \n fock type approximations . among them \n there is a changed phase diagram and an unusual behavior of the correlation functions . in particular \n this mixing leads to a deformation of the dispersion relation . \n we present numerical results for these effects in @xmath1 with two nc coordinates .", "role": "assistant" } ]

[ { "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\nObjectiveTo define chest CT findings and their dynamic changes in patients with coronavirus disease 2019 (COVID-19) from disease onset to the cure.MethodWe analyzed the clinical and chest CT data of 6 patients with RT-PCR-confirmed COVID-19. According to the time from the disease onset to the cure or from the onset to each CT scan, the total of 30 chest CT scans were divided into 4 stages, namely stage 1 (0-4 days), stage 2 (5-9 days), stage 3 (10-14 days), and stage 4 (over 14 days). A semi-quantitative scoring system was used to quantitatively assess the pulmonary involvement on the basis of the involved area. The differences in chest CT signs and the lung injury scores based on CT findings were compared among the 4 stages.ResultsIn stage 1, ground-glass opacities (GGO) was found frequently in the subpleura, and the CT score was the lowest at 4.00+/-0.40. Stage 2 was characterized by an increased and mixed density (crazy-paving pattern) with mild consolidation of the lungs, and the CT score reached its peak level of 7.38+/-3.34 (P < 0.05). In stage 3, an expanded range of consolidation and linear lesions were found in the lungs, and the total CT score averaged 6.86+/-2.91. In stage 4, a gradual resolution of the consolidation occurred with more linear lesions in the lungs, and the total CT score was 6.21+/-1.56. The CT scores of the lower lobes were significantly higher compared with those of the middle/upper lobes (P < 0.05) in stage 3 and stage 4.ConclusionChest CT scans allows dynamic monitoring of the changes in the distribution, density and extent of the pulmonary lesions in the 4 stages, which are closely correlated with the evolution of the disease course of COVID-19.", "role": "user" }, { "content": "[\"Diagnosis\"]", "role": "assistant" } ]

[ { "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: Fortia-FBK at SemEval-2017 Task 5: Bullish or Bearish? Inferring Sentiment towards Brands from Financial News Headlines\n\nIn this paper, we describe a methodology to infer Bullish or Bearish sentiment towards companies/brands. More specifically, our approach leverages affective lexica and word embeddings in combination with convolutional neural networks to infer the sentiment of financial news headlines towards a target company. Such architecture was used and evaluated in the context of the SemEval 2017 challenge (task 5, subtask 2), in which it obtained the best performance.\n\nIntroduction\nReal time information is key for decision making in highly technical domains such as finance. The explosive growth of financial technology industry (Fintech) continued in 2016, partially due to the current interest in the market for Artificial Intelligence-based technologies.\nOpinion-rich texts such as micro-blogging and news can have an important impact in the financial sector (e.g. raise or fall in stock value) or in the overall economy (e.g. the Greek public debt crisis). In such a context, having granular access to the opinions of an important part of the population is of key importance to any public and private actor in the field. In order to take advantage of this raw data, it is thus needed to develop machine learning methods allowing to convert unstructured text into information that can be managed and exploited.\nIn this paper, we address the sentiment analysis problem applied to financial headlines, where the goal is, for a given news headline and target company, to infer its polarity score i.e. how positive (or negative) the sentence is with respect to the target company. Previous research BIBREF0 has highlighted the association between news items and market fluctiations; hence, in the financial domain, sentiment analysis can be used as a proxy for bullish (i.e. positive, upwards trend) or bearish (i.e. negative, downwards trend) attitude towards a specific financial actor, allowing to identify and monitor in real-time the sentiment associated with e.g. stocks or brands.\nOur contribution leverages pre-trained word embeddings (GloVe, trained on wikipedia+gigaword corpus), the DepecheMood affective lexicon, and convolutional neural networks.\n\nRelated Works\nWhile image and sound come with a natural high dimensional embedding, the issue of which is the best representation is still an open research problem in the context of natural language and text. It is beyond the scope of this paper to do a thorough overview of word representations, for this we refer the interest reader to the excellent review provided by BIBREF1 . Here, we will just introduce the main representations that are related to the proposed method.\n\nData\nThe data consists of a set of financial news headlines, crawled from several online outlets such as Yahoo Finance, where each sentence contains one or more company names/brands.\nEach tuple (headline, company) is annotated with a sentiment score ranging from -1 (very negative, bearish) to 1 (very positive, bullish). The training/test sets provided contain 1142 and 491 annotated sentences, respectively.\nA sample instance is reported below:\nHeadline: “Morrisons book second consecutive quarter of sales growth”\nCompany name: “Morrisons”\nSentiment score: 0.43\n\nMethod\nIn Figure FIGREF5 , we can see the overall architecture of our model.\n\nSentence representation and preprocessing\nMinimal preprocessing was adopted in our approach: we replaced the target company's name with a fixed word <company> and numbers with <number>. The sentences were then tokenized using spaces as separator and keeping punctuation symbols as separate tokens.\nThe words are represented as fixed length vectors INLINEFORM0 resulting from the concatenation of GloVe pre-trained embeddings and DepecheMood BIBREF19 lexicon representation. Since we cannot directly concatenate token-based embeddings (provided in GloVe) with the lemma#PoS-based representation available in DepecheMood, we proceeded to re-build the latter in token-based form, applying the exact same methodology albeit with two differences: we started from a larger dataset (51.9K news articles instead of 25.3K) and used a frequency cut-off, i.e. keeping only those tokens that appear at least 5 times in the corpus.\nThese word-level representation are used as the first layer of our network. During training we allow the weights of the representation to be updated. We further add the VADER score for the sentence under analysis. The complete sentence representation is presented in Algorithm UID8 .\nInputInput OutputOutput The sentence embedding INLINEFORM0 INLINEFORM1 \n INLINEFORM0 in INLINEFORM1 INLINEFORM2 = [GloVe( INLINEFORM3 , INLINEFORM4 ), DepecheMood( INLINEFORM5 )] INLINEFORM6 Sentence representation\n\nArchitectural Details\nA 1D convolutional layer with filters of multiple sizes {2, 3, 4} is applied to the sequence of word embeddings. The filters are used to learn useful translation-invariant representations of the sequential input data. A global max-pooling is then applied across the sequence for each filter output.\nWe apply the concatenation layer to the output of the global max-pooling and the output of VADER.\nThe activation function used between layers is ReLU BIBREF24 except for the out layer where tanh is used to map the output into [-1, 1] range.\nDropout BIBREF25 was used to avoid over-fitting to the training data: it prevents the co-adaptation of the neurones and it also provides an inexpensive way to average an exponential number of networks. In addition, we averaged the output of multiple networks with the same architecture but trained independently with different random seeds in order to reduce noise.\nThe loss function used is the cosine distance between the predicted scores and the gold standard for each batch. Even though stochastic optimization methods like Adam BIBREF26 are usually applied to loss functions that are written as a sum of per-sample loss, which is not the case for the cosine, it converges to an acceptable solution. The loss can be written as : DISPLAYFORM0 \nwhere INLINEFORM0 and INLINEFORM1 are the predicted and true sentiment scores for batch INLINEFORM2 , respectively.\nThe algorithm for training/testing our model is reported in Algorithm UID15 .\nInputInput OutputOutput ParameterParameters A set of trained models INLINEFORM0 , and the predictions INLINEFORM1 for the test set INLINEFORM2 The number INLINEFORM3 of models to train INLINEFORM4 see sec 3.1 INLINEFORM5 in INLINEFORM6 INLINEFORM7 ) see Alg. UID8 INLINEFORM8 INLINEFORM9 see Eq. EQREF16 INLINEFORM10 INLINEFORM11 INLINEFORM12 Training/Testing algorithm. To build our model, we set N=10.\n\nResults\nIn this section, we report the results obtained by our model according to challenge official evaluation metric, which is based cosine-similarity and described in BIBREF27 . Results are reported for three diverse configurations: (i) the full system; (ii) the system without using word embeddings (i.e. Glove and DepecheMood); and (iii) the system without using pre-processing. In Table TABREF17 we show model's performances on the challenge training data, in a 5-fold cross-validation setting.\nFurther, the final performances obtained with our approach on the challenge test set are reported in Table TABREF18 . Consistently with the cross-validation performances shown earlier, we observe the beneficial impact of word-representations and basic pre-processing.\n\nConclusions\nIn this paper, we presented the network architecture used for the Fortia-FBK submission to the Semeval-2017 Task 5, Subtask 2 challenge, with the goal of predicting positive (bullish) or negative (bearish) attitude towards a target brand from financial news headlines. The proposed system ranked 1st in such challenge.\nOur approach is based on 1d convolutions and uses fine-tuning of unsupervised word representations and a rule based sentiment model in its inputs. We showed that the use of pre-computed word representations allows to reduce over-fitting and to achieve significantly better generalization, while some basic pre-processing was needed to further improve the performance.\n\nFigure 1: Network architecture\n\nTable 2: Final results\n\nTable 1: Cross-validation results\n\nInquiry: What was their performance?", "role": "user" }, { "content": "{\"answer\": [\"beneficial impact of word-representations and basic pre-processing\"], \"evidence\": [\"In this section, we report the results obtained by our model according to challenge official evaluation metric, which is based cosine-similarity and described in BIBREF27 . Results are reported for three diverse configurations: (i) the full system; (ii) the system without using word embeddings (i.e. Glove and DepecheMood); and (iii) the system without using pre-processing. In Table TABREF17 we show model\\u0027s performances on the challenge training data, in a 5-fold cross-validation setting.\", \"Further, the final performances obtained with our approach on the challenge test set are reported in Table TABREF18 . Consistently with the cross-validation performances shown earlier, we observe the beneficial impact of word-representations and basic pre-processing.\"]}", "role": "assistant" } ]

[ { "content": "Analyze the provided text to identify gene-related entities. \n\nFormat your findings as a JSON object: {\"Gene\": [\"ExampleGene\", ...]}. Use the entity type as the key, and list the entities under it. If no entities are found, use an empty list.\n\nFocus solely on the JSON output.\n\nText:\n\nA recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.", "role": "user" }, { "content": "{\"Gene\": [\"SRY\", \"Steroidogenic factor-1\", \"WNT4\", \"steroidogenic factor-1\", \"NR5A1\"]}", "role": "assistant" } ]

[ { "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:\nurinary tract infections in diabetics are a common occurrence , and they may be complicated by the presence of gas producing organisms . emphysematous infection of the kidney is well known , but such infections are rare in the testis and epididymis .\nthese infections are often referred to the surgeon , because of the likelihood of surgical intervention .\nboth emphysematous pyelonephritis and epididymo - orchitis may not be detected clinically and ultrasound or computed tomography ( ct ) may be needed for the diagnosis .\nthe presentation of epididymo - orchitis with gas bubbles in the scrotum is very rare , and one case that has been reported was secondary to seminal vesicle involvement by diverticulitis of the colon .\n. however , there are no case reports of emphysematous epididymo - orchitis caused by e. coli with a normal seminal vesicle .\na 52-year - old man was brought to emergency with a 3-day history of pain and swelling in the left scrotum with fever [ figure 1 ] .\nclinical examination of the scrotum showed inflamed left scrotum and tender and enlarged left testis and epididymis .\nper rectal examination showed that the prostate was normal in size and consistency , with its upper limit just reachable .\nhe gave a history of previous urinary tract infection , and the culture had shown e. coli .\nan ultrasound of the scrotum was done , which showed gas shadows in the left epididymis and testis with inflammation in the skin of the scrotum and fluid in the tunical sacs [ figure 2 ] . a ct scan of the abdomen and the pelvis showed the pockets of gas in the scrotum and testis , but the seminal vesicles and the sigmoid colon were normal [ figure 2 ] .\nclinical presentation with acute inflamed scrotum with per operative image showing destroyed testicular tunica and parenchyma radiology of the patient showing in clockwise sequence , gas bubbles in the testis and scrotum seen on ultrasound , ct images showing preserved fat planes around the seminal vesicles , gas bubbles seen in the scrotum and substance of the testis , and increased vascularity of the testis seen on doppler images the patient was taken up for surgery in view of the gas shadows in the testicular substance and poor response to clinical parameters after intravenous antibiotics .\nthere was extensive inflammation in the scrotum with gas bubbles , extending through the tunica into the substance of the testis [ figure 1 ] .\nhistopathology of the excised testis showed acute epididymo - orchtis with areas of necrosis and thrombosis in veins .\nfournier 's gangrene can involve the perineum with gas formation but classically spares the testis and epididymis .\nan online search revealed one case of emphysematous epididymo - orchitis , secondary to seminal vesicle involvement in diverticulitis of the sigmoid colon .\nhowever , our patient had normal outline of seminal vesicles with preserved fat planes and no evidence of diverticulitis on ct scan .\npus from the testis cultured e. coli , which has been cultured previously in cases of emphysematous pyelonephritis but has never in emphysematous epididymo - orchitis .\nthere is not much information available about the best modality for the treatment of this condition . initially , most cases merit high - dose broad - spectrum antibiotics till the results of culture sensitivity are available .\naspiration of pus with a wide bore needle may be tried in early cases . as in case of emphysematous pyelonephritis\ndiabetes mellitus could have a role in the pathogenesis of the condition as in emphysematous pyelonephritis .\nthe differential diagnosis of a bright , highly reflective tissue interface on ultrasound of the testis , with distal acoustic shadow , can be either emphysematous infections like fournier 's gangrene or emphysematous epididymo - orchitis , or testicular shrapnel , testicular germ cell neoplasm , or testicular microlithiasis .\nct scan can be a useful adjunct to the diagnosis . with the availability of ultrasound in most emergency departments\n, there is a case for applying the ultrasound probe on diabetic patients with an acutely inflamed scrotum to rule out emphysematous infection .", "role": "user" }, { "content": "emphysematous epididymo - orchitis is a rare cause of an acute scrotum and is a surgical emergency . \n diagnosis is clinically difficult , and sonography with a high - frequency probe is useful to pick up gas shadows in the scrotal wall or testicular substance . a diabetic patient presented with fever , urinary tract infection , and an acute scrotal swelling . \n the patient needed orchidectomy and scrotal debridement . \n as in emphysematous pyelonephritis , this condition occurs in diabetics , and patients may need surgery . \n there is a need to perform sonography in all diabetic patients with an acutely inflamed scrotum , because detection of gas shadows makes surgical intervention more likely .", "role": "assistant" } ]

[ { "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\nIt is urgent to understand the future of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) transmission. We used estimates of seasonality, immunity, and cross-immunity for human coronavirus OC43 (HCoV-OC43) and HCoV-HKU1 using time-series data from the United States to inform a model of SARS-CoV-2 transmission. We projected that recurrent wintertime outbreaks of SARS-CoV-2 will probably occur after the initial, most severe pandemic wave. Absent other interventions, a key metric for the success of social distancing is whether critical care capacities are exceeded. To avoid this, prolonged or intermittent social distancing may be necessary into 2022. Additional interventions, including expanded critical care capacity and an effective therapeutic, would improve the success of intermittent distancing and hasten the acquisition of herd immunity. Longitudinal serological studies are urgently needed to determine the extent and duration of immunity to SARS-CoV-2. Even in the event of apparent elimination, SARS-CoV-2 surveillance should be maintained because a resurgence in contagion could be possible as late as 2024.", "role": "user" }, { "content": "[\"Transmission\", \"Epidemic Forecasting\"]", "role": "assistant" } ]

[ { "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:\na 58-year - old woman presented to the emergency department with a stuporous mental state , ophthalmoplegia , and severe dysarthria .\nshe had a prior history of cardiac valve replacement surgery for both mitral and aortic regurgitations 10 years earlier .\nher national institutes of health stroke scale ( nihss ) score was 14 and modified rankin scale ( mrs ) score was 5 . a ct scan of the head five hours after the onset of symptoms showed a hyperdense basilar artery on two consecutive 5-mm cut images , indicating an acute basilar artery embolism . after obtaining written informed consent for the endovascular therapy from the patient 's family , the angiographic procedure began 5.5 hours after the onset of stroke .\nat this point , a loading dose of abciximab ( 0.25 mg / kg ) was administered intravenously . rapid recanalization was achieved using a minimum dose of thrombolytic agents by performing direct angioplasty first followed by intra - arterial thrombolysis .\nthe balloon catheter was advanced into the occlusion site and inflated to 4 atm for 30 seconds .\nimmediately after the angioplasty , the basilar artery was partially recanalized with a restoration of the blood flow to the both superior cerebellar arteries .\na microcatheter was then placed just proximal to the occlusion site , and 400,000 units of urokinase were infused at a constant rate for one hour .\nthe completion angiograms demonstrated a partial recanalization of the basilar artery with embolus remaining in the basilar tip and the restoration of blood flow to both the posterior and superior cerebellar arteries .\nin addition , angiograms demonstrated a single perforating thalamic artery that was divided into two branches ( figs .\n1b , c ) . after the endovascular procedure , the patient showed progressive clinical improvement and regained complete consciousness within a few hours .\na non - enhanced ct scan obtained immediately after the endovascular therapy showed bilateral symmetrical high attenuations in the paramedian thalamic regions ( fig .\nthe maximum hounsfield unit of hyperdense lesions was 67 . on the following day , her nihss score was 6 and the patient developed hypersomnolence , severe memory impairments , and vertical gaze palsy .\nthe follow - up nonenhanced ct scan obtained 24 hours after completing the intra - arterial thrombolytic therapy showed the disappearance of the hyperdense lesions and the development of hypodensities in the bilateral paramedian thalamic regions without a hemorrhagic transformation ( fig .\nafter three months , the patient improved to functional independence ( nihss score from 14 to 4 ; mrs score from 5 to 1 ) but continued to have both short and long - term memory dysfunction as well as vertical gaze palsy .\na hyperdense lesion observed on the post - therapeutic , nonenhanced ct scans obtained immediately after intraarterial thrombolysis has been described as either a hemorrhage or an extravasation of the contrast medium given during the angiographic procedures performed during the thrombolysis procedures ( 2 - 4 ) .\nyoon et al . ( 1 ) reported that a hyperdense lesion that has different characteristics from a hemorrhage in terms of both the ct findings and the clinical outcome could be categorized as two entities : contrast enhancement and contrast extravasation . in their study ,\ncontrast enhancement was defined as a hyperdense lesion that disappeared on the 24-hour follow - up ct scan , without leaving a hematoma cavity or a mass effect , and contrast extravasation as a hyperdense lesion with a maximum hu > 90 , which persisted on the 24-hour follow - up ct scan .\nthey also concluded that both the contrast enhancement and contrast extravasation develop primarily in the region of the basal ganglia in accordance with the specific vascular territory ( 1 ) .\nthe ct findings in the present case are consistent with contrast enhancement , which occurred in the thalamus after an intra - arterial thrombolysis procedure , according to the definition by yoon et al .\nit has been reported that contrast enhancement and contrast extravasation occur primarily in the basal ganglia after intra - arterial thrombolysis in those patients with an occlusion of the middle cerebral artery ( 1 - 4 ) . to the best of our knowledge ,\nthere are no reports regarding thalamic enhancement after thrombolysis in patients with an acute occlusion of the basilar artery .\nthe prolonged infusion of thrombolytic agents and contrast materials in the vicinity of the perforating thalamic branches may have resulted in the leakage of the contrast medium through the injured blood brain barrier ( bbb ) of the perforating microvessels supplying the thalamus .\nthis can lead to the gradual accumulation of contrast medium , which manifests as contrast enhancement on the nonenhanced ct scans obtained immediately after the thrombolytic procedure .\nin this case , the contrast enhancement occurred in the symmetrical bilateral paramedian regions of both thalami .\nthe suggested mechanism for this finding is a disruption of the bbb of a single perforating thalamic artery ( paramedian artery ) , which supplies the paramedian part of the upper midbrain and thalamus , including the intralaminar nuclear group and most of the dorsomedial nucleus ( 5 ) . in this case , angiography clearly demonstrated a single paramedian artery .\nit was reported that a single perforating thalamic artery can supply the paramedian territory on both sides , and an occlusion of this artery can result in corresponding bilateral infarctions in the paramedian aspects of the thalami ( 6 ) .\na cadaver dissection study reported that the origin of the perforating thalamic arteries was unilateral in eight of 12 brains ( 7 ) . in conclusion\n, contrast enhancement can occur in the thalamus after an intra - arterial thrombolysis procedure in patients with an acute basilar artery occlusion .\nin addition , a pathological process involving a single perforating thalamic artery can result in symmetrical bilateral disease in the paramedian regions of both thalami .", "role": "user" }, { "content": "a 58-year - old woman presented with an acute embolic occlusion of the distal basilar artery . she underwent angioplasty and intra - arterial thrombolysis . \n angiography performed after recanalization revealed a single perforating thalamic artery . \n a nonenhanced ct scan carried out immediately after the procedure revealed hyperdense lesions in the bilateral paramedian portions of the thalami , which disappeared on the 24-hour follow - up ct scan . \n three months later , the patient improved to functional independence , but had some memory dysfunction and vertical gaze palsy . \n this case suggests that contrast enhancement or extravasation can occur in the thalamus after intra - arterial thrombolysis performed to recanalize a basilar artery occlusion .", "role": "assistant" } ]

[ { "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:\nSentiment analysis is directly affected by compositional phenomena in language that act on the prior polarity of the words and phrases found in the text. Negation is the most prevalent of these phenomena and in order to correctly predict sentiment, a classifier must be able to identify negation and disentangle the effect that its scope has on the final polarity of a text. This paper proposes a multi-task approach to explicitly incorporate information about negation in sentiment analysis, which we show outperforms learning negation implicitly in a data-driven manner. We describe our approach, a cascading neural architecture with selective sharing of LSTM layers, and show that explicitly training the model with negation as an auxiliary task helps improve the main task of sentiment analysis. The effect is demonstrated across several different standard English-language data sets for both tasks and we analyze several aspects of our system related to its performance, varying types and amounts of input data and different multi-task setups.\n\nCited Works Summary:\n[1]: \n\n[2]: We propose a unified neural network architecture and learning algorithm that can be applied to various natural language processing tasks including part-of-speech tagging, chunking, named entity recognition, and semantic role labeling. This versatility is achieved by trying to avoid task-specific engineering and therefore disregarding a lot of prior knowledge. Instead of exploiting man-made input features carefully optimized for each task, our system learns internal representations on the basis of vast amounts of mostly unlabeled training data. This work is then used as a basis for building a freely available tagging system with good performance and minimal computational requirements.\n\n[3]: In all previous work on deep multi-task learning we are aware of, all task supervisions are on the same (outermost) layer. We present a multi-task learning architecture with deep bi-directional RNNs, where different tasks supervision can happen at different layers. We present experiments in syntactic chunking and CCG supertagging, coupled with the additional task of POS-tagging. We show that it is consistently better to have POS supervision at the innermost rather than the outermost layer. We argue that this is because “lowlevel” tasks are better kept at the lower layers, enabling the higher-level tasks to make use of the shared representation of the lower-level tasks. Finally, we also show how this architecture can be used for domain adaptation.\n\n[4]: \n\n[5]: Multitask learning has been applied successfully to a range of tasks, mostly morphosyntactic. However, little is known on when MTL works and whether there are data characteristics that help to determine its success. In this paper we evaluate a range of semantic sequence labeling tasks in a MTL setup. We examine different auxiliary tasks, amongst which a novel setup, and correlate their impact to data-dependent conditions. Our results show that MTL is not always effective, significant improvements are obtained only for 1 out of 5 tasks. When successful, auxiliary tasks with compact and more uniform label distributions are preferable.\n\n[6]: This paper suggests that it may be easier to learn several hard tasks at one time than to learn these same tasks separately. In effect, the information provided by the training signal for each task serves as a domain-specific inductive bias for the other tasks. Frequently the world gives us clusters of related tasks to learn. When it does not, it is often straightforward to create additional tasks. For many domains, acquiring inductive bias by collecting additional teaching signal may be more practical than the traditional approach of codifying domain-specific biases acquired from human expertise. We call this approach Multitask Learning (MTL). Since much of the power of an inductive learner follows directly from its inductive bias, multitask learning may yield more powerful learning. An empirical example of multitask connectionist learning is presented where learning improves by training one network on several related tasks at the same time. Multitask decision tree induction is also outlined.", "role": "user" }, { "content": "[6] , which assumes that all layers are shared between tasks except for the final predictive layer, is the simplest way to implement a multi-task model. When the main task and auxiliary task are closely related, this approach has been shown to be an effective way to improve model performance [2] [4] [5] [1] . On the other hand, [3] find that it is better to make predictions for low-level auxiliary tasks at lower layers of a multi-layer MTL setup. They also suggest that under the hard-parameter framework auxiliary tasks need to be sufficiently similar to the main task for MTL to improve over the single-task baseline.", "role": "assistant" } ]

[ { "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: Effect of Replacing Sugar with Non-Caloric Sweeteners in Beverages on the Reward Value after Repeated Exposure\nSummary: Background The reward value of food is partly dependent on learned associations . It is not yet known whether replacing sugar with non-caloric sweeteners in food is affecting long-term acceptance . Objective To determine the effect of replacing sugar with non-caloric sweeteners in a nutrient-empty drink ( soft drink ) versus nutrient-rich drink ( yoghurt drink ) on reward value after repeated exposure . Design We used a r and omized crossover design whereby forty subjects ( 15 men , 25 women ) with a mean±SD age of 21±2 y and BMI of 21.5±1.7 kg/m2 consumed a fixed portion of a non-caloric sweetened ( NS ) and sugar sweetened ( SS ) versions of either a soft drink or a yoghurt drink ( counterbalanced ) for breakfast which were distinguishable by means of colored labels . Each version of a drink was offered 10 times in semi-r and om order . Before and after conditioning the reward value of the drinks was assessed using behavioral tasks on wanting , liking , and expected satiety . In a subgroup ( n=18 ) fMRI was performed to assess brain reward responses to the drinks . Results Outcomes of both the behavioral tasks and fMRI showed that conditioning did not affect the reward value of the NS and SS versions of the drinks significantly . Overall , subjects preferred the yoghurt drinks to the soft drinks and the ss drinks to the NS drinks . In addition , they expected the yoghurt drinks to be more satiating , they reduced hunger more , and delayed the first eating episode more . Conditioning did not influence these effects . Conclusion Our study showed that repeated consumption of a non-caloric sweetened beverage , instead of a sugar sweetened version , appears not to result in changes in the reward value . It can not be ruled out that learned associations between sensory attributes and food satiating capacity which developed preceding the conditioning period , during lifetime , affected the reward value of the drinks\n\n\nReport 2:\nTitle: Representation of pleasant and aversive taste in the human brain.\nSummary: In this study , the representation of taste in the orbitofrontal cortex was investigated to determine whether or not a pleasant and an aversive taste have distinct or overlapping representations in this region . The pleasant stimulus used was sweet taste ( 1 M glucose ) , and the unpleasant stimulus was salt taste ( 0.1 M NaCl ) . We used an ON/OFF block design in a 3 T fMRI scanner with a tasteless solution delivered in the OFF period to control for somatosensory or swallowing-related effects . It was found that parts of the orbitofrontal cortex were activated ( P < 0.005 corrected ) by glucose ( in 6/7 subjects ) and by salt ( in 6/7 subjects ) . In the group analysis , separate areas of the orbitofrontal cortex were found to be activated by pleasant and aversive tastes . The involvement of the amygdala in the representation of pleasant as well as aversive tastes was also investigated . The amygdala was activated ( region of interest analysis , P < 0.025 corrected ) by the pleasant taste of glucose ( 5/7 subjects ) as well as by the aversive taste of salt ( 4/7 subjects ) . Activation by both stimuli was also found in the frontal opercular/insular ( primary ) taste cortex . We conclude that the orbitofrontal cortex is involved in processing tastes that have both positive and negative affective valence and that different areas of the orbitofrontal cortex may be activated by pleasant and unpleasant tastes . We also conclude that the amygdala is activated not only by an affectively unpleasant taste , but also by a taste that is affectively pleasant , thus providing evidence that the amygdala is involved in effects produced by positively affective as well as by negatively affective stimuli\n\n\nReport 3:\nTitle: Visual-Gustatory Interaction: Orbitofrontal and Insular Cortices Mediate the Effect of High-Calorie Visual Food Cues on Taste Pleasantness\nSummary: Vision provides a primary sensory input for food perception . It raises expectations on taste and nutritional value and drives acceptance or rejection . So far , the impact of visual food cues varying in energy content on subsequent taste integration remains unexplored . Using electrical neuroimaging , we assessed whether high- and low-calorie food cues differentially influence the brain processing and perception of a subsequent neutral electric taste . When viewing high-calorie food images , participants reported the subsequent taste to be more pleasant than when low-calorie food images preceded the identical taste . Moreover , the taste-evoked neural activity was stronger in the bilateral insula and the adjacent frontal operculum ( FOP ) within 100 ms after taste onset when preceded by high- versus low-calorie cues . A similar pattern evolved in the anterior cingulate ( ACC ) and medial orbitofrontal cortex ( OFC ) around 180 ms , as well as , in the right insula , around 360 ms . The activation differences in the OFC correlated positively with changes in taste pleasantness , a finding that is an accord with the role of the OFC in the hedonic evaluation of taste . Later activation differences in the right insula likely indicate revaluation of interoceptive taste awareness . Our findings reveal previously unknown mechanisms of cross-modal , visual-gustatory , sensory interactions underlying food evaluation\n\n\nReport 4:\nTitle: Consumption of caloric and non-caloric versions of a soft drink differentially affects brain activation during tasting\nSummary: Sensory-specific satiety , which is defined as a relative decrease in pleasantness , is increased by greater oro-sensory stimulation . Both sensory-specific satiety and pleasantness affect taste activation in the orbitofrontal cortex . In contrast , metabolic satiety , which results from energy intake , is expected to modulate taste activation in reward areas . The aim of this study was to determine the effects of the amount of oro-sensory stimulation and energy content on consumption-induced changes in taste activation . Ten men participated in a 2 × 2 r and omized crossover study . Subjects were scanned twice using functional magnetic resonance imaging : after fasting for at least 2h and after treatment , on four occasions . Treatment consisted of the ingestion of 450 mL of orangeade ( sweetened with 10 % sucrose or non-caloric sweeteners ) at 150 mL/min , with either small ( 5 mL ) or large ( 20 mL ) sips . During scanning , subjects alternately tasted orangeade , milk and tomato juice and rated its pleasantness . Before and after the scans , subjects rated pleasantness , prospect i ve consumption , desire to eat and sweetness for all tastants . Main findings were that , before treatment , the amygdala was activated more by non-caloric than by caloric orangeade . Caloric orangeade activated part of the striatum before , but not after treatment . We observed no main effects of sip size on taste activation and no interaction between sip size and caloric content . In conclusion , the brain responds differentially to caloric and non-caloric versions of a sweet drink and consumption of calories can modulate taste activation in the striatum . Further research is needed to confirm that the observed differences are due to caloric content and not to ( subliminal ) differences in the sensory profile . In addition , implication s for the effectiveness of non-caloric sweeteners in decreasing energy intake need to be established\n\n\nReport 5:\nTitle: Hunger is the best spice: An fMRI study of the effects of attention, hunger and calorie content on food reward processing in the amygdala and orbitofrontal cortex\nSummary: Research indicates that dysfunctional food reward processing may contribute to pathological eating behaviour . It is widely recognized that both the amygdala and the orbitofrontal cortex ( OFC ) are essential parts of the brain 's reward circuitry . The aims of this fMRI study were ( 1 ) to examine the effects of food deprivation and calorie content on reward processing in the amygdala and the OFC , and ( 2 ) to examine whether an explicit evaluation of foods is necessary for OFC , but not amygdalar activity . Addressing the first aim , healthy females were presented with high and low calorie food pictures while being either hungry or satiated . For the second aim , attention focus was manipulated by directing participants ' attention either to the food or to a neutral aspect . This study shows that hunger interacts with the energy content of foods , modulating activity in the posterior cingulate cortex , medial OFC , insula , cau date putamen and fusiform gyrus . Results show that satiated healthy females show an increased reward processing in response to low calorie foods . Confirming our hypothesis , food deprivation increased activity following the presentation of high calorie foods , which may explain why treatments of obesity energy restricting diets often are unsuccessful . Interestingly , activity in both the amygdala and mOFC was only evident when participants explicitly evaluated foods . However , attention independent activity was found in the mPFC following the high calorie foods cues when participants where hungry . Current findings indicate that research on how attention modulates food reward processing might prove especially insightful in the study of the neural substrates of healthy and pathological eating behaviour\n\n\nReport 6:\nTitle: A preliminary study of the human brain response to oral sucrose and its association with recent drinking.\nSummary: BACKGROUND A preference for sweet tastes has been repeatedly shown to be associated with alcohol preference in both animals and humans . In this study , we tested the extent to which recent drinking is related to blood oxygen level-dependent ( BOLD ) activation from an intensely sweet solution in orbitofrontal areas known to respond to primary rewards . METHODS Sixteen right-h and ed , non-treatment-seeking , healthy volunteers ( mean age : 26 years ; 75 % male ) were recruited from the community . All underwent a taste test using a range of sucrose concentrations , as well as functional magnetic resonance imaging ( fMRI ) during pseudor and om , event-driven stimulation with water and a 0.83 M concentration of sucrose in water . RESULTS [ Sucrose > water ] provoked a significant BOLD activation in primary gustatory cortex and amygdala , as well as in the right ventral striatum and in bilateral orbitofrontal cortex . Drinks/drinking day correlated significantly with the activation as extracted from the left orbital area ( r = 0.52 , p = 0.04 after correcting for a bilateral comparison ) . Using stepwise multiple regression , the addition of rated sucrose liking accounted for significantly more variance in drinks/drinking day than did left orbital activation alone ( multiple R = 0.79 , p = 0.002 ) . CONCLUSIONS Both the orbitofrontal response to an intensely sweet taste and rated liking of that taste accounted for significant variance in drinking behavior . The brain response to sweet tastes may be an important phenotype of alcoholism risk", "role": "user" }, { "content": "We confirm the importance of primary taste areas for gustatory processing in human adults .\nWe also provide tentative evidence for reward-related cau date activity in relation to the sweet taste of caloric sugars .", "role": "assistant" } ]

[ { "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:\nWehavealsofoundthatmalePGC-1alpha-deficientmicearesomewhatprotectedagainstdiet-inducedobesity(FigureS4).", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nKatanin is a microtubule-severing protein activated in mitotic Xenopus extracts (Vale, 1991; McNally and Thomas, 1998) and concentrated at mitotic spindle poles.", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "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: Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy\nContent:\nAbstract:\nHuman T-lymphotropic virus type 1( HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis( HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon( IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.\nIntroduction:\nHTLV-1 is an exogenous retrovirus that is widespread in the tropics and subtropics[1],[2]. Chronic infection is characterised by a strong humoral and cellular immune response against the virus[3]. Whilst the majority of HTLV-1 carriers efficiently control the infection and remain clinically asymptomatic lifelong, some 1–4% develop a neurodegenerative inflammatory disorder known as HAM/TSP[1]. Here, mononuclear cell infiltrates in the central nervous system are associated with myelin and axonal destruction[1],[4]. Clinically, patients present with multiple sclerosis-like symptoms including progressive spastic paraparesis, sensory loss and disturbances of bladder or bowel function[1],[5]. The sequence and nature of the events that lead to the observed neuronal damage in HAM/TSP are not known and because of the lack of a suitable animal model a direct investigation of pathogenic mechanisms is not possible. Thus, clinical management of HAM/TSP is unsatisfactory and current treatment remains only palliative. To date, the strongest correlate of risk of HAM/TSP remains a high HTLV-1 proviral load[6], i. e. the percentage of peripheral blood mononuclear cells that carry the provirus. The proviral load can differ among individuals by 1000-fold; the mean proviral load is ∼15-fold higher in patients with HAM/TSP than in asymptomatic HTLV-1 carriers( ACs)[6]. However, a significant proportion of infected individuals who present with high HTLV-1 proviral loads never develop the inflammatory disease, suggesting that additional factors contribute to the pathogenesis of HAM/TSP. Although other risk factors have been proposed, few differ systematically between ACs and patients with HAM/TSP after normalisation for proviral load: the frequency of certain lymphocyte subsets( HTLV-1-specific CD4+ T cells[7]; FoxP3+CD4+ T cells[8]; natural killer( NK) cells[9]); the level of expression of HTLV-1 genes[10] and the pattern of integration of the HTLV-1 provirus in the host cell genome[11]. However, the contribution of each of these factors to the pathology of HAM/TSP is not known. Blood transcriptional profiles have revealed previously unsuspected pathways of pathogenesis in autoimmune and infectious diseases[12],[13]. Exposure to host or pathogen-derived immunogenic factors trigger changes in gene expression in peripheral blood leukocyte populations that reflect the host immune response mounted against pathogens as well as pathologic conditions of the immune system[14]. Thus, patient blood samples provide an easily accessible source of immunophenotypic information and are of particular value in HTLV-1 infection, in which CD4+ T cells constitute the major viral reservoir[15]. Previous studies on gene expression in HTLV-1 infection have focused on specific cell subpopulations( HTLV-1-infected cells, CD4+ T cells, CD8+ T cells)[16]–[21]. In contrast, whole blood studies integrate gene expression profiles of all leukocytes. Thus, the resulting transcriptional profiles provide a comprehensive overview of the status of the immune system and associated pathological changes. In this study, we aimed to identify the principal biological pathways and cell types that are deregulated in HTLV-1 infection and HAM/TSP by quantifying and analyzing differences in blood gene expression patterns of HTLV-1-infected individuals and seronegative controls. Unexpectedly, although the class I-restricted T cell response plays a pivotal role in controlling viral replication and risk of disease[22],[23], the outstanding differences in the transcriptional patterns lay in IFN-stimulated genes. We found that over-expression of a distinct subset of IFN-stimulated genes – a ‘transcriptional signature’ – was associated with presence of the inflammatory disease and positively correlated with clinical severity of HAM/TSP. This IFN-inducible transcriptional signature was absent in patients with multiple sclerosis, suggesting distinct pathogenetic pathways in the two diseases despite their clinical similarities. We conclude that IFNs do not efficiently control chronic HTLV-1 infection but may instead contribute to HAM/TSP pathogenesis. Our results identify IFN signaling as a key factor and a novel therapeutic target in HAM/TSP.\nDiscussion:\nDespite the growing understanding of the mechanisms of HTLV-1 persistence, little is known about the pathogenesis of HAM/TSP and importantly, what distinguishes hosts who develop the disease from those who remain asymptomatic. The aim of this study was to identify biological pathways and molecules in whole blood gene expression profiles of asymptomatic HTLV-1 carriers and patients with HAM/TSP to generate new hypotheses on the mechanisms of viral persistence and the pathogenesis of HAM/TSP pathology. We found that the presence of HAM/TSP was associated with over-expression of a distinct subset of IFN-stimulated genes in circulating leukocytes. The IFN-inducible signature was absent in healthy HTLV-1 carriers and correlated positively with the clinical severity of the inflammatory disease. Gene expression signatures may reflect either differences in the frequencies of specific cell populations or a difference in gene expression at the single-cell level. We observed no significant differences in the frequencies of the blood cell populations( Figure S4): we conclude that the observed IFN-inducible signature resulted from a difference in the intensity of expression of IFN-stimulated genes at the single-cell level. Expression of IFN-stimulated genes was evident in neutrophils and monocytes, but not in T cells, which are the cellular reservoir of HTLV-1 in vivo[15]. It is therefore likely that the HAM/TSP-specific transcriptional profile originated from exposure to IFNs in vivo rather than direct activation of the IFN-response pathway in infected cells. The IFN-stimulated genes identified in HAM/TSP can be induced by both type I and type II IFNs[33] and we did not detect abnormal plasma levels of type I or type II IFNs in patients with HAM/TSP, perhaps because of their short half-lives in blood[34]. However, CD8+ T cells from patients with HAM/TSP produced high levels of IFN-γ in response to a non-specific stimulus ex vivo, which may reflect higher local production of IFN-γ in vivo. IFN-stimulated genes have been shown to mediate potent antiviral and neuroprotective effects[32],[35]. However, several recent studies have implicated IFNs in the pathogenesis of autoimmune disorders such as rheumatoid arthritis[36], systemic lupus erythematosus[37], systemic sclerosis[38] and Sjögren's syndrome[39]. It has been hypothesized that IFNs trigger autoimmunity by promoting the activation and survival of autoreactive T and B cells in genetically predisposed individuals[40]. However, there is little evidence for antigen-specific autoreactivity in HAM/TSP[41]; instead, the risk of disease is linked to high frequencies of poor quality antiviral cytotoxic T cells[42]; i. e. low avidity of HTLV-1 antigen recognition and reduced lytic efficiency. IFNs may contribute to immunopathological processes in the central nervous system by stimulating and propagating a detrimental immune response to HTLV-1; however, the precise pathways responsible have yet to be determined. Despite similarities in clinical presentation the gene expression profiles of HAM/TSP and multiple sclerosis were distinct. The IFN-inducible signature present in HAM/TSP was absent in multiple sclerosis, suggesting that different pathogenetic mechanisms contribute to the axonal damage observed in both diseases. A recent study reported the expression of a subset of type I IFN-stimulated genes in 50% of patients with a particular clinical subtype of multiple sclerosis( relapsing-remitting)[43]. However, in agreement with our findings there was little overlap between the IFN-stimulated genes identified in HAM/TSP and the genes whose expression was altered in multiple sclerosis. Furthermore, we found that different subsets of IFN-stimulated genes are actively expressed in other diseases with IFN-inducible signatures( Figure S3). There are more than 300 known IFN-stimulated genes, the individual actions of many of which are largely uncharacterized. Thus, it is conceivable that there are cell-type-, pathogen- and disease-specific patterns of IFN-stimulated gene expression that contribute to a beneficial or detrimental outcome of immunological processes. Type I IFN therapy is effective in controlling certain persistent viral infections[44], and there is evidence that it can slow down disease progression in multiple sclerosis[45]. However, clinical trials assessing the benefit of IFN-α and IFN-β therapy in the treatment of HAM/TSP have been less successful[46]; few patients showed any improvement and the overall clinical benefit was limited. Although a beneficial net effect of systemically administered IFN cannot be excluded, two findings in the present study support the clinical observation that IFNs do not effectively control HTLV-1 infection:( i) over-expression of IFN-stimulated genes was not observed in healthy HTLV-1 carriers who efficiently control the infection;( ii) while IFN-α reduced the expression of the structural viral protein Gag as reported previously[47], we found that IFN treatment did not affect the expression of the viral transactivator protein Tax or HBZ mRNA. HTLV-1 Tax is essential to the viral life cycle as it has been shown to drive viral replication, promote host cell proliferation and viral cell-to-cell spread[48],[49]. HBZ has been shown to down-modulate Tax function[50],[51] whilst promoting infectivity and viral persistence[52]. A recent study has linked elevated HBZ mRNA levels to increased clinical severity of HAM/TSP[53]. We found that IFN treatment increased HBZ expression but this observation did not reach statistical significance. We conclude that although type I IFN treatment may decrease the production of viral structural complexes, i. e. capsids, it does not completely abrogate viral activity and proliferation of infected cells. In addition, HTLV-1 viral proteins have been reported to manipulate and evade the IFN response by suppressing interferon regulatory factors and up-regulating suppressors of IFN signaling[16],[54],[55]. Perturbations of the p53 signaling pathway were evident in all HTLV-1 infected individuals, irrespective of disease status. The p53 signaling pathway prevents cell proliferation of genomically unstable cells by promoting cell cycle arrest, senescence and apoptosis[56]. Altered p53 signaling could reflect a highly active immune response with rapid cell turnover and clonal expansion. However, abnormal p53 signaling has been implicated in HTLV-1-mediated leukemogenesis[49]. The p53 protein itself is usually intact in HTLV-1 leukemic cells, but there is evidence that the virus inhibits p53-induced anti-viral responses by targeting other components of the p53 signaling pathway[57],[58]. This hypothesis is supported by our finding that HTLV-1-positivity was associated with low mRNA levels of molecules involved in the detection of DNA damage, i. e. the ataxia telangiectasia mutated protein( ATM) and the DNA-dependent protein kinase( PRKDC). The protein products of these genes sense dsDNA breaks due to viral integration into the cell's genome and induce cell cycle arrest and/or apoptosis[59]. Decreased expression of ATM and PRKDC could therefore facilitate the survival of genomically unstable HTLV-1-infected cells and allow premature DNA replication in the presence of genomic lesions, thus contributing to the oncogenic potential of HTLV-1. In summary, our study revealed that over-expression of a specific subset of IFN-stimulated genes distinguishes patients with HAM/TSP from asymptomatic HTLV-1 carriers, which indicates an unexpected role of IFN-stimulated genes in the pathogenesis of central nervous system inflammation in HTLV-1 infection. This finding opens new avenues for research on HAM/TSP pathogenesis and new areas of therapeutic intervention.", "role": "user" }, { "content": "Infection with the Human T Lymphotropic virus is widespread in the tropics and subtropics , where it causes a chronic disabling disease of the nervous system abbreviated as HAM/TSP . There is no effective treatment available for HAM/TSP , because it is not understood how the virus causes the neuronal damage that results in the clinical symptoms of weakness and paralysis of the legs . Here , we compared the frequencies of cell populations and gene expression profiles from diseased and asymptomatic HTLV-1 carriers to identify abnormalities in biological pathways that cause HAM/TSP . We discovered a distinct group of genes that is over-expressed in white blood cells in patients with HAM/TSP , but not asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis . The expression of these genes is induced by interferons , a group of anti-viral proteins that are usually beneficial to the host but can also cause inflammation . We also found that interferons did not efficiently suppress HTLV-1 protein expression in vitro . We conclude that interferons do not control chronic HTLV-1 infection but instead contribute to the development of HAM/TSP . Our study provides new insights into the development of HTLV-1-associated diseases and opens new areas of therapeutic intervention .", "role": "assistant" } ]

[ { "content": "Consider the following research inquiry and associated key terms. Review the dataset summaries provided and determine which datasets are suitable for addressing the research question. Base your decision on your understanding of machine learning datasets.\nProvide your answer as a JSON list. For example, for the inquiry \"Semi supervised image classification\", a possible response could be: [\"CIFAR-10\", \"CIFAR-100\"]. Ensure the response contains only the dataset names in JSON format.\n\nResearch Inquiry: A system for actor-action semantic segmentation.\n\nKey Terms: classification images top-view grid map sequences autonomous driving\n\nDataset Summaries:\nMoVi: Contains 60 female and 30 male actors performing a collection of 20 predefined everyday actions and sports movements, and one self-chosen movement.\nLetter: Letter Recognition Data Set is a handwritten digit dataset. The task is to identify each of a large number of black-and-white rectangular pixel displays as one of the 26 capital letters in the English alphabet.\nKTH: The efforts to create a non-trivial and publicly available dataset for action recognition was initiated at the KTH Royal Institute of Technology in 2004. The KTH dataset is one of the most standard datasets, which contains six actions: walk, jog, run, box, hand-wave, and hand clap.\nEgoHands: The EgoHands dataset contains 48 Google Glass videos of complex, first-person interactions between two people. The main intention of this dataset is to enable better, data-driven approaches to understanding hands in first-person computer vision.\nIMDB-BINARY: IMDB-BINARY is a movie collaboration dataset that consists of the ego-networks of 1,000 actors/actresses who played roles in movies in IMDB. In each graph, nodes represent actors/actress, and there is an edge between them if they appear in the same movie.\nUSPS: USPS is a digit dataset automatically scanned from envelopes by the U.S. Postal Service containing a total of 9,298 16×16 pixel grayscale samples; the images are centered, normalized and show a broad range of font styles.\n\nDataset Options: A: MoVi B: Letter C: KTH D: EgoHands E: IMDB-BINARY F: USPS", "role": "user" }, { "content": "[\"Letter\", \"USPS\"]", "role": "assistant" } ]

[ { "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 paper we propose a novel easily reproducible technique to attack the best public Face ID system ArcFace in different shooting conditions. To create an attack, we print the rectangular paper sticker on a common color printer and put it on the hat. The adversarial sticker is prepared with a novel algorithm for off-plane transformations of the image which imitates sticker location on the hat. Such an approach confuses the state-of-the-art public Face ID model LResNet100E-IR, ArcFace@ms1m-refine-v2 and is transferable to other Face ID models.\n\nCited Works Summary:\n[1]: Deep neural networks are highly expressive models that have recently achieved state of the art performance on speech and visual recognition tasks. While their expressiveness is the reason they succeed, it also causes them to learn uninterpretable solutions that could have counter-intuitive properties. In this paper we report two such properties. First, we find that there is no distinction between individual high level units and random linear combinations of high level units, according to various methods of unit analysis. It suggests that it is the space, rather than the individual units, that contains of the semantic information in the high layers of neural networks. Second, we find that deep neural networks learn input-output mappings that are fairly discontinuous to a significant extend. We can cause the network to misclassify an image by applying a certain imperceptible perturbation, which is found by maximizing the network's prediction error. In addition, the specific nature of these perturbations is not a random artifact of learning: the same perturbation can cause a different network, that was trained on a different subset of the dataset, to misclassify the same input.\n\n[2]: Recent work has demonstrated that neural networks are vulnerable to adversarial examples, i.e., inputs that are almost indistinguishable from natural data and yet classified incorrectly by the network. In fact, some of the latest findings suggest that the existence of adversarial attacks may be an inherent weakness of deep learning models. To address this problem, we study the adversarial robustness of neural networks through the lens of robust optimization. This approach provides us with a broad and unifying view on much of the prior work on this topic. Its principled nature also enables us to identify methods for both training and attacking neural networks that are reliable and, in a certain sense, universal. In particular, they specify a concrete security guarantee that would protect against any adversary. These methods let us train networks with significantly improved resistance to a wide range of adversarial attacks. They also suggest the notion of security against a first-order adversary as a natural and broad security guarantee. We believe that robustness against such well-defined classes of adversaries is an important stepping stone towards fully resistant deep learning models.\n\n[3]: Several machine learning models, including neural networks, consistently misclassify adversarial examples---inputs formed by applying small but intentionally worst-case perturbations to examples from the dataset, such that the perturbed input results in the model outputting an incorrect answer with high confidence. Early attempts at explaining this phenomenon focused on nonlinearity and overfitting. We argue instead that the primary cause of neural networks' vulnerability to adversarial perturbation is their linear nature. This explanation is supported by new quantitative results while giving the first explanation of the most intriguing fact about them: their generalization across architectures and training sets. Moreover, this view yields a simple and fast method of generating adversarial examples. Using this approach to provide examples for adversarial training, we reduce the test set error of a maxout network on the MNIST dataset.", "role": "user" }, { "content": "In [1] the authors propose to use a quasi-newton L-BFGS-B method to solve the task formulated above. Simpler and more efficient method called Fast Gradient-Sign Method (FGSM) is proposed in [3] . This method suggests using the gradients with respect to the input and constructing an adversarial image using the following formula: @math (or @math in case of targeted attack). Here @math is a loss function (e.g. cross-entropy) which depends on the weights of the model @math , input @math , and label @math . Note that usually one step is not enough and we need to do a number of iterations described above each time using the projection to the initial input space (e.g. @math ). It is called projected gradient descent (PGD) [2] .", "role": "assistant" } ]

[ { "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\nWe present clinical and chest computed tomography (CT) features of 5 cases of pediatric patients with 2019 novel coronavirus. Two patients had fever and dry cough, whereas the rest of 3 patients were asymptomatic. Three patients had unilateral ground glass opacities with or without consolidation in the subpleural region on high-resolution chest CT, 1 patient had bilateral ground glass opacities, and 1 patient was negative for CT. We note that up to 66.7% asymptomatic patients had pulmonary lesions, so the asymptomatic children with Wuhan contact are recommended to do a 2019 novel coronavirus real-time fluorescence polymerase chain reaction screening. Unlike adult patients, only a small amount of patients had multilobes affected, so we speculate that the pediatric patients generally have milder CT findings than adults.", "role": "user" }, { "content": "[\"Case Report\"]", "role": "assistant" } ]

[ { "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:\nFor ego-motion estimation, the feature representation of the scenes is crucial. Previous methods indicate that both the low-level and semantic feature-based methods can achieve promising results. Therefore, the incorporation of hierarchical feature representation may benefit from both methods. From this perspective, we propose a novel direct feature odometry framework, named DFO, for depth estimation and hierarchical feature representation learning from monocular videos. By exploiting the metric distance, our framework is able to learn the hierarchical feature representation without supervision. The pose is obtained with a coarse-to-fine approach from high-level to low-level features in enlarged feature maps. The pixel-level attention mask can be self-learned to provide the prior information. In contrast to the previous methods, our proposed method calculates the camera motion with a direct method rather than regressing the ego-motion from the pose network. With this approach, the consistency of the scale factor of translation can be constrained. Additionally, the proposed method is thus compatible with the traditional SLAM pipeline. Experiments on the KITTI dataset demonstrate the effectiveness of our method.\n\nCited Works Summary:\n[1]: The dominant paradigm for feature learning in computer vision relies on training neural networks for the task of object recognition using millions of hand labelled images. Is it possible to learn useful features for a diverse set of visual tasks using any other form of supervision? In biology, living organisms developed the ability of visual perception for the purpose of moving and acting in the world. Drawing inspiration from this observation, in this work we investigate if the awareness of egomotion can be used as a supervisory signal for feature learning. As opposed to the knowledge of class labels, information about egomotion is freely available to mobile agents. We show that given the same number of training images, features learnt using egomotion as supervision compare favourably to features learnt using class-label as supervision on visual tasks of scene recognition, object recognition, visual odometry and keypoint matching.", "role": "user" }, { "content": "These methods may fail under certain conditions such as low texture, stereo ambiguities and occlusions. The quality of feature points is essential for the feature-based SLAM method. Agrawal al [1] show that features learned from a convolution neural network outperform the traditional hand-designed features. Learning-based slam may become a promising direction.", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nCognitive function was measured using a computerized task battery that measures multiple modalities of cognitive performance (Green et al, 1995b).", "role": "user" }, { "content": "Method", "role": "assistant" } ]

[ { "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: Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction\nContent Overview:\nAbstract:\nImmunotherapy, represented by immune checkpoint inhibitors( ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score( TIGS), which combines tumor mutational burden( TMB) and an expression signature of the antigen processing and presenting machinery( APM). In both correlation with pan-cancer ICI objective response rates( ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor-inherent biomarker for ICI-response prediction.\nIntroduction:\nImmunotherapy, represented by immune checkpoint inhibitors( ICI), including anti-PD-1 antibodies, anti-PD-L1 antibodies, anti CTLA-4 antibodies or their combinations, is transforming the treatment of cancer. Compared to conventional therapies, ICI can induce significantly improved clinical responses in patients with various types of late-stage metastatic cancers. However, the majority of unselected patients will not respond to ICI. Most tumor types show response rates below 40% to PD-1 inhibition, and the response rates of each tumor type are reported to be correlated with the tumor mutational burden( TMB) of that tumor type( Yarchoan et al., 2017). Multiple factors are reported to affect ICI effectiveness, including: PD-L1 expression( Herbst et al., 2014; Shukuya and Carbone, 2016), TMB( Rizvi et al., 2015; Snyder et al., 2014), DNA mismatch repair deficiency( Le et al., 2015), the degree of cytotoxic T cell infiltration( Tang et al., 2016), mutational signature( Miao et al., 2018; Wang et al., 2018), antigen presentation defects( Chowell et al., 2018; Zaretsky et al., 2016), interferon signaling( Ayers et al., 2017), tumor aneuploidy( Davoli et al., 2017) and T-cell signatures( Jiang et al., 2018). These biomarkers have various rates of accuracy and utility, and the identification of a robust ICI-response biomarker is still a critical challenge in the field( Nishino et al., 2017). ICI help a patient’s immune system to recognize and attack cancer cells. The immunogenicity of cancer cells is the fundamental determinant of ICI response. Theoretically, tumors of very low or no immunogenicity will not respond to therapeutic strategies that enhance the immune response. Hence, ICI can only be used to treat tumors that have sufficient immunogenicity. Furthermore, enhancing tumor immunogenicity can potentially transform an immunotherapy-non-responsive tumor into an immunotherapy-responsive tumor. The actual immunogenicity of a tumor is not easy to measure. In theory, tumor immunogenicity is determined by the tumor cell itself, and is also influenced by factors related to the tumor microenvironment, such as the functioning of professional antigen-presenting cells like dendritic cells( DCs)( Mellman and Steinman, 2001). Fundamental determinants of tumor immunogenicity include tumor antigenicity, and antigen processing and presenting efficiency( Blankenstein et al., 2012). Antigen presentation defects have already been shown to contribute to ICI-response failure( Chowell et al., 2018; Zaretsky et al., 2016). To measure antigen processing and presenting efficiency systematically, we applied a gene set variation analysis( GSVA) method to generate an antigen processing and presenting machinery( APM) score( APS)( Hänzelmann et al., 2013), which was calculated from the mRNA expression status of APM genes. Tumor immunogenicity score( TIGS) was then calculated by combining the APM score and the TMB. The antigen-presentation gene expression signature and tumor immunogenicity landscape of 32 cancer types from The Cancer Genome Atlas( TCGA) project are provided. TIGS exhibits improved performance in both pan-cancer ICI objective response rate( ORR) correlation and accuracy of ICI clinical response prediction when compared with TMB. Our results suggest that TIGS represents a novel and effective tumor-inherent biomarker for the prediction of immunotherapy response.\nDiscussion:\nImmunogenicity is an important inherent feature of tumor cells. This feature is determined by the tumor cell itself, and is also influenced by the tumor microenvironment. Two key determinants of tumor immunogenicity are tumor antigenicity and the ability to present such antigenicity. Here, we proposed an initial method to measure the immunogenicity of a tumor. This measured tumor immunogenicity score( TIGS) shows consistently improved correlations with immunotherapy ORR in various types of cancer when compared to TMB. TIGS also shows improved performance in ICI clinical response prediction when compared with TMB and other biomarkers that are based on gene expression profiling( TIDE, interferon gamma signature and so on) in both prediction accuracy and pan-cancer applicability. Furthermore, our tumor-immunogenicity-based biomarker could guide the treatment to transform some ICI-non-responsive tumors into ICI-responsive tumors. Stimulating the APM pathway could enhance tumor immunogenicity, and possibly ICI responsiveness. Our study demonstrates that TIGS is an effective biomarker for ICI-response prediction. TIGS capture two key aspects of tumor immunogenicity, antigen presentation and tumor antigenicity, which could be the reason for its improved performance in ICI-response prediction when compared to known biomarkers. Furthermore, our formula for TIGS calculation can point to a new way to transform some ICI-non-responsive tumors into responsive tumors by enhancing the tumor immunogenicity. One approach is to enhance the efficiency of antigen presentation. Our GSEA indicates that interferon signaling is the top gene signature associated with APS-High, and interferon signaling has been reported to influence APM gene expression( Beatty and Paterson, 2001; Ikeda et al., 2002). We may enhance antigen presentation by stimulating interferon signaling in patients who are initially not responsive to ICI, especially in cancer types that have low APS, such as prostate cancer and breast cancer. Our study identified several cancer types in which antigen presentation status makes a significant contribution in ICI response. Breast cancer and prostate cancer have usual TMB but fairly low ICI-response rates, probably because of low APS; renal clear cell carcinoma has good ICI response rate, possibly as a result of high APS. Furthermore, our linear correlation formula— ORR = 21. 4 × TIGS – 2. 7( this formula is based on the data in Figure 4C)— can be used to make hypotheses with respect to the ORR in tumor types for which anti–PD-1 therapy has not been explored. For example, we anticipate a clinically meaningful ORR of 12. 3%( 95% confidence interval[CI], 8. 8% to 15. 8%) for uterine corpus endometrial carcinoma( UCEC) on the basis of a median TIGS of 0. 7. This study reports the first quantification of tumor immunogenicity. Several situations need to be considered for future improvement of this quantification. First, other factors including tumor germline antigen, copy number variation status, tumor purity and intra-tumor heterogeneity should also be considered to enable more accurate measurement of the antigenicity of tumor cells. Second, for quantifying antigen presentation efficiency, APM protein expression and function assessment will be more accurate than APM mRNA expression measurement. Third, other factors that influence TIGS should also be considered, including the function of professional antigen presentation cells( dendritic cells for example) in the immune microenvironment. This manuscript primarily focused on the cytosolic or endogenous neoantigen presentation pathway mediated by MHC class I. This does not mean that the potential neoantigen presentation by MHC class II is not important, and further studies are needed to improve the methods for the quantification of antigen presentation in cancer patients. In addition, a sex difference in the predictive power of TMB has been reported recently in lung cancer( Wang et al., 2019b; Wang et al., 2019c). To explore the potential sex difference in TIGS’s predictive power, we need larger datasets with more patients. TIGS is an extension and enhancement of the immunotherapy biomarker TMB. TIGS is tumor cell-based, and is distinct from the recent immunotherapy biomarkers immunophenoscore( Charoentong et al., 2017) or T-cell dysfunction and exclusion signature( Jiang et al., 2018). Both of these ICI biomarkers are based on tumor immune microenvironment. As a tumor inherent biomarker, TIGS can not only be used for predicting immunotherapy response, but also point ways to manipulate the immunogenicity of tumors, and consequently the response to immunotherapy.", "role": "user" }, { "content": "In the last decade a new kind of cancer therapy , called immunotherapy , has changed how doctors treat cancer patients . These therapies mean that previously incurable cancers , including some skin and lung cancers , can now sometimes be cured . Immunotherapy does this by activating the patient’s own immune system so that it will attack the cancer cells . But for this to work , the cancer cells , much like invading bacteria or viruses , need to be recognized as foreign . Cancer cells contain many DNA mutations that cause the cell to make mutated proteins it would not normally make . These proteins betray the cancer cells as foreign to the immune system . The extent to which cancer cells make mutated proteins – also called the ‘tumor mutational burden’ – can sometimes predict whether a patient will respond to immunotherapy . In general , patients with a high mutational burden respond well to immunotherapy , but overall fewer than one in five cancer patients are cured by this treatment . An important question is whether there are better ways of predicting if a cancer patient will respond to immunotherapy . Wang et al . have addressed this problem by adding a second variable to the prediction . Not only do cancer cells have to make mutated proteins , but these proteins also have to be ‘seen’ by immune cells . Cancer cells , like normal cells , have mechanisms to present protein fragments to immune cells . Wang et al . hypothesized that patients with a high mutational burden would not respond to immunotherapy if they were lacking the machinery required for presenting protein fragments . The experiments revealed that measuring both tumor mutational burden and the levels of the machinery that presents protein fragments resulted in better predictions of patients’ responses to immunotherapy than measuring tumor mutational burden alone . Additionally , this new way of predicting responses to immunotherapy was successful across many different cancer types . The combined measurement of these two variables could be applied in clinical practice as a way to predict cancer patients’ response to immunotherapy . This should allow doctors to determine which course of treatment will work best for a specific patient . The results also suggest that inducing tumor cells to produce more of the machinery that presents protein fragments to the immune system could increase their responsiveness to immunotherapy . In the future , predicting how well a patient will respond to immunotherapy could become even more accurate by incorporating additional variables .", "role": "assistant" } ]

[ { "content": "You will be presented with the full text of a scientific research paper. Write an abstract summarizing the key points. Your response should contain only the abstract without any other text.\n\nArticle text:\nastronomers commonly make the copernican assumption that our milky way is in no way unusual ; then they can exploit the fact that we live in it to study galaxy formation in special detail .\npast assumptions about our galactic bulge grew out of our developing understanding of galaxy formation .\nit is well known that spiral galaxies consist of three main components , an invisible dark matter halo , an embedded , flat disk , and a central bulge .\nthe bulge of our galaxy is @xmath499% made of stars that are at least 5 gyr old @xcite with a wide range of metal abundances @xcite . in this respect and many others , big bulges are similar to ( diskless ) elliptical galaxies .\nthe formation of ellipticals is well understood .\nhierarchical gravitational clustering of initial fluctuations in the cosmological density results in galaxy collisions and mergers that scramble flat disks into rounder ellipticals @xcite .\nsignificant energy has been invested in developing this very successful theory of galaxy formation , and it was natural to think that our galactic bulge is a product of it . there is little danger that the picture is fundamentally wrong @xcite .\nbut it is incomplete .\nthe theme of this paper is that our galactic bulge is indeed normal but that it is prototypical of different formation processes than are usually assumed .\na complementary suite of evolution processes shapes isolated galaxies .\nthey evolve by rearranging energy and angular momentum ; this grows central components that masquerade as classical bulges but that formed directly out of disks without any collisions @xcite . to distinguish them from merger remnants , we call them `` pseudobulges '' .\nthey come in two varieties .\nsome are flattened ; they are grown out of disk gas transported inward by nonaxisymmetries such as bars .\nanother variety is recognized only in edge - on galaxies .\nwhen bars form out of disks , they buckle vertically and heat themselves into thickened structures that look box - shaped when seen edge - on @xcite .\nour galaxy contains such a box - shaped @xcite pseudobulge @xcite .\nthe identification of this boxy structure as an edge - on bar is particularly compelling because infrared imagery shows a parallelogram - shaped distortion @xcite that is naturally explained as a perspective effect : the near end of the bar is closer to us than the far end .\nso its vertical extent is taller on the near side than on the far side @xcite .\n@xcite developed the first rapidly rotating bar model that fitted this distortion .\nzhao s model was based on the @xcite orbit superposition technique , so it was self - consistent and in steady state , but it did not evolve into that state from plausible initial conditions . also , little stellar kinematic data were available to constrain zhao s steady - state model and early @xmath0-body models @xcite , and subsequent radial velocity data from a survey of planetary nebulae , although compared with a range of dynamical models @xcite , led to only limited conclusions because of the small numbers and uncertain population membership of the planetary nebulae . in this paper , we simulate numerically the self - consistent formation of a bar that buckles naturally into a thickened state , and we scale that model to fit new kinematic data on bulge rotation and random velocities .\nthe radial velocity observations are provided by the bulge radial velocity assay ( _ brava _ ; @xcite ) .\nthis is a spectroscopic survey of the stellar radial velocities of m - type giant stars whose population membership in the bulge is well established .\nthese giants provide most of the 2 @xmath5 m radiation whose box - shaped light distribution motivates bar models .\n_ brava _ emphasizes measurements in two strips at latitude @xmath6 and @xmath7 and at longitude @xmath8 @xmath9 @xmath10 . a strip along the minor axis ( @xmath11 ) has also been observed .\nwe use nearly 5,000 stellar radial velocities in this report .\na preliminary analysis of data found strong cylindrical rotation @xcite consistent with an edge - on , bar - like pseudobulge , although a precise fit of a bar model to the data was not available .\nthis success leads us here to construct a full evolutionary @xmath0-body model that we can fit to the radial velocity data .\nthe galaxy rotates clockwise as seen in the face - on projection .\nbottom panel : model surface brightness map in galactic coordinates as seen from the sun s location .\nour perspective makes the box - shaped , edge - on bar look taller on its nearer side . the galactic boxy bulge is observed to be similarly distorted . ]\nwe use a cylindrical particle - mesh code @xcite to build fully self - consistent @xmath0-body galaxies .\nit is well suited to study the evolution of disk galaxies : we model the disk with at least 1 million particles to provide high particle resolution near the center where the density is high .\nwe try to construct the simplest self - consistent @xmath0-body models that fit the _ brava _ data , avoiding contrived models with too many free parameters .\ninitially , they contained only an unbarred disk and a dark halo .\nthe profile of the galactic halo is poorly constrained observationally ; we adopt a rigid pseudo - isothermal halo potential . here\n@xmath12 @xmath3 250 km s@xmath13 is the asymptotic circular - orbit rotation velocity at infinity , and @xmath14 kpc is the core radius inside which the potential is effectively constant .\nthis halo gives a nearly flat rotation curve of @xmath3 220 km s@xmath13 between 5 to 20 kpc .\na simple halo form allows us to run many simulations quickly ; this is important for a parameter search such as the present one .\na rigid halo also omits dynamical friction on the bar , but the central density of the cored halo we adopt is low enough so that friction will be very mild ( e.g. * ? ? ?\n* ; * ? ? ?\nmore importantly , we are mainly interested in the bulge , which is embedded well interior to @xmath15 .\nso the exact profile of the dark halo at large radii is not critical .\nwe will explore more sophisticated halos in a future study .\nstrip ; the middle two panels are for the @xmath7 strip ; and the right two panels are for the @xmath16 minor axis . the black diamonds and their error bars are the _ brava _ data ; the green diamonds are for m - type giant stars @xcite , and the red triangles are the data on red clump giant stars @xcite .\nthis is the first time that a single dynamical model has been compared with data of such quality .\nthe agreement is striking . ]\nmajor - axis strip as we vary the bar angle relative to the line that connects the sun to the galactic center .\nthe red , black , green , blue , and cyan curves are the model results for bar angles of @xmath17 , @xmath2 ( the adopted best - fit value ) , @xmath18 , @xmath19 , and @xmath20 , respectively .\nall data points are plotted as black diamonds regardless of source .\nclearly bar angles of @xmath17 and @xmath2 are favored over larger values . ]\nin our models , a bar develops self - consistently from the initially unbarred , thin disk . bar formation enhances the radial streaming motions of disk particles , so the radial velocity dispersion quickly grows much bigger than the vertical one . consequently the disk buckles vertically out of the plane like a fire hose ; this is the well known buckling or corrugation instability @xcite .\nit raises the vertical velocity dispersion and increases the bar s thickness .\nthis happens on a short dynamical timescale and saturates in a few hundred million years .\nthe central part of the buckled bar is elevated well above the disk mid - plane and resembles the peanut morphology of many bulges including the one in our galaxy @xcite . out of a large set of @xmath0-body models\n, we find the one that best matches our _ brava _ kinematic data after suitable mass scaling .\nthe barred disk evolved from a thin exponential disk that contains @xmath21 , about 55 % of the total mass at the truncation radius ( 5 scale - lengths ) . the scale - length and scale - height of the initial disk\nare @xmath3 1.9 kpc and 0.2 kpc , respectively .\nthe disk is rotationally supported and has a toomre - q of 1.2 .\nthe amplitude of the final bar is intermediate between the weakest and strongest bars observed in galaxies .\nthe bar s minor - to - major axial ratio is about 0.5 to 0.6 , and its half - length is @xmath3 4 kpc .\nfigure 1 ( top three panels ) shows face - on and side - on views of the projected density of the best - fitting model .\na distinctly peanut shaped bulge is apparent in the edge - on projection .\nfigure 1 ( bottom panel ) shows the surface brightness distribution in galactic coordinates as seen from the sun s vantage point .\nnearby disk stars dilute the peanut shape , but the bar still looks boxy .\nmoreover , from close up , an asymmetry in the longitudinal direction is apparent ; this means that the bar can not be aligned with the direction from the sun to the galactic center .\nrather , its near end is at positive galactic longitude , so it looks taller in that quadrant , and it extends farther from the galactic center on the near side than on the far side . both the boxy shape and the asymmetry are in good agreement with the morphology revealed by the cobe satellite near - infrared images @xcite .\nfigure 2 compares the best - fitting model kinematics ( solid lines ) with the mean velocity and velocity dispersion data from the _ brava _ and other surveys @xcite . all velocities presented here have been converted to galactocentric values ( the line - of - sight velocity that would be observed by a stationary observer at the sun s position ) . for the first time , our model is able simultaneously to match the mean velocities and velocity dispersions along two galactic latitudes ( @xmath22 and @xmath23 ) and along the minor axis .\nfigure 3 constrains the angle between the bar and the line that connects the sun to the galactic center .\nit compares the model results with the data in the @xmath6 major - axis strip as we vary the above angle .\nclearly the smallest bar angles give the best match to the velocity dispersions .\nintriguingly , we find that the velocity dispersions provide much stronger constraints than the mean velocity profile .\na bar angle of @xmath17 also matches the kinematics well .\nhowever , the photometric asymmetry excludes a bar that is pointed at the sun .\nwe therefore conclude that the overall best - fitting model has a bar angle of @xmath24 .\nother studies converged on a similar bar angle @xcite .\nthe excellent match to the data in figures 1 3 strongly supports the suggestion that the boxy pseudobulge of the milky way is an edge - on , buckled bar that evolved from a cold , massive disk .\nthe thickened disk in the pseudobulge - forming process may have contributed to the thick disk of the milk way , as hinted from chemical similarities of galactic bulge and local thick disk stars @xcite . the model in figures 1 3 contains no classical bulge component .\ncould a small classical bulge also be present ? could it have been spun up by the formation of a bar , flattened thereby and made hard to detect ? to constrain such multi - component models with _ brava _\nkinematics , we also constructed models with a pre - existing classical bulge .\nthe distribution function for the live classical bulge component was generated iteratively @xcite to ensure that both the disk and the classical bulge were initially in equilibrium , and we required that the bulge parameters are close to the fundamental plane for classical bulges and ellipticals @xcite .\nthe setup of the disk is the same as in the disk - only model .\nwe show in figure 4 that inclusion of a classical bulge \none widely thought to be typical of sbc spiral galaxies like our own greatly worsens the model fit to the data .\nthe degradation is especially obvious along the galaxy s minor axis . including a classical bulge with just 8% of the disk mass considerably worsens the fit of the model to the data .\nour models rule out that the milky way has a significant classical bulge whose mass is @xmath25 15 % of the disk mass\n. could a smaller , merger - built bulge hide inside the boxy bar ?\nthe only result that we are aware of that might point to such a conclusion is the observed drop in stellar metal abundances with increasing height above the galactic plane @xcite .\n@xcite argue that this means that the bulge must consist of both a classical and an edge - on bar component . however , no kinematic gradient or transition corresponding to the abundance gradient is observed .\nmoreover , an abundance gradient can be produced within the context of secular pseudobulge formation if some of the vertical thickening is produced by resonant heating of stars that scatter off the bar @xcite .\nif the most metal - poor stars are also the oldest stars , then they have been scattered for the longest time and now reach the greatest heights .\nour results have important implications for galaxy formation .\nwe demonstrate that the boxy pseudobulge is not a separate component of the galaxy but rather is an edge - on bar .\nbars are parts of disks .\nto be sure , the stars in our galactic bar are older than most disk stars . but\nthose stars could have formed over a short period of time but long before the bar structure formed @xcite , their old age @xcite is therefore not an argument against the internal secular evolution model .\nour kinematic observations show no sign that the galaxy contains a significant merger - made , `` classical '' bulge .\nso , from a galaxy formation point of view , we live in a pure - disk galaxy .\nour galaxy is not unusual : it is very similar to another giant edge - on galaxy with a boxy bulge , ngc 4565 .\n@xcite recently show that ngc 4565 does not contain even a small classical bulge component and that it therefore is another giant , pure - disk galaxy that contains no sign of a merger remnant .\nin fact , giant , pure - disk galaxies are common in environments like our own that are far from rich clusters of galaxies @xcite .\nclassical - bulge - less , pure - disk galaxies present an acute challenge to the current picture of galaxy formation in a universe dominated by cold dark matter growing a giant galaxy via hierarchical clustering ( @xmath26 km s@xmath13 in the milky way ) involves so many mergers that it seems almost impossible to avoid forming a substantial classical bulge @xcite .\nhow did our galaxy grow so large with no observational sign that it suffered a major merger after the time 9 10 gyr ago ( e.g. * ? ? ?\n* ) when the first disk stars formed ?", "role": "user" }, { "content": "bulges are commonly believed to form in the dynamical violence of galaxy collisions and mergers . here \n we model the stellar kinematics of the bulge radial velocity assay ( _ brava _ ) , and find no sign that the milky way contains a classical bulge formed by scrambling pre - existing disks of stars in major mergers . \n rather , the bulge appears to be a bar , seen somewhat end - on , as hinted from its asymmetric boxy shape . \n we construct a simple but realistic @xmath0-body model of the galaxy that self - consistently develops a bar . \n the bar immediately buckles and thickens in the vertical direction . \n as seen from the sun , the result resembles the boxy bulge of our galaxy . \n the model fits the _ brava _ stellar kinematic data covering the whole bulge strikingly well with no need for a merger - made classical bulge . \n the bar in our best fit model has a half - length of @xmath1 and extends @xmath2 from the sun - galactic center line . \n we use the new kinematic constraints to show that any classical bulge contribution can not be larger than @xmath3 8% of the disk mass . \n thus the galactic bulge is a part of the disk and not a separate component made in a prior merger . \n giant , pure - disk galaxies like our own present a major challenge to the standard picture in which galaxy formation is dominated by hierarchical clustering and galaxy mergers .", "role": "assistant" } ]

[ { "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 the real world, the environment is constantly changing with the input variables under the effect of noise. However, few algorithms were shown to be able to work under those circumstances. Here, Novelty-Organizing Team of Classifiers (NOTC) is applied to the continuous action mountain car as well as two variations of it: a noisy mountain car and an unstable weather mountain car. These problems take respectively noise and change of problem dynamics into account. Moreover, NOTC is compared with NeuroEvolution of Augmenting Topologies (NEAT) in these problems, revealing a trade-off between the approaches. While NOTC achieves the best performance in all of the problems, NEAT needs less trials to converge. It is demonstrated that NOTC achieves better performance because of its division of the input space (creating easier problems). Unfortunately, this division of input space also requires a bit of time to bootstrap.\n\nCited Works Summary:\n[1]: In this paper we present a novel method, called Evolution- ary Acquisition of Neural Topologies (EANT), of evolving the structure and weights of neural networks. The method introduces an ecien t and compact genetic encoding of a neural network onto a linear genome that enables one to evaluate the network without decoding it. The method explores new structures whenever it is not possible to further exploit the structures found so far. This enables it to nd minimal neural structures for solving a given learning task. We tested the algorithm on a benchmark control task and found it to perform very well.\n\n[2]: Standard methods for simultaneously inducing the structure and weights of recurrent neural networks limit every task to an assumed class of architectures. Such a simplification is necessary since the interactions between network structure and function are not well understood. Evolutionary computations, which include genetic algorithms and evolutionary programming, are population-based search methods that have shown promise in many similarly complex tasks. This paper argues that genetic algorithms are inappropriate for network acquisition and describes an evolutionary program, called GNARL, that simultaneously acquires both the structure and weights for recurrent networks. GNARL's empirical acquisition method allows for the emergence of complex behaviors and topologies that are potentially excluded by the artificial architectural constraints imposed in standard network induction methods. >\n\n[3]: An important question in neuroevolution is how to gain an advantage from evolving neural network topologies along with weights. We present a method, NeuroEvolution of Augmenting Topologies (NEAT), which outperforms the best fixed-topology method on a challenging benchmark reinforcement learning task. We claim that the increased efficiency is due to (1) employing a principled method of crossover of different topologies, (2) protecting structural innovation using speciation, and (3) incrementally growing from minimal structure. We test this claim through a series of ablation studies that demonstrate that each component is necessary to the system as a whole and to each other. What results is significantly faster learning. NEAT is also an important contribution to GAs because it shows how it is possible for evolution to both optimize and complexify solutions simultaneously, offering the possibility of evolving increasingly complex solutions over generations, and strengthening the analogy with biological evolution.\n\n[4]: This paper presents a new evolutionary system, i.e., EPNet, for evolving artificial neural networks (ANNs). The evolutionary algorithm used in EPNet is based on Fogel's evolutionary programming (EP). Unlike most previous studies on evolving ANN's, this paper puts its emphasis on evolving ANN's behaviors. Five mutation operators proposed in EPNet reflect such an emphasis on evolving behaviors. Close behavioral links between parents and their offspring are maintained by various mutations, such as partial training and node splitting. EPNet evolves ANN's architectures and connection weights (including biases) simultaneously in order to reduce the noise in fitness evaluation. The parsimony of evolved ANN's is encouraged by preferring node connection deletion to addition. EPNet has been tested on a number of benchmark problems in machine learning and ANNs, such as the parity problem, the medical diagnosis problems, the Australian credit card assessment problem, and the Mackey-Glass time series prediction problem. The experimental results show that EPNet can produce very compact ANNs with good generalization ability in comparison with other algorithms.", "role": "user" }, { "content": "Neuroevolution, where both the structure and parameters are evolved, is a relatively new research area. Therefore, there are fewer algorithms. To cite some: GNARL [2] , NEAT [3] , EANT [1] and EPNet [4] .", "role": "assistant" } ]

[ { "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: drinking five cups of black tea a day quadrupled the body's immune defense system after two weeks, probably because of theanine.\n\nResearch Abstract:\nThis review focused on the use of plant-based foods for enhancing the immunity of all aged groups against COVID-19.\nIn humans, coronaviruses are included in the spectrum of viruses that cause the common cold and, recently, severe acute respiratory syndrome (SARS).\nEmerging infectious diseases, such as SARS present a major threat to public health.\nThe novel coronavirus has spread rapidly to multiple countries and has been declared a pandemic by the World Health Organization.\nCOVID-19 is usually caused a virus to which most probably the people with low immunity response are being affected.\nPlant-based foods increased the intestinal beneficial bacteria which are helpful and make up of 85% of the immune system.\nBy the use of plenty of water, minerals like magnesium and Zinc, micronutrients, herbs, food rich in vitamins C, D and E, and better life style one can promote the health and can overcome this infection.\nVarious studies investigated that a powerful antioxidant glutathione and a bioflavonoid quercetin may prevent various infections including COVID-19.\nIn conclusion, the plant-based foods play a vital role to enhance the immunity of people to control of COVID-19.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "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\nPhα1β toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels. Phα1β toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Phα1β when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Phα1β on Ca(2+) transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Phα1β reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, ω-conotoxin MVIIA (a selective N-type Ca(2+) channel blocker) was effective only when administered intrathecally. Phα1β, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca(2+) transients in DRG neurons. The simultaneous administration of Phα1β and SB366791 inhibited the capsaicin-induced Ca(2+) transients that were additive suggesting that they act through different targets. Moreover, Phα1β did not inhibit capsaicin-activated currents in patch-clamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Phα1β may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors.", "role": "user" }, { "content": "{\"Chemical\": [\"Ca(2+)\", \"nifedipine\", \"calcium\", \"SB366791\", \"capsaicin\", \"mibefradil\"]}", "role": "assistant" } ]

[ { "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:\nCorticalastrocytesdissociatedfromnewbornmousecorticesweregrownincultureflasksat37degreesCinahumidifiedatmospherewith5%CO2untilconfluent.", "role": "user" }, { "content": "[\"CO2\"]", "role": "assistant" } ]

[ { "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: Two subunits of human ORC are dispensable for DNA replication and proliferation\nContent Overview:\nAbstract:\nThe six-subunit Origin Recognition Complex( ORC) is believed to be an essential eukaryotic ATPase that binds to origins of replication as a ring-shaped heterohexamer to load MCM2-7 and initiate DNA replication. We have discovered that human cell lines in culture proliferate with intact chromosomal origins of replication after disruption of both alleles of ORC2 or of the ATPase subunit, ORC1. The ORC1 or ORC2-depleted cells replicate with decreased chromatin loading of MCM2-7 and become critically dependent on another ATPase, CDC6, for survival and DNA replication. Thus, either the ORC ring lacking a subunit, even its ATPase subunit, can load enough MCM2-7 in partnership with CDC6 to initiate DNA replication, or cells have an ORC-independent, CDC6-dependent mechanism to load MCM2-7 on origins of replication DOI: http://dx. doi. org/10. 7554/eLife. 19084. 001\nIntroduction:\nThe discovery of the six-subunit ORC( Bell and Stillman, 1992) identified the long sought initiator protein that binds to replicator sequences to initiate DNA replication in eukaryotes. ORC is an essential six-subunit, ring-shaped ATPase complex that recruits and co-operates with the CDC6 protein to promote the loading of CDT1 and then the MCM2-7 subunits of the replicative helicase during the ‘licensing’ of origins of replication( Bleichert et al., 2015; Yeeles et al., 2015; Bell and Stillman, 1992; Blow and Tada, 2000; Masai et al., 2010). Of the six subunits of human ORC, ORC2-5 form a tight core complex( Dhar et al., 2001). ORC1 is the only subunit responsible for the ATPase activity of ORC( Chesnokov et al., 2001; Giordano-Coltart et al., 2005; Klemm et al., 1997) All six ORC subunit genes are essential for the viability of S. cerevisiae and S. pombe( Bell et al., 1993; Foss et al., 1993; Herskowitz, 1993; Loo et al., 1995; Micklem et al., 1993). It is therefore expected that eukaryotic cells will not be viable, and will not replicate, if any of the ORC subunit genes are deleted. However, we have now deleted both alleles of human ORC2 or of ORC1, to discover that cells can still survive and replicate in the complete absence of either of these two critical subunits of Origin Recognition Complex.\nDiscussion:\nThe surprising results from this genetic investigation of ORC in human cell lines suggest that two subunits of ORC are dispensable for DNA replication. Although we believe that no ORC2 protein is synthesized in the ORC2-/- cells, we have to entertain the caveat that up to 1530 ORC2 molecules can escape the limits of detection with our current antibodies. This number is still too few to license the 52, 000 origins of replication mapped by two independent methods. It is unlikely that a single ORC complex can catalytically load thirty-five MCM2-7 hexamers distributed 100 kb apart over 3. 5 Mb of chromosomal DNA. Since knockdown of ORC5 still affects DNA synthesis in the ORC1-/- or ORC2-/- cells, we cannot yet conclude that replication initiation can occur in the absence of all subunits of ORC. To reach that conclusion we have to successfully delete both alleles of the other four subunits, ORC3-6. However, even if the remaining ORC subunits are functional for loading MCM2-7 our result requires reconsideration of existing models of ORC function in replication initiation.( 1) The crystal structure suggests that ORC2-3-5-4-1 are arranged in a gapped ring( with a central channel that is wide enough to surround a DNA double-helix), and that later in licensing, CDC6 slips into the gap between ORC2 and ORC1 to close the gap. The ORC-CDC6 ring is proposed to interact with the MCM2-7 ring end-on-end during the loading of MCM2-7( Bleichert et al., 2015). Loss of one subunit in the five-membered ORC ring makes it difficult for the remaining subunits to form a ring large enough( i) to surround a DNA double-helix in the same manner as wild type ORC or( ii) to interact with the MCM2-7 ring end-on-end.( 2) Human ORC1 and ORC4 are the only subunits that have intact Walker A and B motifs. Multiple groups have shown that the ATPase activity of ORC( in S. cerevisiae, in D. melanogaster and in H. sapiens) depends exclusively on the Walker A and B motifs of the ORC1 subunit, and that this ATP binding and hydrolysis activity is essential for ORC function( Chesnokov et al., 2001; Giordano-Coltart et al., 2005; Klemm et al., 1997). Even if an altered or partial ORC is initiating replication, we have to conclude that any ATPase activity necessary can be provided by ORC4 or CDC6. There is a report arguing that ORC1 is not essential for endoreplication in Drosophila, because ORC1-/- larvae still allowed endoreplication in salivary gland cells, with only a twofold reduction of ploidy( Park and Asano, 2008). However the paper did not show the sensitivity of the western-blot to measure the level of residual ORC, so that it is theoretically possible that there was enough residual maternal ORC in the endoreplicating cells. The classic model of replication initiation where ORC first associates with the DNA, helps load CDC6, which then helps load CDT1 and MCM2-7 may still be important for efficient MCM2-7 loading. The surprise is that inefficient MCM2-7 loading, perhaps with the help of CDC6, is sufficient for replication initiation and cell survival in the absence of six-subunit ORC. The other surprise is that the six-subunit ORC does not appear to associate with chromatin as a holocomplex. Clearly ORC6 associates with chromatin normally despite a decrease in ORC1( in the ORC2-/- or ORC1-/- cells) or ORC2-5 loading( in the ORC2-/- cells). Similarly ORC2-5 loading is independent of ORC1 loading( in the ORC1-/- cells). The origin plasticity of eukaryotes is attributed to the loading of excess subunits of MCM2-7 on chromatin. It is thus also surprising that the plasticity persists despite a significant reduction in the association of MCM2-7 on chromatin. In summary, we suggest that the absolute requirement for six-subunit ORC for licensing bi-directional origins of replication can be bypassed in some cell lines.", "role": "user" }, { "content": "Most of the DNA in human cells is packaged into structures called chromosomes . Before a cell divides , the DNA in each chromosome is carefully copied . This process begins at multiple sites ( known as origins ) on each chromosome . A group of six proteins collectively known as the Origin Recognition Complex ( or ORC for short ) binds to an origin and then recruits several additional proteins . When the cell is ready , the assembled proteins are activated and DNA copying begins . It is thought that all of the ORC proteins are essential for cells to survive and copy their DNA . Here , Shibata et al . reveal that human cells can survive without ORC1 or ORC2 , two of the six proteins in the ORC complex . Disrupting the genes that encode the ORC1 and ORC2 proteins in human cancer cell lines had little effect on the ability of the cells to copy their DNA and survive . Furthermore , these cells spend the same amount of time copying their DNA and use a similar set of origins as normal cells . However , the experiments also reveal that cells without ORC1 or ORC2 are more dependent on the presence of one particular protein recruited to the origin after the ORC assembles . Reducing the availability of this protein , CDC6 , decreased the ability of these cells to survive and divide . Future efforts will aim to identify the mechanism by which cells bring together the proteins required to copy DNA in the absence of a complete ORC .", "role": "assistant" } ]

[ { "content": "Examine the citation provided below. Determine the primary purpose of this citation within the context of the research paper. \n\nCitation:\n\nHearing loss and tinnitus have been linked, both pathophysiologically (Eggermont and Roberts, 2004; Jastreboff, 1990) and clinically (De Ridder et al., 2015a; Norena et al., 2002; Schecklmann et al., 2012b).", "role": "user" }, { "content": "Background", "role": "assistant" } ]