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[ { "content": "You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should only include the abstract and no additional text.\n\nPaper text:\nultrasound showed a 1.7-cm , well demarcated , heterogeneous , low echoic solid mass in the lower pole of the right thyroid ( fig .\n1 ) . a computed tomography scan of the neck revealed a 3.3-cm , exophytic , low - attenuated mass in the lower pole of the right thyroid .\nthe fna biopsy of the mass was performed , which was accompanied by the standard papanicolaou stain .\nthe smear was composed of not only cohesive three dimensional clusters and sheets but also singly scattered cells ( fig .\nthe tumor cells showed mild anisonucleosis and high nuclear : cytoplasmic ( n / c ) ratios .\nnuclei were round to ovoid with irregular nuclear contours and small , distinct nucleoli ( fig .\nsome tumor cells showed dense orangeophilic cytoplasm , which is suggestive of individual cell keratinization ( fig . 2c ) .\nsome lymphocytes were found on the background and within clusters , which was accompanied by the presence of a few stripped nuclei ( fig .\nthe aspirate was interpreted as a high - grade malignant thyroid neoplasm without further definitive classification .\nthe mass had a lobular , tan - colored cut surface and a firm consistency ( fig .\nthe tumor was well - circumscribed and it was composed of variably sized and irregularly shaped lobules of cohesive polygonal tumor cells which were separated by bands of dense fibrous stroma ( fig .\nthe tumor cells had high n / c ratios , eosinophilic cytoplasm and ill - defined cell borders .\nthe tumor cells showed positivity for cd5 , carcinoembryonic antigen , high molecular weight keratin ( hmwk ) , cytokeratin 5 ( ck5 ) , and p63 .\none regional lymph node was found and involved by tumor . over a 27-month follow - up period ,\nthe cytological diagnoses were mentioned in previous 14 reports consisting of 40 cases . malignant tumor or poorly - differentiated carcinoma were the most frequent cytological diagnosis in cases of castle , except for six cases ( table 1).2 - 15 one case was diagnosed as castle for which no cytological findings have been described.11 in previously reported cases of castle , the most common cytological findings include tight clusters and sheets of round tumor cells with high n / c ratios , vesicular nuclei , prominent nucleoli , amphophilic cytoplasm , and lymphocytic background , which correspond well with the present case.2 - 4,6 in the present case and those of hirokawa et al.,2 keratinized cells were present .\nyouens et al.6 reported indistinct cell borders , intranuclear grooves and sparse mitotic figures , which were also seen in the present case .\nyouens et al.6 reported not only intranuclear cytoplasmic inclusions and papillary - like structures but also granular chromatin and rosette - like structures .\nthe differential diagnoses of castle include papillary carcinoma , hrthle cell neoplasm , undifferentiated carcinoma , medullary carcinoma and metastatic lymphoepithelioma - like carcinoma .\ncastle may show intranuclear pseudoinclusions or papillary - like structures , but it does not show fine pale chromatin and monolayer sheets of cells with dense cytoplasm .\nalthough hrthle cell neoplasm contains cellular aggregates with abundant cytoplasm and prominent nucleoli , lymphocytic background of castle is lacking .\nit is very difficult to distinguish castle from metastatic lymphoepithelioma - like carcinoma , which also shows sheets of poorly differentiated round cells intermixed with small lymphocytes .\nsubtle differences , such as frequent mitotic activity and a polymorphous inflammatory background , favor metastatic lymphoepithelioma - like carcinoma.4 castle may resemble undifferentiated thyroid carcinoma with squamous differentiation , but it does not show marked cytologic atypia , frequent mitotic activity and necrotic background characteristic of undifferentiated carcinoma .\nalthough castle may show rosette - like structures and granular chromatin , along with an abundance of single tumor cells as in medullary carcinoma , it is lacking of typical plasmacytoid cells , pink cytoplasmic granules and amyloid deposition.6 immunocytochemical study for cd5 is helpful to differentiate castle from other malignant thyroid neoplasm .\ncd5 is a surface glycoprotein expressed on mature t cells and a subset of b cells.16 thymic carcinoma cells are also known to be positive for cd5.17 cd5 is almost always expressed in castle .\ncastle is positive for hmwk , ck5 , and p63 because it is also a squamous cell carcinoma .\nhowever , thyroid squamous cell carcinoma and poorly - differentiated carcinoma were negative for cd5.17 ito et al.11 reported that the sensitivity and specificity for cd5 immunohistochemistry were 82% and 100% , respectively , in making a diagnosis of castle . in conclusion ,\nthe presence of poorly - differentiated tumor cells with a focal keratinization and a lymphocytic background on the fna biopsy is suggestive of castle .", "role": "user" }, { "content": "carcinoma showing thymus - like differentiation ( castle ) is a rare carcinoma of the thyroid or adjacent soft tissue of the neck with a histologic resemblance to thymic epithelial tumors . \n although the fine - needle aspiration ( fna ) plays a central role in the initial evaluation of thyroid nodules , few reports about the cytologic findings of castle have been found according to a review of literatures . \n we report cytologic findings of a case of castle . a 34-year - old woman presented with a 2-month history of sore throat . \n the fna showed that the smear was composed of three dimensional clusters and sheets . \n the tumor cells were round to ovoid with high nuclear : cytoplasmic ratios . \n the nuclei were vesicular with small nucleoli . \n there were some tumor cells showing keratinization . \n some lymphocytes were found on the background and within clusters . \n the presence of poorly - differentiated tumor cells with a focal keratinization and a lymphocytic background on the fna is suggestive of castle .", "role": "assistant" } ]

[ { "content": "You will be presented with a citation segment from the section of an NLP research paper, as well as the context surrounding that citation. Classify the intent behind this citation by choosing from one of the following categories:\n- Background: provides context or foundational information related to the topic.\n- Extends: builds upon the cited work.\n- Uses: applies the methods or findings of the cited work.\n- Motivation: cites the work as inspiration or rationale for the research.\n- CompareOrContrast: compares or contrasts the cited work with others.\n- FutureWork: cites the work as a direction for future research.\n\nYour answer should be a single word from the following list of options: [\"Background\", \"Extends\", \"Uses\", \"Motivation\", \"CompareOrContrast\", \"FutureWork\"]. Do not include any other text in your response.\n\nSection Title:\nNone\n\nContext before the citation:\nThe problem of handling ill-formed input has been studied by Carbonell and Hayes (1983), Granger (1983), Jensen et al. (1983), Kwasny and Sondheimer (1981), Riesbeck and Schank (1976), Thompson (1980), Weischedel and Black (1980), and Weischedel and Sondheimer (1983). A detailed description of the kinds of expectation mechanisms appearing in these systems appears in Fink (1983). While some of these systems did exhibit expectation capabilities at the sentence level, none acquired dialogues of the kind described here for the sake of dialogue level expectation and error correction.\n\nCitation Sentence:\nThe problem of handling ill-formed input has been studied by Carbonell and Hayes ( 1983 ) , Granger ( 1983 ) , Jensen et al. ( 1983 ) , Kwasny and Sondheimer ( 1981 ) , Riesbeck and Schank ( 1976 ) , Thompson ( 1980 ) , Weischedel and Black ( 1980 ) , and Weischedel and Sondheimer ( 1983 ) .\n\nContext after the citation:\nA wide variety of techniques have been developed for addressing problems at the word, phrase, sentence, and in some cases, dialogue level. However, these methodologies have not used historical information at the dialogue level as described here. In most cases, the goal of these systems is to characterize the ill-formed input into classes of errors and to correct on that basis. The work described here makes no attempt to classify the errors, but treats them as random events that occur at any point in a sentence.", "role": "user" }, { "content": "CompareOrContrast", "role": "assistant" } ]

[ { "content": "You will be shown biomedical passages and your task is to answer the provided question. Provide a concise and accurate response and do not include any additional text in the response other than the answer.\n\nQuestion: What is the link between psoriatic arthritis and depression\n\nContext: Depression Is Associated with an Increased Risk of Psoriatic Arthritis among Patients with Psoriasis\nmerging data also suggest associations between psoriasis and other comorbidities beyond psoriatic arthritis, including chronic kidney disease, inflammatory bowel disease, hepatic disease, certain malignancies, infections, and mood disorders.\nDo depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis?\nTo investigate the predictive value of baseline depression/anxiety on the likelihood of achieving joint remission in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as the associations between baseline depression/anxiety and the components of the remission criteria at follow-up.\nRate of depression was higher in patients with PsA compared to non-PsA patients. The rate of suicidal behaviors was similar between the two cohorts.\nOver the past decade, multiple studies have shown that not only is there an association between psoriasis and psoriatic arthritis, depression, and substance abuse, but psoriasis patients also have a higher incidence of obesity, diabetes, heart disease and stroke.\nPsoriasis is a chronic disease that affects more than the skin. It has an impact on every facet of an individual's life and is associated with numerous comorbidities, such as obesity, diabetes, cardiovascular disease, psoriatic arthritis, metabolic syndrome, squamous cell carcinoma, lymphoma, depression, anxiety and other immune-related conditions, such as Crohn's disease.\nWe found an increased risk of depression in US women with psoriasis compared with those without psoriasis.\nThe impact of comorbidities (psoriatic arthritis, cardiovascular disease, diabetes, and depression) on relative importance scores of each attribute was assessed by analyses of varianc\nFurthermore, obesity and psychological diseases such as depression and anxiety disorders are linked with psoriasis and play a central role in its management.\nRecommendations were synthesized into 19 final recommendations ranging mainly from grade C to D, and relating to a large spectrum of comorbidities observed in clinical practice: CVD, obesity, osteoporosis, depression, infections, and cancer. Level of agreement ranged from 80.9% to 95.8%.CONCLUSION: These practical evidence-based recommendations can guide management of comorbidities in patients with RA, PsA, and PsO and optimize outcome\nAnxiety and depressive symptoms and illness perceptions in psoriatic arthritis and associations with physical health-related quality of life.\nThe rate of depression and anxiety is significantly higher in patients with PsA than in those with PsC. Depression and anxiety are associated with disease-related factors.\nThe prevalence of anxiety symptoms and the prevalence of depression symptoms are high among patients suffering psoriatic arthritis in the studied population.\nPsoriasis (Pso) is a common chronic cutaneous inflammatory disease involving the skin that is associated with serious comorbidities. Comorbidities in Pso include psoriatic arthritis (PsA), reduced quality of life, malignancy, depression, but also a constellation of associated conditions that enhance the cardiovascular (CV) risk.\nDermatologists and primary care providers share roles in screening for associated comorbidities (including cardiovascular disorders, chronic kidney disease, Crohn disease, dyslipidemia, diabetes mellitus/insulin resistance, depression, metabolic syndrome, obesity, and psoriatic arthritis),", "role": "user" }, { "content": "comorbidity", "role": "assistant" } ]

[ { "content": "You will be presented with a citation sentence from a research paper. Classify the intent behind this citation by choosing from one of the following categories:\n\n- Method: Cites the paper for its methodology or procedure.\n- Background: Cites the paper to provide background information.\n- Result: Cites the paper for its findings or results.\n\nYour answer should be a single word from the following list of options: [\"Method\", \"Background\", \"Result\"]. Do not include any other text in your response.\n\nCitation sentence:\n\nIt should be noted that a WURS cut-off score of 46 or higher can discriminate individuals with a history of childhood attention-deficit/ hyperactivity disorder (Kafka & Prentky, 1998; Roy-Byrne et al., 1997; Ward et al., 1993; Wender, 1995).", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Finding\", \"Bacterium\", \"ProfessionalOrOccupationalGroup\", \"InjuryOrPoisoning\", \"Eukaryote\", \"BodySystem\", \"Virus\", \"ResearchActivity\", \"BodySubstance\", \"PopulationGroup\", \"Chemical\", \"AnatomicalStructure\", \"SpatialConcept\", \"HealthCareActivity\", \"Organization\", \"BiomedicalOccupationOrDiscipline\", \"Food\", \"ClinicalAttribute\", \"MedicalDevice\", \"BiologicFunction\", \"IntellectualProduct\"].\n\nPlease return the output as a JSON object of the format: {\"Virus\": [\"HIV\", ...], \"Bacterium\": [\"MRSA\", ...], \"AnatomicalStructure\": [\"Lung\", ...], \"BodySystem\": [\"CNS\", ...], \"BodySubstance\": [\"Serum\", ...], \"Finding\": [\"Headache\", ...], \"InjuryOrPoisoning\": [\"Fracture\", ...], \"BiologicFunction\": [\"Death\", ...], \"HealthCareActivity\": [\"Biopsy\", ...], \"ResearchActivity\": [\"Clinical trial\", ...], \"MedicalDevice\": [\"Lenses\", ...], \"SpatialConcept\": [\"Camps\", ...], \"BiomedicalOccupationOrDiscipline\": [\"Forensic medicine\", ...], \"Organization\": [\"WHO\", ...], \"ProfessionalOrOccupationalGroup\": [\"Provider\", ...], \"PopulationGroup\": [\"Swimmers\", ...], \"Chemical\": [\"Gold\", ...], \"Food\": [\"Rice\", ...], \"IntellectualProduct\": [\"RPAM\", ...], \"ClinicalAttribute\": [\"Biomarker\", ...], \"Eukaryote\": [\"Dogs\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nGlomus tumor in teen and repetition pneumonia: Case report Glomus tumors are uncommon tumors that are originated from smooth muscle cells of the neuromioarterials glomus bodies located in the arteriovenous anastomoses subcutaneous tissue or deep dermis of the extremities, mainly in the palms of the hands, wrists and subungual areas of the fingers. Carcinoid tumor, as the glomus tumor, can show an organoid pattern, increased vascularity, and uniform, round cells with eosinophilic cytoplasm, but usually are positive for cytokeratin and always stained with chromogranin and synaptophysin showing negative for smooth muscle markers which is presented in our case. Glomus tumors have a good prognosis and surgical resection is the treatment of choice. In our case, the patient underwent pulmonary bilobectomy because of the location of the tumor in the transition between the middle lobe and the basal bronchial trunk right lower lobe divisions. It is presented thus a glomus tumor with exceptional localization (pulmonary and bronchial) of benign histological features, according to most of the cases reported in the literature emphasizing their particular rare location, histological, and immunohistochemical profile, which helps the differential diagnosis with other most common tumors of bronchial location.", "role": "user" }, { "content": "{\"AnatomicalStructure\": [\"basal bronchial trunk right lower lobe\", \"smooth muscle\", \"fingers\", \"dermis\", \"smooth muscle cells\", \"middle lobe\", \"bronchial\", \"eosinophilic cytoplasm\", \"subcutaneous tissue\", \"extremities\", \"neuromioarterials glomus bodies\", \"arteriovenous anastomoses\", \"subungual areas\"], \"Bacterium\": [], \"BiologicFunction\": [\"Carcinoid tumor\", \"glomus tumor\", \"Glomus tumor\", \"Glomus tumors\", \"tumors\", \"pneumonia\", \"tumor\"], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [\"synaptophysin\", \"chromogranin\", \"markers\"], \"ClinicalAttribute\": [\"histological\"], \"Eukaryote\": [], \"Finding\": [\"organoid pattern\", \"negative\", \"histological features\", \"positive for cytokeratin\", \"good prognosis\"], \"Food\": [], \"HealthCareActivity\": [\"surgical resection\", \"profile\", \"pulmonary bilobectomy\", \"treatment\", \"reported\", \"differential diagnosis\"], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"Case report\", \"literature\"], \"MedicalDevice\": [], \"Organization\": [], \"PopulationGroup\": [\"teen\"], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [], \"SpatialConcept\": [\"palms of the hands\", \"wrists\", \"deep\", \"location\", \"located\"], \"Virus\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with a paragraph from a COVID-19 literature. Your task is to classify the topics of this piece of text by choosing from the following categories:\n\n- Epidemic Forecasting: The content relates to predictions about the spread of COVID-19.\n- Treatment: The paragraph discusses therapeutic methods or medication for COVID-19.\n- Prevention: The content covers measures to prevent the spread of COVID-19.\n- Mechanism: The paragraph explains the biological mechanisms of the virus.\n- Case Report: The content is a report of a COVID-19 case.\n- Transmission: The paragraph discusses how COVID-19 is transmitted.\n- Diagnosis: The content is about diagnosing COVID-19 in individuals.\n\nYour classification should be provided as an element within a JSON array. The array should be formatted with topics enclosed in double quotes and separated by commas, following the JSON format, for example: [\"Topic1\", \"Topic2\", ...]. Include all applicable categories within the array. \nYour output should be a valid JSON array, and no additional text should be included in your response.\n\nArticle:\n\nIn this article we propose a modified compartmental model describing the transmission of COVID-19 in Morocco. It takes account on the asymptomatic people and the strategies involving hospital isolation of the confirmed infected person, quarantine of people contacting them, and home containment of all population to restrict mobility. We establish a relationship between the containment control coefficient c 0 and the basic reproduction number R 0 . Different scenarios are tested with different values of c 0 , for which the stability of a Disease Free Equilibrium point is correlated with the condition linking R 0 and c 0 . A worst scenario in which the containment is not respected in the same way during the period of confinement leads to several rebound in the evolution of the pandemic. It is shown that home containment, if it is strictly respected, played a crucial role in controlling the disease spreading.", "role": "user" }, { "content": "[\"Prevention\"]", "role": "assistant" } ]

[ { "content": "You are presented with multiple paper abstracts, a literature review title, and a specific chapter title. Your task is to write a focused literature review chapter that aligns with the given chapter title. The review should synthesize the content from the provided abstracts, draw connections between different works, highlight major findings, and identify any gaps in the existing research.\nLiterature Review Title: Many-Objective Evolutionary Algorithms: A Survey \nChapter Title: Interactive Preference-Based Algorithms \n1. Abstract of Cited Paper (BIB001): In this paper, we borrow the concept of reference direction approach from the multi-criterion decision-making literature and combine it with an EMOprocedure to develop an algorithm for finding a single preferred solution in a multi-objective optimization scenario efficiently. EMO methodologies are adequately used to find a set of representative efficient solutions over the past decade. This study is timely in addressing the issue of optimizing and choosing a single solution using certain preference information. In this approach, the user supplies one or more reference directions in the objective space. The population approach of EMO methodologies is exploited to find a set of efficient solutions corresponding to a number of representative points along the reference direction. By using a utility function, a single solution is chosen for further analysis. This procedure is continued till no further improvement is possible. The working of the procedure is demonstrated on a set of test problems having two to ten objectives and on an engineering design problem. Results are verified with theoretically exact solutions on two-objective test problems. \n2. Abstract of Cited Paper (BIB002): The simultaneous optimisation of four or more conflicting objectives is now recognised as a challenge for evolutionary algorithms seeking to obtain full representations of trade-off surfaces for the purposes of a posteriori decision-making. Whilst there is evidence that some approaches can outperform both random search and standard Paretobased methods, best-in-class algorithms have yet to be identified. We consider the concept of co-evolving a population of decision-maker preferences as a basis for determining the fitness of competing candidate solutions. The concept is realised using an existing co-evolutionary approach based on goal vectors. We compare this approach and a variant to three realistic alternatives, within a common optimiser framework. The empirical analysis follows current best practice in the field. As the number of objectives is increased, the preference-driven co-evolutionary approaches tend to outperform the alternatives, according to the hypervolume indicator, and so make a strong claim for further attention in many-objective studies. \n3. Abstract of Cited Paper (BIB003): Evolutionary Multi-objective Optimization (EMO) approaches have been amply applied to find a representative set of Pareto-optimal solutions in the past decades. Although there are advantages of getting the range of each objective and the shape of the entire Pareto front for an adequate decision-making, the task of choosing a preferred set of Pareto-optimal solutions is also important. In this paper, we combine a preference-based strategy with an EMO methodology and demonstrate how, instead of one solution, a preferred set of solutions in the preferred range can be found. The basic idea is that each objective function corresponds to a marginal utility function, which indicates the decision-maker's preferred range for each objective. The corresponding utility function denotes the decision-maker's satisfaction. Such procedures will provide the decision-maker with a set of solutions near his preferred ranges so that a better and more reliable decision can be made. \n4. Abstract of Cited Paper (BIB004): Despite the high number of existing works in software testing within the SBSE community, there are very few ones that address the problematic of agent testing. The most prominent work in this direction is by Nguyen et al. [13], which formulates this problem as a bi-objective optimization problem to search for hard test cases from a robustness viewpoint. In this paper, we extend this work by: 1 proposing a new seven-objective formulation of this problem and 2 solving it by means of a preference-based many-objective evolutionary method. The obtained results show that our approach generates harder test cases than Nguyen et al. method ones. Moreover, Nguyen et al. method becomes a special case of our method since the user can incorporate his/her preferences within the search process by emphasizing some testing aspects over others. \n5. Abstract of Cited Paper (BIB005): Multi-objective optimization problems (MOPs) with interval parameters are ubiquitous in real-world applications. Existing evolutionary optimization methods, however, aim to obtain a set of well-converged and evenly-distributed Pareto-optimal solutions. In this paper, we presented a novel evolutionary algorithm (EA) that interacts with a decision maker (DM) during the optimization process to obtain the most preferred solution. The theory of preference polyhedron for the optimization problem with interval parameters was developed first. An interactive evolutionary algorithm (IEA) for MOPs with interval parameters was then proposed based on the theory of preference polyhedron. The algorithm periodically provides a set of non-dominated solutions to the DM; a preference polyhedron is constructed in the objective space by taking the worst solution chosen by the DM as the vertex. The solutions with the same rank are sorted based on the polyhedron constructed. Finally, our method was empirically evaluated on several MOPs with interval parameters where the value functions were used to simulate the DM's responses. The numerical results indicated that our method is simpler and more efficient than the a posteriori method. \n6. Abstract of Cited Paper (BIB006): Preference-inspired co-evolutionary algorithm (PICEA) is a novel class of multi-objective evolutionary algorithm. In PICEA, the usual candidate solutions are guided toward the Pareto optimal front by co-evolving a set of decision maker preferences during the search process. PICEA-g is one realization of PICEAs in which goal vectors are taken as preferences. This study points out one limitation of this method -the obtained solutions are distributed unevenly along the Pareto optimal front. To handle this limitation, an improved fitness assignment method is proposed in which the density information of the solutions is considered. Experimental results, in terms of the selected performance metrics, show this improved fitness assignment method is effective. \n7. Abstract of Cited Paper (BIB007): The simultaneous optimization of many objectives (in excess of 3), in order to obtain a full and satisfactory set of tradeoff solutions to support a posteriori decision making, remains a challenging problem. The concept of coevolving a family of decision-maker preferences together with a population of candidate solutions is studied here and demonstrated to have promising performance characteristics for such problems. After introducing the concept of the preference-inspired coevolutionary algorithm (PICEA), a realization of this concept, PICEA-g, is systematically compared with four of the best-in-class evolutionary algorithms (EAs); random search is also studied as a baseline approach. The four EAs used in the comparison are a Pareto-dominance relation-based algorithm (NSGA-II), an e-dominance relation-based algorithm [ e-multiobjective evolutionary algorithm (MOEA)], a scalarizing function-based algorithm (MOEA/D), and an indicator-based algorithm [hypervolume-based algorithm (HypE)]. It is demonstrated that, for bi-objective problems, all of the multi-objective evolutionary algorithms perform competitively. As the number of objectives increases, PICEA-g and HypE, which have comparable performance, tend to outperform NSGA-II, e-MOEA, and MOEA/D. All the algorithms outperformed random search.\n\nLiterature Review:", "role": "user" }, { "content": "In interactive algorithms (selection during search, shown in Table XIII), the DMs need to provide preference information to the algorithms interactively. These algorithms can reduce the computational load online and introduce the preference information progressively BIB001 ]. There are several different preference models, such as goal point(s), reference direction, and preference polyhedron. 8.2.1. Goal Specification. Reference point based NSGA-II (R-NSGA-II) introduced a preference operator that prefers solutions closer to the goal points and de-emphasizes solutions within a -neighborhood of a goal point . In BIB005 , R-NSGA-II was integrated into a preference-based many-objective evolutionary testing (P-MOET) method to solve a seven-objective software engineering problem. Jaimes et al. [2011b Jaimes et al. [ , 2013 used the Tchebycheff preference relation to compare solutions. The region of interest (ROI) is defined as a neighborhood region near the goal point. For two solutions in the ROI, the Tchebycheff preference becomes classical Pareto dominance. Otherwise, the one nearer to the goal point is preferred. The experimental results showed that the Tchebycheff relation improves the convergence of NSGA-II without sacrificing the distribution [Jaimes et al. 2013 ]. 8.2.2. Reference Direction. In reference direction based NSGA-II (RD-NSGA-II) BIB002 , the DMs are supposed to supply a reference direction in the objective space in each iteration. Then the solutions are ranked with the aid of an achievement scalarizing function and the crowding distance value. The algorithm is tested on DTLZ functions with up to 10 objectives. 8.2.3. Preference Polyhedron. BIB006 proposed an interactive evolutionary algorithm (IEA) based on the preference polyhedron theory. During the search process, the DM periodically obtains a nondominated solution set and chooses the most preferred one. BIB007 ] WFG (7) Preference solutions PICEA-w WFG (7) PICEA-g BIB008 ] WFG(10) BIB003 WFG(13) LPICEA-g ] WFG(4) MUF-EA BIB004 DTLZ (10) Marginal utility function", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nA resin-modified glass ionomer restorative: three-year clinical results.\nAbstract 1:\nResin modified glass ionomer ( RMGI ) restorative material s have gained popularity in recent years . Their use is most often indicated in Class III and Class V cavities in adults and in numerous applications in children . This popularity in use has taken place in the absence of scientific knowledge of the RMGI material s. Lacking are adequate clinical trials to vali date the proposed indications . The purpose of this study was to examine a representative RMGI in cervical abrasions and root caries in adults . Patients were recalled up to three years to evaluate st and ard clinical criteria . Results found the RMGI to be inferior to conventional composite resin in similar applications . The most noted deficiencies were in color stability and anatomic form , or wear of the RMGI . The results of this prospect i ve clinical trial would suggest a limited longevity for RMGI compared to traditional restorative material s. This study also reinforces the need for evidence of clinical performance prior to making decisions regarding material selection\n\n\nTitle 2:\nPrevalence and Distribution of Root Caries in Pomerania, North-East Germany\nAbstract 2:\nThe aim of this study was to assess the prevalence and distribution of root caries in the adult population of Pomerania , Germany . The study sample comprised 6,267 r and omly selected subjects who were scheduled for examination from 1997 to 2001 ( population -based cross-sectional study , response rate : 69 % , age range 20–79 years ) . 499 edentulous persons were excluded from the dental examination ( 12 % ) performed according to WHO guidelines ( 1997 ) . In the statistical analysis , frequency distributions , means and median values were calculated and subdivided for different age groups . The percentage of exposed and affected root surfaces increased with age ( root caries index 4.6–10.6 % ) . The mean number of carious/filled root surfaces ( RDFS ) rose from 0.4 per person ( 25–34 years ) to 2.3 ( 55–64 years ) and dropped for seniors due to the low number of retained teeth . Fillings comprised the largest proportion of the RDFS ( 69.5 % ) . Most caries/fillings were found on buccal surfaces , the highest rate in m and ibular premolars . With about half of over-45-year-olds having at least one carious/filled root surface and increasing number of retained teeth in seniors , root caries is a relevant and probably growing disease in Pomerania and East Germany\n\n\nTitle 3:\nART and Conventional Root Restorations in Elders after 12 Months\nAbstract 3:\nSuccessful use of atraumatic restorative treatment ( ART ) in children has been reported , but little information is available regarding its use in older adults . The hypothesis of this study was that survival rates of root restorations placed by both ART and the conventional technique were similar . Root-surface caries lesions in 103 institutionalized elders in Hong Kong were treated r and omly by either : ( 1 ) the conventional approach — caries removed by dental burs , and the cavity filled with light-cured resin-modified glass ionomer ; or ( 2 ) the ART approach — caries removed by h and instruments , and the cavity filled with chemically cured high-strength glass ionomer . In total , 84 conventional and 78 ART restorations were placed . After 12 months , 63 conventional and 59 ART restorations were review ed , and the respective 12-month survival rates were 91.7 % and 87.0 % ( p > 0.05 ) . It is concluded that the survival rates of both types of root restorations were high and similar\n\n\nTitle 4:\nTwo-year clinical performance of glass ionomer and resin composite restorations in xerostomic head- and neck-irradiated cancer patients\nAbstract 4:\nThe aim of this study was to evaluate the clinical performance of adhesive filling material s in class V cavities in xerostomic head- and neck-irradiated cancer patients , in terms of marginal adaptation , anatomical form and recurrent caries . We selected 35 high-caries-risk , post-radiation , xerostomic adults with ≥3 cervical carious lesions in the same arch . Every patient received a KetacFil ( KF ) , PhotacFil ( PF ) and Herculite XRV ( HX ) restoration . Patients were instructed to use a neutral 1 % sodium fluoride gel in custom trays , on a daily basis . After 6 , 12 , 18 and 24 months , the restorations were examined for material loss , marginal integrity and recurrent caries . Fluoride compliance was determined at each recall appointment and recorded as the percentage of recommended use during that interval [ compliance of ≤50 % = NFUs , > 50 % = FUs ] . Only 30 patients were available for recall at 6 months , with 28 patients at 12 and 18 months , and 27 patients at 24 months . In the NFU group , differences in recurrent caries were found between KF and HX at all observation times ( p < 0.05 ) . Differences ( p < 0.05 ) in adaptation and /or anatomical form were found between KF and PF in NFUs after 18 and 24 months . In FUs , significant differences were observed between KF and PF , and KF and HX after 6 and 12 months , between KF and HX , PF and HX after 18 and 24 months . In summary , glass ionomers ( especially the conventionally setting formulation ) provide clinical caries inhibition but erode easily , while composite resin provides greater structural integrity\n\n\nTitle 5:\nA clinical evaluation of the restoration of root surface caries.\nAbstract 5:\nRoot surface caries is of growing importance because its prevalence increases with age , and the population of the United States is growing older while edentulism and tooth loss rates have declined . Few clinical studies have evaluated material s used for the restoration of active root caries lesions . This study evaluated a Type II glass ionomer cement and a microfilled composite resin , both placed in preparations without mechanical retention or acid etching of enamel , in the restoration of root caries . Fifty adult volunteers with active root caries received one or both material s with the material chosen r and omly . Patients were recalled after 24 months to evaluate restorations for retention , additional caries , marginal integrity , and overall clinical acceptability . Seventy-seven restorations were available for reevaluation . Forty-five percent of the glass ionomer and 73 % of the composite restorations were clinical ly acceptable after 24 months . Of the glass ionomers , 39 % were fully retained compared with 73 % of composite restorations . Among those partially or fully retained , 25 % of the glass ionomer restorations had minimal loss of marginal integrity and 30 % had extensive loss while 53 % and 9 % of composite restorations had minimal and extensive loss , respectively . Most restorations were clinical ly unacceptable because of restorative material loss . Substantial numbers of glass ionomer cement and composite resin restorations were lost . This may be the result of difficulties in maintaining isolation and obtaining a proper gingival seal . Thus , routine use of mechanical retention is still highly recommended to reduce the loss of restorative material\n\n\nTitle 6:\nA clinical comparison of glass ionomer, resin-modified glass ionomer and resin composite restorations in the treatment of cervical caries in xerostomic head and neck radiation patients.\nAbstract 6:\nControversy exists as to whether there is less secondary caries at the margins of glass ionomer restorations compared with other material s that do not release fluoride . This study examined the incidence of secondary caries for three types of restorative material s in Class V restorations in xerostomic patients . The study group consisted of 45 high caries-risk adult patients who had undergone head and neck irradiation for the treatment of cancer . All were substantially xerostomic and in need of at least three restorations in the same arch . Every patient received a restoration with each of the test material s , a conventional glass ionomer ( GI ) , a resin modified glass ionomer ( RMGI ) and a resin composite ( C ) . Patients were instructed in the daily use of a neutral pH sodium fluoride gel in custom trays . Recall appointments were made at 6 , 12 , 18 and 24 months , and the restorations were examined for material loss , marginal integrity and recurrent caries at the restoration margin . Fluoride compliance was determined at each recall period and recorded as the percentage of recommended use during that interval . Patients were categorized at the end of the study as fluoride non-users if their average compliance was 50 % or less . Those with greater than 50 % compliance were categorized as fluoride users . In the latter group , no recurrent caries was found for any of the restorations , whereas a material -dependent incidence of recurrent caries was found in the fluoride non-user group . None of the GI , one RMGI and eight C restorations failed due to recurrent caries . For the fluoride non-user patients , Fishers exact test ( p=0.05 ) showed no statistical difference between GI and RMGI but statistical differences were found among those material s and resin composite at each recall period . Recurrent caries reductions for GI and RMGI relative to C were greater than 80 % in xerostomic patients not using topical fluoride supplementation\n\n\nTitle 7:\nA clinical comparison of glass ionomer (polyalkenoate) and silver amalgam restorations in the treatment of Class 5 caries in xerostomic head and neck cancer patients.\nAbstract 7:\nFifty-four pairs of restorations ( one glass ionomer and the other amalgam ) were placed in the mouths of 36 xerostomic head and neck cancer patients . Patients were either fluoride users or fluoride nonusers . In patients who used a daily application of a mildly acidic ( pH 5.8 ) sodium fluoride gel , glass-ionomer cements failed and amalgam restorations did not ( P < 0.0001 ) . In patients who neglected to use their topical fluoride as directed , glass-ionomer cement restorations did not fail , but amalgam restorations did ( P < 0.001 ) . The mean time to restoration loss for both restorative material s was 8.5 months . In severely xerostomic patients these findings were exaggerated\n\n\nTitle 8:\nCONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials\nAbstract 8:\nThe CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . To encourage dissemination of the CONSORT 2010 Statement , this article is freely accessible on bmj.com and will also be published in the Lancet , Obstetrics and Gynecology , PLoS Medicine , Annals of Internal Medicine , Open Medicine , Journal of Clinical Epidemiology , BMC Medicine , and Trials", "role": "user" }, { "content": "There is a need for more research in this area as many of the studies identified in this systematic review treated post-radiation , xerostomic patients which are not typical of the general population .", "role": "assistant" } ]

[ { "content": "You will be shown a paragraph from a biomedical research article. Your task is to extract all drug combinations appearing in a specific sentence within the paragraph. Each drug combination should be assigned to one of the following three categories:\n\n- POS: Indicates a positive interaction between the drugs in the combination; for instance, drugs that have an additive or synergistic effect.\n- NEG: Indicates a negative interaction between the drugs in the combination; for instance, combining these drugs might result in adverse side effects, or might reduce their efficacy.\n- COMB: Indicates that the drugs are given in combination, but the type of interaction between the drugs cannot be determined based on the provided context.\n\nPlease format your answer as a JSON array. Each entry in the array should itself be an array formatted as [<drug_1>, <drug_2>, ..., <drug_n>, <category>] where <category> is one of the three categories listed above and <drug_1>, ..., <drug_n> are drug names copied verbatim from the input sentence. Different combinations may involve different numbers of drugs; in other words, the `n` in <drug_n> may vary.\n\nAs an example, the following output describes two extracted drug combinations; one between two drugs, and one between three drugs:\n\n[[\"artesunate\", \"artemether\", \"COMB\"], [\"Nifedipine\", \"Labetalol\", \"Prazosin\", \"POS\"]]\n\nThe paragraph and specific sentence are below. You should only extract relationships expressed in the specific sentence; the paragraph is provided for context.\n\nIn your output, return only the JSON array and no other text. If no drug combinations appear, return an empty array `[]`.\n\nparagraph: Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer . Metronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.\n\nsentence: Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer .", "role": "user" }, { "content": "[[\"5-fluorouracil\", \"oxaliplatin\", \"irinotecan\", \"COMB\"]]", "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:\ndomain wall fermions provide a very elegant solution to the problem of chiral fermions on the lattice ; in the limit of infinite length @xmath0 of the fifth dimension chiral symmetry becomes exact even when the lattice spacing does not vanish .\nsince practical implementations can only deal with finite @xmath0 some residual chiral symmetry breaking is induced .\nthis breaking goes to zero as @xmath0 goes to infinity .\nit is therefore important to chose the parameters of the simulation so that an acceptably small chiral symmetry breaking is achieved at a reasonably small @xmath0 .\nrecently , rbc @xcite and cp - pacs @xcite reported that by using the iwasaki gauge action , rather than the wilson action , a significant reduction of the residual chiral symmetry breaking is achieved for the same @xmath0 and lattice spacing @xmath1 .\nit is instructive therefore to study the effects of the gauge action in a systematic way .\nwe report here our results from our studies of the residual chiral symmetry breaking for the 1-loop symanzik , iwasaki @xcite , and dbw2 actions .\nthe dbw2 action was introduced in @xcite and it was shown by qcd - taro in @xcite that it is a good approximation of the rg flow on the two dimensional plane of the plaquette and rectangle couplings .\nall the above gauge actions can in general be written as @xmath2 where @xmath3 is the standard plaquette in the @xmath4 plane , and @xmath5 and @xmath6 denote the real part of the trace of the ordered product of su(3 ) link matrices along @xmath7 rectangles and @xmath8 paths , respectively .\nfor the 1-loop symanzik action the coefficients @xmath9 , @xmath10 , and @xmath11 are computed in tadpole improved one loop perturbation theory @xcite . while @xmath12 and @xmath13 for both iwasaki and dbw2 , @xmath14 and @xmath15 respectively . as a measure of the chiral symmetry breaking we\nuse the so called residual mass .\nthe residual mass is defined as @xmath16 where @xmath17 is the mid - point chiral symmetry breaking term which appears in the axial ward identity of domain wall fermions , and @xmath18 is sufficiently large to avoid short - distance lattice artifacts .\nin addition , for each configuration we have defined the ratio @xmath19 which is very useful in monitoring the chiral symmetry breaking on each configuration .\nwe measured the light hadron spectrum , the residual mass , and the ratio @xmath20 of eq .\n[ eq : cnfmres ] on @xmath21 lattices .\nwe used 50 symanzik and iwasaki lattices , and 90 dbw2 lattices .\nfor all the actions tested the lattice spacing was tuned to @xmath22 using the @xmath23 mass at the chiral limit to set the scale .\nthis matches the wilson gauge action at @xmath24 .\nthe corresponding @xmath25 values are given in table [ table : sim ] .\nwe have optimized the value of the domain wall height @xmath26 . for all actions except the dbw2\n, the optimum value of @xmath26 was found to be 1.8 .\nfor the dbw2 action the optimum @xmath26 is 1.7 , which is what we used for the results reported below .\n.the simulation parameters for all the actions [ cols=\"<,<,<,<,<\",options=\"header \" , ] + in figure [ fig : spikes ] we plot the the ratio of eq . [ eq : cnfmres ] summed over time slices 4 to 16 .\nas we can see , the wilson and symanzik action data ( squares and stars ) show very large fluctuations .\nbut the iwasaki and dbw2 show a baseline of small fluctuations interrupted by spikes .\npresumably the large fluctuations observed for the wilson and symanzik action are due to a very high frequency of spikes .\nthe important feature of figure [ fig : spikes ] is that the number of spikes is drastically reduced for the dbw2 action .\nit is expected that these spikes are spatially localized and occur on configurations that have eigenvalues of the transfer matrix in the 5th dimension very close to 1 .\nwe have confirmed these expectations by measuring both the spacial structure of the spikes and studying the spectral flow of the 4d wilson dirac operator on these configurations ( see talk by t. izubuchi at this conference ) . for bare quark mass 0.02 summed over t from 4 to 16 .\nthe fancy squares correspond to wilson action , the bursts to symanzik , the diamonds to iwasaki and the octagons to dbw2.,width=264 ] in fig .\n[ fig : mres_vs_ls ] we show the @xmath0 dependence of the residual mass .\nall data are for @xmath27 and bare quark mass @xmath28 .\nthe value of @xmath29 is within @xmath30 of @xmath31 .\nsince we are interested in differences by factors of ten , and since we know that the @xmath32 depends mildly on the quark mass @xcite , the data can be directly compared as is . for completeness\nwe also present the cp - pacs residual mass results @xcite .\nwe have confirmed their results for @xmath33 ( diamond in fig .\n[ fig : mres_vs_ls ] ) . for the symanzik action we ran at @xmath33 only ; the residual mass turns out to be smaller by a factor of three than the wilson residual mass at the same @xmath0 , and it is larger by a factor of two than that of the iwasaki action .\nthe dbw2 action not only gives the smallest residual mass , but also has the steepest decrease as a function of @xmath0 .\nsince we have only three points , we can not claim that we know the asymptotic behavior ; it is interesting to note however , that a simple fit gives us @xmath34 with @xmath35 .\nshamir s one loop perturbative @xcite result is @xmath36 .\ndependence of @xmath37 at @xmath38 .\nthe octagons correspond to the dbw2 action , the squares ( cp - pacs @xcite ) and diamond ( rbc ) to iwasaki , the burst to symanzik , and the fancy squares to wilson.,width=264 ] for the dbw2 action , in addition to the residual mass tests we have also measured the light hadron spectrum and pseudoscalar decay constants at both @xmath39 and @xmath40 .\nthe residual mass at @xmath40 is about a factor of two smaller than the wilson residual mass at @xmath39 ( @xmath33 ) .\nthis allows simulations at coarser lattice spacing and at moderate values of @xmath0 with minimal chiral symmetry breaking .\nour spectrum results show that the already very good scaling of domain wall fermions with wilson gauge action is preserved with the dbw2 action . for a detailed presentation of our spectrum data\nsee the talk by y. aoki at this conference .\nit has been argued @xcite that the enhancement of chiral symmetry breaking is caused by configurations which also represent changing topology ( _ i.e. _ small instantons and/or dislocations ) .\nour data ( fig .\n[ fig : spikes ] ) indicate that both the iwasaki and the dbw2 actions suppress these configurations .\nin fact , iwasaki @xcite has argued that his choice of the @xmath10 coefficient is on the boundary separating the space of actions which have stable instantons and those which have unstable instantons .\nconsequently , when these improved actions are used , the question whether the topology changes arises .\nwe have measured the topological charge on all the actions we tested , and we have concluded that the topology changes with a significantly lower rate for the dbw2 action .\nthe problem gets more severe as we get closer to the continuum limit .\nthe iwasaki action also shows signs of slow topology changing .\nwe believe that this slowdown in the topology change can be overcome by using over - relaxed heatbath algorithm and by simply running for a long time before saving configurations . given the considerable cost of measuring fermionic observables with dwf we can afford to do so .\nusing the dbw2 action , we have essentially eliminated the problem of residual chiral symmetry breaking for domain wall fermions at @xmath41 with @xmath33 .\nthe dbw2 residual mass is about an order of magnitude smaller than the iwasaki @xmath37 , and two orders of magnitude smaller than the wilson @xmath37 . assuming a @xmath42 string tension , the bare dbw2 residual mass is about @xmath43 .\nthe observed topology change slowdown may be handled by using longer running between measurements .\nfinally , our results suggest that the dbw2 action should also be useful for overlap fermions , since it probably makes the approximation to the sign function converge faster by eliminating the small eigenvalues of the hermitian wilson dirac operator .", "role": "user" }, { "content": "we study the chiral properties of quenched domain wall fermions with several gauge actions . \n we demonstrate that the nearly translationally invariant modes in the fifth dimension that dominate the residual mass for wilson gauge action can be substantially suppressed using improved gauge actions . in particular , we study the symanzik action , the iwasaki action , the dbw2 action and compare them to the wilson action .", "role": "assistant" } ]

[ { "content": "You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your response other than the answer.\n\nParagraph: They regulate various biological processes, such as homeostasis, differentiation, embryonic development, and organ physiology [1] [2] [3] . The NR superfamily has been classified into seven families: NR0 (knirps or DAX like) [4, 5] ; NR1 (thyroid hormone like), NR2 (HNF4-like), NR3 (estrogen like), NR4 (nerve growth factor IB-like), NR5 (fushi tarazu-F1 like), and NR6 (germ cell nuclear factor like). Since they are involved in almost all aspects of human physiology and are implicated in many major diseases such as cancer, diabetes and osteoporosis, nuclear receptors have become major drug targets [6, 7] , along with G protein-coupled receptors (GPCRs) [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] , ion channels [18] [19] [20] , and kinase proteins [21] [22] [23] [24] . Identification of drug-target interactions is one of the most important steps for the new medicine development [25, 26] . The method usually adopted in this step is molecular docking simulation [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] . However, to make molecular docking study feasible, a reliable 3D (three dimensional) structure of the target protein is the prerequisite condition. Although X-ray crystallography is a powerful tool in determining protein 3D structures, it is time-consuming and expensive. Particularly, not all proteins can be successfully crystallized. For example, membrane proteins are very difficult to crystallize and most of them will not dissolve in normal solvents. Therefore, so far very few membrane protein 3D structures have been determined. Although NMR (Nuclear Magnetic Resonance) is indeed a very powerful tool in determining the 3D structures of membrane proteins as indicated by a series of recent publications (see, e.g., [44] [45] [46] [47] [48] [49] [50] [51] and a review article [20] ), it is also time-consuming and costly. To acquire the 3D structural information in a timely manner, one has to resort to various structural bioinformatics tools (see, e.g., [37] ), particularly the homologous modeling approach as utilized for a series of protein receptors urgently needed during the process of drug development [19, [52] [53] [54] [55] [56] [57] . Unfortunately, the number of dependable templates for developing high quality 3D structures by means of homology modeling is very limited [37] . To overcome the aforementioned problems, it would be of help to develop a computational method for predicting the interactions of drugs with nuclear receptors in cellular networking based on the sequences information of the latter. The results thus obtained can be used to pre-exclude the compounds identified not in interaction with the nuclear receptors, so as to timely stop wasting time and money on those unpromising compounds [58] . Actually, based on the functional groups and biological features, a powerful method was developed recently [59] for this purpose. However, further development in this regard is definitely needed due to the following reasons. (a) He et al. [59] did not provide a publicly accessible web-server for their method, and hence its practical application value is quite limited, particularly for the broad experimental scientists; (b) The prediction quality can be further enhanced by incorporating some key features into the formulation of NR-drug (nuclear receptor and drug) samples via the general form of pseudo amino acid composition [60] . The present study was initiated with an attempt to develop a new method for predicting the interaction of drugs with nuclear receptors by addressing the two points. As demonstrated by a series of recent publications [10, 18, [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] and summarized in a comprehensive review [60] , to establish a really effective statistical predictor for a biomedical system, we need to consider the following steps: (a) select or construct a valid benchmark dataset to train and test the predictor; (b) represent the statistical samples with an effective formulation that can truly reflect their intrinsic correlation with the object to be predicted; (c) introduce or develop a powerful algorithm or engine to operate the prediction; (d) properly perform cross-validation tests to objectively evaluate the anticipated accuracy of the predictor; (e) establish a user-friendly web-server for the predictor that is accessible to the public. Below, let us elaborate how to deal with these steps. The data used in the current study were collected from KEGG (Kyoto Encyclopedia of Genes and Genomes) [71] at http://www.kegg.jp/kegg/. KEGG is a database resource for understanding high-level functions and utilities of the biological system, such as the cell, the organism and the ecosystem, from molecular-level information, especially large-scale molecular datasets generated by genome sequencing and other high-throughput experimental technologies. Here, the benchmark dataset can be formulated as\n\nwhere is the positive subset that consists of the interactive drug-NR pairs only, while the negative subset that contains of the non-interactive drug-NR pairs only, and the symbol represents the union in the set theory. The so-called \"interactive\" pair here means the pair whose two counterparts are interacting with each other in the drug-target networks as defined in the KEGG database [71] ; while the \"non-interactive\" pair means that its two counterparts are not interacting with each other in the drug-target networks. The positive dataset contains 86 drug-NR pairs, which were taken from He et al. [59] . The negative dataset contains 172 non-interactive drug-NR pairs, which were derived according to the following procedures: (a) separating each of the pairs in into single drug and NR; (b) re-coupling each of the single drugs with each of the single NRs into pairs in a way that none of them occurred in ; (c) randomly picking the pairs thus formed until reaching the number two times as many as the pairs in . The 86 interactive drug-NR pairs and 172 non-interactive drug-NR pairs are given in Supplementary Information S1, from which we can see that the 86 + 172 = 258 pairs in the current benchmark dataset are actually formed by 25 different NRs and 53 different compounds. Since each of the samples in the current network system contains a drug (compound) and a NR (protein), the following procedures were taken to represent the drug-NR pair sample. First, for the drug part in the current benchmark dataset, we can use a 256-D vector to formulate it as given by\n\nwhere D represents the vector for a drug compound, and d i its i-th (i = 1,2, ,256) component that can be derived by following the \"2D molecular fingerprint procedure\" as elaborated in [10] . The 53 molecular fingerprint vectors thus obtained for the 53 drugs in are, respectively, given in Supplementary Information S2. The protein sequences of the 25 different NRs in are listed in Supplementary Information S3. Suppose the sequence of a nuclear receptor protein P with L residues is generally expressed by\n\nwhere 1 R represents the 1st residue of the protein sequence P , 2 R the 2nd residue, and so forth. Now the problem is how to effectively represent the sequence of Equation (3) with a non-sequential or discrete model [72] . This is because all the existing operation engines, such as covariance discriminant (CD) [17, 65, [73] [74] [75] [76] [77] [78] [79] , neural network [80] [81] [82] , support vector machine (SVM) [62] [63] [64] 83] , random forest [84, 85] , conditional random field [66] , nearest neighbor (NN) [86, 87] ; K-nearest neighbor (KNN) [88] [89] [90] , OET-KNN [91] [92] [93] [94] , and Fuzzy K-nearest neighbor [10, 12, 18, 69, 95] , can only handle vector but not sequence samples. However, a vector defined in a discrete model may completely lose all the sequence-order information and hence limit the quality of prediction. Facing such a dilemma, can we find an approach to partially incorporate the sequence-order effects? Actually, one of the most challenging problems in computational biology is how to formulate a biological sequence with a discrete model or a vector, yet still keep considerable sequence order information. To avoid completely losing the sequence-order information for proteins, the pseudo amino acid composition [96, 97] or Chou's PseAAC [98] was proposed. Ever since the concept of PseAAC was proposed in 2001 [96] , it has penetrated into almost all the areas of computational proteomics, such as predicting anticancer peptides [99] , predicting protein subcellular location [100] [101] [102] [103] [104] [105] [106] , predicting membrane protein types [107, 108] , predicting protein submitochondria locations [109] [110] [111] [112] , predicting GABA(A) receptor proteins [113] , predicting enzyme subfamily classes [114] , predicting antibacterial peptides [115] , predicting supersecondary structure [116] , predicting bacterial virulent proteins [117] , predicting protein structural class [118] , predicting the cofactors of oxidoreductases [119] , predicting metalloproteinase family [120] , identifying cysteine S-nitrosylation sites in proteins [66] , identifying bacterial secreted proteins [121] , identifying antibacterial peptides [115] , identifying allergenic proteins [122] , identifying protein quaternary structural attributes [123, 124] , identifying risk type of human papillomaviruses [125] , identifying cyclin proteins [126] , identifying GPCRs and their types [15, 16] , discriminating outer membrane proteins [127] , classifying amino acids [128] , detecting remote homologous proteins [129] , among many others (see a long list of papers cited in the References section of [60] ). Moreover, the concept of PseAAC was further extended to represent the feature vectors of nucleotides [65] , as well as other biological samples (see, e.g., [130] [131] [132] ). Because it has been widely and increasingly used, recently two powerful soft-wares, called \"PseAAC-Builder\" [133] and \"propy\" [134] , were established for generating various special Chou's pseudo-amino acid compositions, in addition to the web-server \"PseAAC\" [135] built in 2008. According to a comprehensive review [60] , the general form of PseAAC for a protein sequence P is formulated by\n\nwhere the subscript  is an integer, and its value as well as the components ( 1, 2, , ) u u   will depend on how to extract the desired information from the amino acid sequence of P (cf. Equation (3)). Below, let us describe how to extract useful information to define the components of PseAAC for the NR samples concerned. First, many earlier studies (see, e.g., [136] [137] [138] [139] [140] [141] ) have indicated that the amino acid composition (AAC) of a protein plays an important role in determining its attributes. The AAC contains 20 components with each representing the occurrence frequency of one of the 20 native amino acids in the protein concerned. Thus, such 20 AAC components were used here to define the first 20 elements in Equation (4); i.e., (1) ( 1, 2, , 20) ii fi   (5) where f i (1) is the normalized occurrence frequency of the i-th type native amino acid in the nuclear receptor concerned. Since AAC did not contain any sequence order information, the following steps were taken to make up this shortcoming. To avoid completely losing the local or short-range sequence order information, we considered the approach of dipeptide composition. It contained 20 × 20 = 400 components [142] . Such 400 components were used to define the next 400 elements in Equation (4); i.e., (2) 20 ( 1, 2, , 400) jj fj\n\nwhere (2) j f is the normalized occurrence frequency of the j-th dipeptides in the nuclear receptor concerned. To incorporate the global or long-range sequence order information, let us consider the following approach. According to molecular evolution, all biological sequences have developed starting out from a very limited number of ancestral samples. Driven by various evolutionary forces such as mutation, recombination, gene conversion, genetic drift, and selection, they have undergone many changes including changes of single residues, insertions and deletions of several residues [143] , gene doubling, and gene fusion. With the accumulation of these changes over a long period of time, many original similarities between initial and resultant amino acid sequences are gradually faded out, but the corresponding proteins may still share many common attributes [37] , such as having basically the same biological function and residing at a same subcellular location [144, 145] . To extract the sequential evolution information and use it to define the components of Equation (4), the PSSM (Position Specific Scoring Matrix) was used as described below. According to Schaffer [146] , the sequence evolution information of a nuclear receptor protein P with L amino acid residues can be expressed by a 20 L matrix, as given by\n\nwhere (7) were generated by using PSI-BLAST [147] to search the UniProtKB/Swiss-Prot database (The Universal Protein Resource (UniProt); http://www.uniprot.org/) through three iterations with 0.001 as the E-value cutoff for multiple sequence alignment against the sequence of the nuclear receptor concerned.\n\nQuestion: What biological factors for nuclear receptors regulate?", "role": "user" }, { "content": "homeostasis, differentiation, embryonic development, and organ physiology", "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:\nthe digital sky project is an npaci ( national partnership for advanced computing infrastructure , an nsf computer science initiative ) sponsored program to study the role of advanced computational systems ( both processor and network oriented ) in the distribution of data from multiple large area , digital sky surveys .\nthis project was originally conceived by tom prince , the principal investigator for the project , in 1996 as way to leverage high performance computing to tackle some of the incipient problems involved in federating and mining the large amounts of astronomical information that were beginning to become available .\nthe project was initially funded in 1997 , and has since grown to include a large number of participants from caltech astronomy , the caltech center for advanced computing research , the infrared processing and analysis center , the jet propulsion laboratory , and the san diego center for supercomputing .\none of the fundamental tenets of the digital sky project is the requirement not to develop another analysis tool ( which is the last thing needed by the astronomical community ) .\ninstead , we conceived that the project would be able to optimally achieve its goals by serving as a technology demonstrator .\ninitially , we focused on identifying the set of requirements to create a prototype virtual observatory ( _ i.e. _ , the `` digital sky '' ) .\nafterwards , we researched the core problem of astronomical data federation .\ncurrently , we are exploring the concept of image data mining .\noverall , our approach is designed to employ a minimalist design , that focuses more on integrating existing components in cooperation with community experts ( see figure 1 for an overview ) .\nany knowledge or applications developed in the course of this project have been disseminated to the appropriate experts within the community who are in interested in identifying and attempting to solve the complex problems that arise in federating disparate , large area , digital sky surveys .\nthe first major task we tackled was the identification of the types of issues which needed to be successfully addressed in order to seamlessly federate highly distributed datasets in order to facilitate knowledge discovery ( see also , szalay & brunner 1998 ) .\nthis highly desirable end - result is now more commonly known as a virtual observatory .\nformally , we split our list of identified issues into two categories : basic and advanced , based on the difficulty of successfully implementing the appropriate service .\nthe basic services listed below often are provided as part of a commercial database system , which most of the major archive centers already utilize .\ncatalog search engines . : : in order to be fully operable within a virtual observatory framework , a dataset must be able to support , at a minimum , basic query functionality , such as spatial range queries .\nsystem metadata .\n: : in order to develop general purpose tools , as well as simplify the learning process , archives need to implement a standardized format for describing both the data contained within an archive and the services which the archive can perform . relationship generators . : : a virtual observatory must be able to support the cross - identification of billions of sources in both a static and dynamic state over thousands of square degrees in a multi - wavelength domain ( radio to x - ray ) . image metadata search engines . : : image data should be able to be selected based on the actual metadata of the images , for example , spatial location , observational date , _ etc . _ image archive access .\n: : archived image data should be accessible to an end user , even if it is merely served from an ftp site .\nquery optimizations .\n: : within a virtual observatory , a query could be distributed to multiple archives . as a result\ncertain optimizations can be performed depending on the status of the underlying network topology ( _ e.g. _ , network weather ) in order to balance the resulting server load .\noptimistically , a learning mechanism can be applied to analyze queries , and using the accumulated knowledge gained from past observations ( _ i.e. _ , artificial intelligence ) , queries can be rearranged in order to provide further performance enhancements .\nthe following set of services are more advanced , requiring extra effort , beyond the more common basic services , to be fully implemented .\nthese services often require post - processing of extracted data in order to be performed , and can , therefore , make use of specialized hardware . computational & data grid .\n: : numerous , complex queries will swamp traditional archive topologies . instead , a virtual observatory should be implemented to minimize network traffic by utilizing advanced computational systems to perform complex analysis ( _ e.g. _ , correlation analysis ) on the server side as opposed to the client .\nthis solution can efficiently capitalize on parallel i / o and computing resources , as well as replicated and persistent datasets , in order to simplify the implementation of the following advanced services .\nimage processing .\n: : often , a user will want to post - process an image data request in order to obtain a scientifically useful result . in order to implement this feature\n, basic image processing operations need to be available on the image server , or close to it , to perform , at a minimum , basic image operations such as mosaicing , sub - setting and registration . statistical analysis .\n: : in some cases , a user will be more interested in a particular statistical analysis of a query result than the actual resulting dataset itself ( _ e.g. _ , a histogram , statistical measure , or cluster finding code ) .\nin such cases , a user of a virtual observatory should be able to filter the query result using either an available toolkit or else custom developed statistical codes as necessary .\n: : undoubtedly , a major component of a virtual observatory is the ability to visualize data , which might stem from simple graphical representations of catalog data ( as part of a statistical analysis ) , seamless serving of image data , or virtual explorations of parameter space . in certain scenarios , such as defining a new aggregate class of objects ( _ e.g.\n_ , clusters ) or to aid in the mining of the aggregate data , this process is integrally linked to the actual analysis which is the desired end - goal .\nmachine learning .\n: : when exploring the forthcoming datasets , especially after they have been federated , traditional techniques will quickly be swamped and rendered hopelessly antiquated .\nthe only efficient technique to explore the vast , newly opened portions of parameter space is to capitalize on the inherent capabilities of the very compute resources which are facilitating the construction of the virtual observatory .\nthese capabilities give rise to the adoption of algorithms which let the computer mine for the priceless nuggets in the mountains of data , and include techniques which can be either supervised ( _ e.g. _ , find everything similar to this particular object ) or unsupervised ( _ e.g. _ , find interesting things ) .\nthe overriding design principle that we have advocated is to encapsulate the archival services ( both in design and implementation ) which will simplify the effort required to provide interoperability between different archives ( _ i.e. _ , a plug - n - play model ) .\nthis approach allows for future growth by providing a blueprint for new archives to follow and thereby capitalize on existing infrastructures via the adoption of community standards .\nthis common service approach , reduces the overall cost to the community by providing a standardized code base , and facilitates interoperability for analysis tool providers . in order to be successful\n, a virtual observatory must be able to grow through the incorporation of new surveys and datasets in addition to its original tenants .\nthis requirement necessitates the adoption of archival standards for exchanging not only the actual data , but also both metadata and metaservices between constituent archives .\nthis will allow for different analysis tools to be able to seamlessly work with data extracted from different archives .\nall of this work will culminate in the creation of a national ( and eventually global ) virtual observatory , which will eventually enable and empower scientists and students anywhere to do important , cutting - edge research .\nbefore any advanced data exploration or mining tools can be employed , however , the data of interest must be federated .\nindeed , this data federation service is one of the primary requirements for the national virtual observatory ( nvo ) . federating these different datasets , however , is a challenging task . as this project s initial focus , we researched solutions to the problems inherent in the dynamic , multi - wavelength cross - identification of large numbers of astronomical sources .\nspecifically , we identified the following topics , which we feel must be addressed in order to develop a robust cross - identification service .\nfirst , in order to handle the large amounts of dynamic , multi - wavelength information , including custom user datasets , a data federation framework must utilize the forthcoming national computational grid to optimally perform the necessary calculations .\nthese calculations can be quite complex , particularly in the case of multi - wavelength data which has varying positional accuracies ( i.e. , beam widths ) or involves different physical phenomena . as a result , this framework must be able to incorporate not only user defined probabilistic associations within the federation algorithms , but also multiple associations ( i.e. , binaries and clusters ) and previously published results during the cross - identification process . finally , the newly generated data must be able to remain persistent so that data mining algorithms can be applied to the ( potentially computationally expensive ) result . as an initial technology demonstration , we developed a custom data federation service which utilized an optimal data - chunking algorithm allowing it to easily scale with the size of the resulting datasets ( see figure 2 for a demonstration ) .\nthe majority of these tests focused on data from the 2mass ( 2 micron all sky survey , _ cf . _\nskrutskie _ et al . _ ) and dposs ( digitized palomar observatory sky survey , djorgovski _ et al . _ 1998 )\nprojects . as a result of its efficacy ,\nthis software was incorporated by the 2mass survey into its quality assurance pipeline as well as the infrared science archive ( irsa ) as the core of its data federation service .\nwe also developed probabilistic association techniques , building on some of the pioneering work by lonsdale _\net al . _ ( 1998 ) in order to federate the rosat bright source catalog ( which has relatively large spatial uncertainties ) with available optical datasets ( _ e.g. _ , rutledge _ et al . _ 2000\nthis work is now being extended to provide an unbiased quantification of quasars and their environments ( brunner _ et al . _\n2001 , in preparation ) .\nwith the success of the ongoing cross - identification work , the project has now refocused on the challenges of exploring image ( or pixel ) parameter space .\nideally , a virtual observatory should be able to generate seamless views of the universe from any available image dataset .\nthis process , however , is complicated by various observational artifacts ( see figure 3 for a demonstration ) . in order to simplify the development ,\nwe have initially separated the overall task into the generation of scientifically calibrated datasets from the generation of visually clean images ( which are ideally suited for public outreach ) . as a demonstration of the former , we have mosaiced multiple dposs plates in an effort to explore diffuse emission over very large angular scales ( see , _\ne.g. _ , mahabal _ et al .\n_ and jacob _ et al . _\nthis volume ) . the latter project has developed into an astronomical equivalent of the popular teraserver project , which provides the ability to pan and zoom around space - based images of earth .\nthis new project , aptly named virtualsky , is accesible online at ( williams , r 2000 , private communication ) , allows a user to pan and zoom around various astronomical datasets in an analogous fashion .\nwe wish to thank the members of the digital sky project , which is funded through the npaci program ( nsf cooperative agreement aci-96 - 19020 ) , and the many pasadena area virtual observatory enthusiasts for stimulating discussions .\ndjorgovski , s. , de carvalho , r.r . , gal , r.r . ,\npahre , m.a . ,\nscaramella , r. , and longo , g. 1998 , in b. mclean , editors , _ the proceedings of the @xmath0 iau on new horizons from multi - wavelength sky surveys _ ,\niau symposium no .", "role": "user" }, { "content": "astronomy is entering a new era as multiple , large area , digital sky surveys are in production . \n the resulting datasets are truly remarkable in their own right ; however , a revolutionary step arises in the aggregation of complimentary multi - wavelength surveys ( _ i.e. _ , the cross - identification of a billion sources ) . \n the federation of these large datasets is already underway , and is producing a major paradigm shift as astronomy has suddenly become an immensely data - rich field . \n this new paradigm will enable _ quantitatively and qualitatively new science _ , from statistical studies of our galaxy and the large - scale structure in the universe , to discoveries of rare , unusual , or even completely new types of astronomical objects and phenomena . \n federating and then exploring these large datasets , however , is an extremely challenging task . \n the digital sky project was initiated with this task in mind and is working to develop the techniques and technologies necessary to solve the problems inherent in federating these large databases , as well as the mining of the resultant aggregate data . \n # 1_#1 _ # 1_#1 _ = # 1 1.25 in .125 in .25 in", "role": "assistant" } ]

[ { "content": "You will be presented with a paragraph from a COVID-19 literature. Your task is to classify the topics of this piece of text by choosing from the following categories:\n\n- Epidemic Forecasting: The content relates to predictions about the spread of COVID-19.\n- Treatment: The paragraph discusses therapeutic methods or medication for COVID-19.\n- Prevention: The content covers measures to prevent the spread of COVID-19.\n- Mechanism: The paragraph explains the biological mechanisms of the virus.\n- Case Report: The content is a report of a COVID-19 case.\n- Transmission: The paragraph discusses how COVID-19 is transmitted.\n- Diagnosis: The content is about diagnosing COVID-19 in individuals.\n\nYour classification should be provided as an element within a JSON array. The array should be formatted with topics enclosed in double quotes and separated by commas, following the JSON format, for example: [\"Topic1\", \"Topic2\", ...]. Include all applicable categories within the array. \nYour output should be a valid JSON array, and no additional text should be included in your response.\n\nArticle:\n\nCoronavirus disease (COVID-19) has been identified as a pandemic by the World Health Organization (WHO). It was initially detected in Wuhan, China and spread to other cities of China and all countries. It has caused many deaths and the number of infections became greater than 18 million as of 5 August 2020. This study aimed to analyze the situation of COVID-19 in Thailand and the challenging disease control by employing a dynamic model to determine prevention approaches. We employed a statistical technique to analyze the ambient temperature influencing the cases. We found that temperature was significantly associated with daily infected cases (p-value <0.01). The SEIR (Susceptible Exposed Infectious and Recovered) dynamic approach and moving average estimation were used to forecast the daily infected and cumulative cases until 16 June as a base run analysis using STELLA dynamic software and statistical techniques. The movement of people, both in relation to local (Thai people) and foreign travel (both Thai and tourists), played a significant role in the spread of COVID-19 in Thailand. Enforcing a state of emergency and regulating social distancing were the key factors in reducing the growth rate of the disease. The SEIR model reliably predicted the actual infected cases, with a root mean square error (RMSE) of 12.8. In case of moving average approach, RMSE values were 0.21, 0.21, and 0.35 for two, three and five days, respectively. The previous records were used as input for prediction that caused lower values of RMSE. Two-days and three-days moving averages gave the better results than SEIR model. The SEIR model is suitable for longer period prediction, whereas the moving average approach is suitable for short term prediction. The implementation of interventions, such as governmental regulation and restrictions, through collaboration among various sectors was the key factor for controlling the spreading of COVID-19 in Thailand.", "role": "user" }, { "content": "[\"Prevention\"]", "role": "assistant" } ]

[ { "content": "You are provided with the abstract of a scientific paper and the abstracts of the papers it references. Your task is to write a Related Work section for the main paper. This section should concisely summarize and integrate the key points from the cited abstracts, reflecting how they relate to the main paper's contributions and context. In your summary, use numerical citation markers like [1], [2], etc., to refer to the corresponding papers.\n\nMain Abstract:\nDespite the great success object detection and segmentation models have achieved in recognizing individual objects in images, performance on cognitive tasks such as image caption, semantic image retrieval, and visual QA is far from satisfactory. To achieve better performance on these cognitive tasks, merely recognizing individual object instances is insufficient. Instead, the interactions between object instances need to be captured in order to facilitate reasoning and understanding of the visual scenes in an image. Scene graph, a graph representation of images that captures object instances and their relationships, offers a comprehensive understanding of an image. However, existing techniques on scene graph generation fail to distinguish subjects and objects in the visual scenes of images and thus do not perform well with real-world datasets where exist ambiguous object instances. In this work, we propose a novel scene graph generation model for predicting object instances and its corresponding relationships in an image. Our model, SG-CRF, learns the sequential order of subject and object in a relationship triplet, and the semantic compatibility of object instance nodes and relationship nodes in a scene graph efficiently. Experiments empirically show that SG-CRF outperforms the state-of-the-art methods, on three different datasets, i.e., CLEVR, VRD, and Visual Genome, raising the Recall@100 from 24.99 to 49.95 , from 41.92 to 50.47 , and from 54.69 to 54.77 , respectively.\n\nCited Abstract(s):\n[1]: Most state-of-the-art techniques for multi-class image segmentation and labeling use conditional random fields defined over pixels or image regions. While region-level models often feature dense pairwise connectivity, pixel-level models are considerably larger and have only permitted sparse graph structures. In this paper, we consider fully connected CRF models defined on the complete set of pixels in an image. The resulting graphs have billions of edges, making traditional inference algorithms impractical. Our main contribution is a highly efficient approximate inference algorithm for fully connected CRF models in which the pairwise edge potentials are defined by a linear combination of Gaussian kernels. Our experiments demonstrate that dense connectivity at the pixel level substantially improves segmentation and labeling accuracy.\n\n[2]: Convolutional networks are powerful visual models that yield hierarchies of features. We show that convolutional networks by themselves, trained end-to-end, pixels-to-pixels, exceed the state-of-the-art in semantic segmentation. Our key insight is to build \"fully convolutional\" networks that take input of arbitrary size and produce correspondingly-sized output with efficient inference and learning. We define and detail the space of fully convolutional networks, explain their application to spatially dense prediction tasks, and draw connections to prior models. We adapt contemporary classification networks (AlexNet, the VGG net, and GoogLeNet) into fully convolutional networks and transfer their learned representations by fine-tuning to the segmentation task. We then define a novel architecture that combines semantic information from a deep, coarse layer with appearance information from a shallow, fine layer to produce accurate and detailed segmentations. Our fully convolutional network achieves state-of-the-art segmentation of PASCAL VOC (20 relative improvement to 62.2 mean IU on 2012), NYUDv2, and SIFT Flow, while inference takes one third of a second for a typical image.\n\n[3]: \n\n[4]: Models for many natural language tasks benefit from the flexibility to use overlapping, non-independent features. For example, the need for labeled data can be drastically reduced by taking advantage of domain knowledge in the form of word lists, part-of-speech tags, character n-grams, and capitalization patterns. While it is difficult to capture such inter-dependent features with a generative probabilistic model, conditionally-trained models, such as conditional maximum entropy models, handle them well. There has been significant work with such models for greedy sequence modeling in NLP (Ratnaparkhi, 1996; , 1998).\n\n[5]: State-of-the-art named entity recognition systems rely heavily on hand-crafted features and domain-specific knowledge in order to learn effectively from the small, supervised training corpora that are available. In this paper, we introduce two new neural architectures---one based on bidirectional LSTMs and conditional random fields, and the other that constructs and labels segments using a transition-based approach inspired by shift-reduce parsers. Our models rely on two sources of information about words: character-based word representations learned from the supervised corpus and unsupervised word representations learned from unannotated corpora. Our models obtain state-of-the-art performance in NER in four languages without resorting to any language-specific knowledge or resources such as gazetteers.\n\n[6]: \n\n[7]: This paper develops a novel framework for semantic image retrieval based on the notion of a scene graph. Our scene graphs represent objects (“man”, “boat”), attributes of objects (“boat is white”) and relationships between objects (“man standing on boat”). We use these scene graphs as queries to retrieve semantically related images. To this end, we design a conditional random field model that reasons about possible groundings of scene graphs to test images. The likelihoods of these groundings are used as ranking scores for retrieval. We introduce a novel dataset of 5,000 human-generated scene graphs grounded to images and use this dataset to evaluate our method for image retrieval. In particular, we evaluate retrieval using full scene graphs and small scene subgraphs, and show that our method outperforms retrieval methods that use only objects or low-level image features. In addition, we show that our full model can be used to improve object localization compared to baseline methods.", "role": "user" }, { "content": "Kr \"a henb \"u hl al [1] propose an efficient CRFs mean-field approximate inference algorithm for image segmentation. They model each image as a fully connected grid graph and use CRFs to refine segmentation results obtained from Fully Convolutional Network [2] . Zheng al [6] [3] combines the strengths of CNNs with CRFs , and formulate mean-field inference as Recurrent Neural Networks. In the mean time, CRFs reasoning is widely used to classify named object instances [4] [5] in text into pre-defined categories. Inspired by the great success of CRFs in image segmentation and named-entity recognition, Johnson al [7] design a CRFs model that reasons about the connections between an image and its ground-truth scene graph, and use these scene graphs as queries to retrieve images with similar semantic meanings.", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"RNA\", \"CellType\", \"CellLine\", \"Protein\", \"DNA\"].\n\nPlease return the output as a JSON object of the format: {\"DNA\" : [\"TAL1\", ...], \"RNA\": [\"mRNAs\", ...], \"CellLine\": [\"T cells\", ...], \"CellType\": [\"monocytes\", ...], \"Protein\": [\"IL-2\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nDetection of the chromosome 16 CBF beta-MYH11 fusion transcript in myelomonocytic leukemias. Karyotypic detection of chromosomal 16 abnormalities classically associated with AML M4Eo can be difficult. Characterization of the two genes involved in the inv (16) (p13q22), CBF beta and MYH11, has allowed the detection of fusion transcripts by reverse-transcriptase polymerase chain reaction (RT-PCR). We have analyzed CBF beta-MYH11 fusion transcripts by RT-PCR in myelomonocytic leukemias, with or without eosinophilia, to determine whether their presence correlates with morphology. Fifty-three cases (11 AML M4Eo; 1 AML M4 with atypical abnormal eosinophils (AML M4 \" Eo \"); 29 AML M4; 8 AML M5; 3 CMML; and 1 AML M2 with eosinophilia) were analyzed. All 11 typical AML M4Eo were CBF beta-MYH11 positive. The single case of AML M4 with distinctive eosinophil abnormalities was negative by karyotype, RT-PCR and fluorescent in situ hybridization (FISH). Three of 29 (10%) AML M4 without abnormal eosinophils were CBF beta-MYH11 positive, 1 of which did not show any apparent chromosome 16 abnormalities by classical metaphase analysis (2 not tested). Both cases tested also showed MYH11 genomic rearrangement. None of the other leukemias were RT-PCR positive. Follow-up of three patient showed residual positivity in apparent complete remission. These data show that CBF beta-MYH11 fusion transcripts occur not only in the vast majority of typical AML M4Eo, but also in approximately 10% of AML M4 without eosinophilic abnormalities, a much higher incidence than the sporadic reports of chromosome 16 abnormalities in AML M4 would suggest. Taken together with the detection of CBF beta-MYH11 transcripts in the absence of apparent chromosome 16 abnormalities by classical banding techniques, these data show that additional screening by either RT-PCR or FISH should be performed in all AML M4, regardless of morphologic features, to allow accurate evaluation of the prognostic importance of this fusion transcript.", "role": "user" }, { "content": "{\"CellLine\": [], \"CellType\": [\"atypical abnormal eosinophils\", \"abnormal eosinophils\"], \"DNA\": [\"CBF beta\", \"chromosome 16\", \"MYH11\", \"- MYH11\"], \"Protein\": [], \"RNA\": [\"fusion transcripts\", \"chromosome 16 CBF beta - MYH11 fusion transcript\", \"MYH11 transcripts\", \"CBF beta - MYH11 fusion transcripts\", \"fusion transcript\"]}", "role": "assistant" } ]

[ { "content": "You are presented with multiple paper abstracts, a literature review title, and a specific chapter title. Your task is to write a focused literature review chapter that aligns with the given chapter title. The review should synthesize the content from the provided abstracts, draw connections between different works, highlight major findings, and identify any gaps in the existing research.\nLiterature Review Title: DSSI for pile supported asymmetrical buildings : a review \nChapter Title: 1.1.Direct Method \n1. Abstract of Cited Paper (BIB001): It is becoming increasingly necessary to construct on land that was previously considered inappropriate for construction, such as soft clay. The properties of soft clay make it highly compressible and low in shear strength, meaning that bearing capacity failure and excessive settlement are of concern. ::: ::: Piled embankments are a ground improvement technique that can provide a solution for this problem. Piled embankments have the ability to transfer the greater part of the embankment load and any surcharge to more competent material at greater depth due to the 'arching' concept. Consequently, the soft foundation soil has little direct impact on the performance of the embankment. The concept of 'arching' of granular soil over an area where there is partial loss of support from underlying strata has long been recognised in the study of soil mechanics (e. g. Terzaghi, 1943). However, a number of competing theories exist to quantify this behaviour in piled embankments. ::: ::: In addition, the use of geotextile reinforcement in piled embankments placed above the pile caps in principle provides a number of technical as well as economical benefits. As the embankment fill is placed, tension is created in the reinforcement and it is the vertical component of this tension that transfers the embankment load onto the piles and reduces the load carried by the soft clay hence transferring the load of the embankment on to the piles. ::: ::: Differential settlement can be a problem for piled embankments of low height. Significant differential settlement can cause undesirable effects on any structures constructed on the embankment. 'Arching' limits the amount of differential settlement in embankments and the use of geotextile geogrid can also potentially have additional benefits. ::: ::: This thesis presents a series of centrifuge tests examining the performance of unreinforced and reinforced piled embankments constructed over soft subsoil in terms of stress acting on the subsoil, and differential movement at the surface of the embankment. A large range of embankment heights are considered, and the results for stress on the subsoil are compared with existing predictive methods, allowing generic conclusions to be drawn regarding the predictions of various methods. ::: ::: The effect of a 'working platform' below pile cap level and thus directly loading the subsoil is also considered, and used to examine the concept of a 'Ground Reaction Curve' (Iglesia et al, 1999) for arching in the embankment. In principle this can be used to consider compatibility of displacements at the base of the embankment, and thus improve design simultaneously considering the effect of arching in the embankment and underlying support from the subsoil and layers of reinforcement acting in tension.\n\nLiterature Review:", "role": "user" }, { "content": "In direct method the inertial and kinematic interaction is estimated by modelling soil and structure together. Kinematic interaction develops due to vibration of supporting soil mass and wave propagation through the soil whereas the inertial interaction causes once the vibration reaches to the base of structure and induces a vibration in the structure BIB001 . The response of the coupled system is calculated from the following governing equation given by Krammer (2003) . [M]{Ü} + [C]{Ú} +[K]{U}= - [M] {Üg} BIB002 Where, M, C and K are the mass, damping and stiffness matrices of the integrated system which includes the structure and foundation system. Ü, Ú and U are the acceleration, velocity and displacement of the system and Üg is the ground motion acceleration.", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Participant\", \"Outcome\", \"Intervention\"].\n\nPlease return the output as a JSON object of the format: {\"Participant\": [\"patients with COPD\", ...], \"Intervention\": [\"Atenolol\", ...], \"Outcome\": [\"blood pressure\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\n[ Whole gut irrigation with isotonic mannitol solution in the treatment of gastrointestinal bleeding due to cirrhosis : a controlled study ( author 's transl ) ] .", "role": "user" }, { "content": "{\"Intervention\": [\"[ Whole gut irrigation with isotonic mannitol solution\"], \"Outcome\": [\"gastrointestinal bleeding\"], \"Participant\": [\"gastrointestinal bleeding due to cirrhosis :\"]}", "role": "assistant" } ]

[ { "content": "You are presented with multiple paper abstracts, a literature review title, and a specific chapter title. Your task is to write a focused literature review chapter that aligns with the given chapter title. The review should synthesize the content from the provided abstracts, draw connections between different works, highlight major findings, and identify any gaps in the existing research.\nLiterature Review Title: Trust Computations and Trust Dynamics in Mobile Adhoc Networks: A Survey \nChapter Title: Trust and soft security: \n1. Abstract of Cited Paper (BIB001): In recent years, several trust and reputation models have been proposed to enhance the security of mobile ad hoc networks. However, they either fail to capture evidence of trustworthiness within the limitations of the network, or introduce additional problems while capturing the evidence. In this paper, we propose a reputation-based trust model known as secure MANET routing with trust intrigue (SMRTI). In our model, the evidence of trustworthiness is captured in an efficient manner and from broader perspectives including direct interactions with neighbours, observing interactions of neighbours and through recommendations. SMRTI captures evidence from direct interactions with neighbours in order to identify their benign and malicious behaviours. It also captures evidence for misbehaviours by observing the interactions of neighbours. Lastly, the evidence captured from recommendations is used to summarize the benign behaviour of multi-hop nodes. Unlike other models, we adopt a novel approach to capture evidence from recommendations, which eliminates recommender's bias, free-riding, and honest- elicitation. SMRTI utilizes the captured evidence to predict whether a node is either benign or misbehaving. It then applies the prediction to enhance the security of communications depending on the decision policies, such as whether to send a packet to or forward a packet on behalf of other nodes. Finally, we demonstrate the performance of our model through simulation results. \n2. Abstract of Cited Paper (BIB002): Evaluating and quantifying trust stimulates collaboration in mobile ad hoc networks (MANETs). Many existing reputation systems sharply divide the trust value into right or wrong, thus ignoring another core dimension of trust: uncertainty. As uncertainty deeply impacts a node's anticipation of others' behavior and decisions during interaction, we include uncertainty in the reputation system. Specifically, we use an uncertainty metric to directly reflect a node's confidence in the sufficiency of its past experience, and study how the collection of trust information may affect uncertainty in nodes' opinions. Higher uncertainty leads to higher transaction cost and reduced acceptance of communication and cooperation. After defining a way to reveal and compute the uncertainty in trust opinions, we exploit mobility, one of the important characteristics of MANETs, to efficiently reduce uncertainty and to speed up trust convergence. A two-level mobility assisted uncertainty reduction scheme (MAURS) that offers controllable trade-off between time and cost to achieve a convergence objective of trust is also provided. Extensive analytical and simulation results are presented to support our proposal.\n\nLiterature Review:", "role": "user" }, { "content": "A malicious node detection mechanism based on trust computations for wireless adhoc network is proposed in BIB001 . In this approach a trust authority collects the complaint reports (alarms) from users about the neighbours malicious activities. Trust authority integrates its direct observations on malicious node with the complaint reports it received from authenticated devices to create a global reputation vector. This vector will be distributed by the agent to all members of the network. Authenticated nodes aggregate the global trust vector received from the trust agent with their local trust vector to decide what level of trust to assign to a device. Malicious nodes will be detected whenever this trust level drops below a certain threshold. A trust-based misbehavior detection and secure routing model known as Secure MANET Routing with Trust Intrigue (SMRTI) is proposed in BIB002 . A similar approach of hy- Propagation has to be controlled by efficient algorithms otherwise it will lead to additional over heads. Mobility helps to propagate the trust naturally BIB003 . The more mobility the quicker will be the propagation of trust. More dense the network is, more faster will be the trust propagation as the connectivity increases with density. Link breakage makes the trust propagation worse. More volatile the link more severe its effect on propagating the trust information.", "role": "assistant" } ]

[ { "content": "You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.\n\nTitle:\nFlow chemistry as a discovery tool to access sp²–sp³cross-coupling reactions via diazo compounds\n\nPaper sections:\nIntroduction\n<p>Chemical processes dene our modern world in terms of providing society's functional materials. 1 Many of these processes involve complex reaction pathways and proceed via transient reactive intermediates. The lifetime of these reactive species can vary enormously and their selectivity can oen be difficult to exploit. Their high level of reactivity, when generated in batch mode, can be problematic because of incompatibilities with their chemical environment or functional groups, or because of associated exothermic properties. A case in point relates to diazo compounds which are valuable reactive intermediates. 2 For example, isolated stabilised diazo compounds, bearing one or more electron withdrawing groups, have been extensively investigated in a wide range of applications such as dipolar cycloadditions, 3 carbonyl homologation 4 and cyclopropanation. 5 However, their unstabilised alkyl and aryl diazo counterparts are much more difficult to harness. 2,6 Their chemical preparation is limited due to the oen tedious, corrosive or toxic synthesis protocols. 6a,7 In situ generation of diazo compounds therefore represents an interesting opportunity for synthesis, 8 although any new procedure must be compatible with both the generation of the diazo compound and with its subsequent chemical transformation.</p><p>Manganese dioxide (MnO 2 ) has been used previously in batch mode to generate diazo compounds from hydrazones, although with low efficiency and with very specic substrates. 9 Following on from the advantages that accrue when using MnO 2 under continuous ow reactions, 10 we believed that we could devise a system capable of delivering reactive unstable diazo compounds on demand. Also, with the aim of better exploiting the potential of the ow chemistry, 11,12 we anticipated that these ow-generated transient species could be rapidly transferred into another chemical environment, in order to react the aforementioned species with a suitable partner, hence avoiding interference by spent reagents (Scheme 1). This generation/ translocation/reaction sequence should immediately provide access to new chemical space for the discovery of new reactions for these reactive intermediates.</p><p>Metal free sp 2 -sp 3 cross-coupling reactions have recently become a new focus of the chemical community. 13 In 2009, Barluenga et al. reported an efficient coupling between tosylhydrazones and boronic acids. 13a Further studies with saturated heterocyclic sulfonylhydrazones by Nakagawa, 13c Kirschning, 13e and ourselves, 13f demonstrated a wider scope for the reaction (Scheme 2). Recently, Wang and co-workers reported an efficient synthesis of a-aryl esters and nitriles via a diazotization method for the generation of stabilised diazo compounds. 13g However, the relatively harsh reaction conditions (up to 110 C), large amount of inorganic additives (bases, NaNO 2 , NH 4 Cl) and low atom economy represent potential drawbacks of these transformations. We envisaged that we could access new reactivities of unstabilised diazo compounds, in particular their coupling with boronic acids at room temperature.</p>\n\nGeneration of diazo compound\n<p>Initial investigations focused on 4-bromophenyl hydrazone (1a) as model substrate for the generation of the diazo compound 2a. To evaluate the generation of the transient diazo species, the material processed was quenched with acetic acid to yield the corresponding acetic acid ester 3a (Scheme 3). 6 Amorphous MnO 2 packed into the ow cartridge gave very poor conversion to 2a with mainly starting material being recovered. By contrast, a column packed with activated MnO 2 gave full conversion to various products but with aldehyde 4a being the main product observed. This result was also consistent with batch studies where aldehyde or azine by-products were generally observed at ca. 30% yield, even under carefully controlled reaction conditions. 9b,c,f However, conditioning of the packed column with a small amount of sacricial hydrazone 14 effectively reduced the formation of aldehyde and increased the production of diazo compound 2a as determined via the formation of ester 3a. Furthermore, addition of a base (Hünig's base, 2 equiv.) to the feedstock solution provided a reliable system with greatly reduced amounts of by-products generated. 15 Under the optimised conditions, a 0.1 M solution of hydrazone 1 was passed through a conditioned MnO 2 column (0.86 g, activated MnO 2 ) at 0.5 mL min À1 with 2 equiv. of Hünig's base in CH 2 Cl 2 . In-line IR data (collected using an in-line infrared spectrometer) suggested that a typical load of activated MnO 2 (10 mmol) could cleanly generate 2 mmol of diazo compound over 40 minutes. The generation of diazo compound, which proved to be highly practical as the whole process was carried out at room temperature, was followed by an esterication step of the transient species produced.</p><p>To explore the general application of this process, different hydrazone derivatives were examined (Table 1). The generated diazo compound was quenched with different carboxylic acids (3a-3c) and one phenol substrate (3d). The reaction was compatible with both electron poor and electron rich aromatic hydrazones. Electron poor aryl diazo compound gave in general better yields as they are more stabilised. Investigation of the reactivity of a vinylic diazo compound revealed the formation of two regioisomers (3j and 3j 0 ) aer reaction with excess AcOH. However, when geranyl hydrazone was processed via our protocol only one isomer was obtained, though only in moderate yield (3k). On the other hand, diphenyl ketone hydrazone gave ester 3i in excellent yield.</p>\n\nCoupling reaction with boronic acids\n<p>Diazo compounds are commonly proposed as intermediates for several useful transformations, in particular carbon-carbon sp 2 -sp 3 coupling between tosylhydrazone and boronic acids. 13 High temperature and an inorganic base are typically required as the generation of the diazo compound is reported to be the limiting step of these reactions. We speculated that with our new protocol the chemical reactivity of diazo compounds could be studied separately without interference from the generation step. Pleasingly, aer its generation, the stream of the diazo compound 2a reacted quickly at room temperature with boronic acid 7a in the rst attempt, giving the coupled product 8a in very good yield (Scheme 4). This extremely mild and fast reaction conditions demonstrated the high chemical reactivity of diazo compounds and highlighted the advantages of the ow protocol for these reactive intermediates where the equivalent batch mode reaction was found to be unsuccessful.</p><p>Different coupling combinations were investigated using the ow procedure for the generation of clean diazo compounds (Table 2). With much milder reaction conditions compared to the original Barluenga coupling, the electronic properties exerted a strong inuence on the reaction time. For electron rich or neutral boronic acids the transformation was complete within 1 hour (compounds 8a-c). By contrast, electron poor aryl boronic acids required longer reaction time or harsher reaction conditions (8d-e). Similar trends were observed with other diazo compounds. Electron poor (more stabilised) diazo compounds required, in general, longer reaction times when reacted with the same boronic acid (8j vs. 8b). Interestingly, vinyl diazo compounds are also compatible with this protocol giving the desired products in good yields (8n-q). Notably, in these cases a mixture of products was obtained resulting from a 1,3-borotropic rearrangement and the regioselectivity of the products mixtures was strongly inuenced by the electronic properties of the two aromatic rings, ranging from 2 : 1 (8n) to 15 : 1 (8q). Different functionalities are tolerated such as halogens, nitro groups and ethers. Heterocycles such as pyridine (8e) are also compatible with this protocol. The highly reactive geranyl diazo gave the geranylated product (8l) in good yield, based on the titration of the corresponding diazo compound. This process is remarkable as it provides a complementary method for geranylation, where the normal Friedel-Cras alkylation fails. Additionally, we were able to access sp 2 -sp 3 coupling transformations for aryl-alkyl diazomethane derivatives in quite good yield (8m).</p><p>Since the boronic acids are oen the more functionalised of the two starting materials, the ow-generated diazo partner was used in excess to fully convert the boronic acid 7b to the desired coupling product (Scheme 5). Pleasingly, the diaryl compound 8f was obtained in 96% isolated yield using only a slight excess of diazo compound (1.5 equiv.). In this case, the excess diazo was subsequently quenched via an acidic aqueous work-up protocol. The main by-products detected were both the corresponding azine and alcohol.</p><p>The strong dependence of the reaction kinetics on the electronic properties of both starting materials reveals some insight about the reaction mechanism. It is generally assumed that aer nucleophilic attack of the diazo compound to the boronic acid, a rst ate complex 9 is formed. This intermediate rapidly undergoes a 1,2-carbon migration forming the boronic species 10 which isomerises to the most stable isomer prior to a protodeboronation to give the coupling product 8 (Scheme 6). Although this mechanism is assumed to describe the actual chemical combinations of the intermediates involved, no report has either identied the kinetics of this kind of transformation or the nature of the species involved. The reasons behind this are linked to the harsh conditions employed to generate the reactive intermediate. 13 We started by investigating the kinetics involved in the sequence of events. Initial NMR studies focused on a model reaction between diazo compound 2b and boronic acid 7b and the analysis showed a two-step mechanism (Scheme 6), where the rst step happens at a much faster rate than the second one. Using the data collected over a large series of dynamic experiments, we were able to dene that the reaction is rst order with respect to the diazo compound.</p><p>Remarkably, using our mild ow protocol we were also able for the rst time to intercept the secondary boronic intermediate 10, proving the presence of this intermediate prior to protodeboronation. Indeed, we envisaged that the generation of a relatively stable boronic intermediate 10 would reduce the rate of proto-deboronation and this new reactive intermediate could be intercepted via an alternative reaction pathway. This idea was realised with the use of acetophenone hydrazone (1b) as starting material, which was passed through the oxidantcolumn, packed with activated MnO 2 , to form the corresponding diazo compound (as detected by in-line IR); the transient diazo species was translocated to react with boronic acid 7a and then further reacted with a solution of hydrogen peroxide. The analysis of the material revealed the prevalence of alcohol 11 (68%) within the mixture, corroborating the presence of a boronic species 10c as an intermediate.</p><p>To increase the efficiency of the new protocol, the regeneration and re-use of MnO 2 column was briey investigated. The spent manganese oxide could be oxidised by passage of a Scheme 5 Boronic acid 7b used as limiting reagent.</p><p>Scheme 6 Mechanistic studies of coupling reaction between diazo compound and boronic acid. solution of tert-butyl hydroperoxide (TBHP, 1 M in CH 2 Cl 2 ) (Scheme 7). Interestingly, the regenerated column produced diazo compound without the need for a pre-conditioning phase.</p><p>The heterogeneous oxidant was recycled over three different cycles with just a slight decrease in reactivity aer each recycle as detected by in-line IR (Fig. 1). Moreover, in a preliminary attempt with tube-in-tube technology, 16 oxygen gas also proved to be a useful re-oxidant for a low cost regeneration of MnO 2 but with lower efficiency. 17</p>\n\nConclusion\n<p>In summary, we have reported a practical ow generation of unstable diazo compounds as reactive intermediate using the cheap, recyclable and non-toxic oxidant, MnO 2 . The diazo ow stream can be accurately titrated or followed by in-line IR. Using our protocol, we were able to deliver sp 2 -sp 3 coupling reactions of the freshly generated diazo species with boronic acids, under extremely mild and simple reaction conditions providing alkylated products in good to excellent yield. The mechanistic studies demonstrated for the rst time the presence of a specic boronic intermediate. These results demonstrate that ow generation/translocation/reaction of transient species opens up opportunities for the exploitation and study of new chemical reactivities. Further studies in this area are underway in our laboratories.</p>", "role": "user" }, { "content": "The work takes advantage of an important feature of flow chemistry, whereby the generation of a transient species (or reactive intermediate) can be followed by a transfer step into another chemical environment, before the intermediate is reacted with a coupling partner. This concept is successfully applied to achieve a room temperature sp 2 -sp 3 cross coupling of boronic acids with diazo compounds, these latter species being generated from hydrazones under flow conditions using MnO 2 as the oxidant.Scheme 1 Flowing scheme for the generation, translocation and reaction of the diazo species.", "role": "assistant" } ]

[ { "content": "You will be presented with a sentence from biomedical research text. Extract all terms that correspond to chemical entities of biological interest (ChEBI).\nReturn your identified terms in a JSON array, formatted like this: [\"Entity1\", \"Entity2\", ...].\nIf no such entities are detected, respond by providing an empty JSON array [].\n\nBiomedical context:\nAstrocytes,cerebellarPurkinje-cellsandneocorticalpyramidalneuronsexhibitedboth,AnnexinA7inthecytosolandinthenuclei.", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "You will be presented with a citation sentence from a research paper. Classify the intent behind this citation by choosing from one of the following categories:\n\n- Method: Cites the paper for its methodology or procedure.\n- Background: Cites the paper to provide background information.\n- Result: Cites the paper for its findings or results.\n\nYour answer should be a single word from the following list of options: [\"Method\", \"Background\", \"Result\"]. Do not include any other text in your response.\n\nCitation sentence:\n\nThe patients’ paroxetine plasma concentrations at week 6 were measured using a high-performance liquid chromatography (HPLC) method developed in our laboratory [51,52].", "role": "user" }, { "content": "Method", "role": "assistant" } ]

[ { "content": "You will be shown a claim about public health and the abstract of a biomedical research paper. Each sentence from the abstract will be on a separate line. Your task is to return a JSON object with two fields:\n\n- \"verdict\": The fact-checking verdict. If the information in the abstract supports the claim, write \"SUPPORT\". If the abstract contradicts the claim, write \"CONTRADICT\". If the abstract does not provide enough information to arrive at a verdict, write \"NEI\" (for \"not enough information\").\n- \"evidence\": An array of sentences providing evidence for the verdict. Please copy all relevant sentences verbatim from the abstract. If the verdict was \"NEI\", then return an empty array.\n\nFor instance, if the model were given the claim \"wearing masks can prevent the spread of COVID\", the output might be:\n{\n \"verdict\": \"SUPPORT\",\n \"evidence\": [\"Our findings indicate that mass mask-wearing reduces the transmission rate for COVID-19.\"]\n}\n\nClaim: there is strong evidence that the covid-19 virus can spread through food.\n\nAbstract:\nThe current outbreak of the novel coronavirus disease 2019 (COVID-19) in more than 250 countries has become a serious threat to the health of people around the world.\nHuman-to-human transmission of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs most often when people are in the incubation stage of the disease or are carriers and have no symptoms.\nTherefore, in this study, was discussed the role of environmental factors and conditions such as temperature, humidity, wind speed as well as food, water and sewage, air, insects, inanimate surfaces, and hands in COVID-19 transmission.\nThe results of studies on the stability of the SARS-CoV-2 on different levels showed that the resistance of this virus on smooth surfaces was higher than others.\nTemperature increase and sunlight can facilitate the destruction of SARS-COV-2 and the stability of it on surfaces.\nWhen the minimum ambient air temperature increases by 1 °C, the cumulative number of cases decreases by 0.86%.\nAccording to the latest evidence, the presence of coronavirus in the sewer has been confirmed, but there is no evidence that it is transmitted through sewage or contaminated drinking water.\nAlso, SARS-COV-2 transmission through food, food packages, and food handlers has not been identified as a risk factor for the disease.\nAccording to the latest studies, the possibility of transmitting SARS-COV-2 bioaerosol through the air has been reported in the internal environment of ophthalmology.\nThe results additionally show that infectious bio-aerosols can move up to 6 feet.\nThere have been no reports of SARS-COV-2 transmission by blood-feeding arthropods such as mosquitoes.", "role": "user" }, { "content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"Also, SARS-COV-2 transmission through food, food packages, and food handlers has not been identified as a risk factor for the disease.\"]}", "role": "assistant" } ]

[ { "content": "You are presented with multiple paper abstracts, a literature review title, and a specific chapter title. Your task is to write a focused literature review chapter that aligns with the given chapter title. The review should synthesize the content from the provided abstracts, draw connections between different works, highlight major findings, and identify any gaps in the existing research.\nLiterature Review Title: Intrusion Learning: An Overview of an Emergent Discipline \nChapter Title: Literature Review \n1. Abstract of Cited Paper (BIB001): Human operators of modern surveillance systems are confronted with an increasing amount of trajectory data from moving objects, such as people, vehicles, vessels, and aircraft. A large majority of ...\n\nLiterature Review:", "role": "user" }, { "content": "We performed a systematic narrative review to identify the latest advancements published in the academic literature with respect to machine learning, streaming network data, and intrusion detection. Articles in English-language journals published from 2010 to 2015 in North America and Europe were reviewed. We organized the literature into five themes: i) feature extraction, ii) learning algorithms, iii) clustering, iv) datasets, and v) tools. The purpose of this article is to provide a definition of intrusion learning, identify its distinctive aspects, and provide recommendations for advancing intrusion learning as a practice domain. The authors define intrusion learning as the collection of online network algorithms that learn from and monitor streaming network data resulting in effective intrusion-detection methods for enabling the security and resiliency of enterprise systems. The network algorithms build on advances in cyber-defensive and cyber-offensive capabilities. Intrusion learning is an emerging domain that draws from machine learning, intrusion detection, and streaming network data. Intrusion learning offers to significantly enhance enterprise security and resiliency through augmented perimeter defense and may mitigate increasing threats facing enterprise perimeter protection. The article will be of interest to researchers, sponsors, and entrepreneurs interested in enhancing enterprise security and resiliency. He, 2005; . Intrusion detection systems use feature extraction to determine what features or attributes can assist with detecting malicious traffic BIB002 . We found two feature extraction challenges in the context of streaming network data. First, the dynamic changing nature of the streams results in challenges pertaining to the evolution of features (the emergence of new features), concept evolution (new classes evolving into the stream), and concept drift (underlying concepts change) . The second challenge is that data streams are, in principle, of infinite length BIB001 . Most existing data stream classification techniques address only the infinite length and concept-drift problems; concept evolution and feature evolution are ignored. In the face of a dynamic adversary, ignoring concept evolution and feature evolution increases enterprise risk.", "role": "assistant" } ]

[ { "content": "You will be shown biomedical passages and your task is to answer the provided question. Provide a concise and accurate response and do not include any additional text in the response other than the answer.\n\nQuestion: Which is the main calcium pump of the sarcoplasmic reticulum?\n\nContext: sarcoplasmic reticulum (SR) calcium pump (SERCA)\nthe sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA)\nSERCA, an endoplasmic reticulum (ER) calcium pump, is solely responsible for transporting cytosolic calcium into the ER lumen.\nSarcoplasmic reticulum Ca(2+)-ATPase (SERCA) is the pump crucial for calcium homeostasis and its impairment results in pathologies such as myopathy, heart failure or diabetes.\nSarcoplasmic reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was found to be a key factor in the alteration of calcium cycling.\nThe calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF).\nCalcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes).\nsarco(endo)plasmic reticulum calcium pump (SERCA)\nSERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores.\nThree different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart.\nThe sarcoplasmic reticulum Ca�z ATPase (SERCA) is a membrane-bound pump that utilizes ATP to drive calcium ions from the myocyte cytosol against the higher calcium concentration in the sarcoplasmic reticulum.", "role": "user" }, { "content": "Sarcoplasmic reticulum Ca(2+)-ATPase", "role": "assistant" } ]

[ { "content": "Given an abstract from a research paper, your task is to identify and label relationships between chemical compounds and genes mentioned in the abstract.\n\nThe relationship type must be one of ['DOWNREGULATOR', 'SUBSTRATE', 'INDIRECT-REGULATOR', 'PART-OF', 'MODULATOR-ACTIVATOR', 'REGULATOR', 'INHIBITOR', 'COFACTOR', 'UPREGULATOR', 'ACTIVATOR', 'ANTAGONIST', 'NOT', 'INDIRECT-DOWNREGULATOR', 'SUBSTRATE_PRODUCT-OF', 'INDIRECT-UPREGULATOR', 'AGONIST', 'PRODUCT-OF', 'MODULATOR', 'DIRECT-REGULATOR', 'UNDEFINED', 'AGONIST-INHIBITOR', 'AGONIST-ACTIVATOR', 'MODULATOR-INHIBITOR'].\n\nPlease format your output as a JSON array. Each entry in the array should express a single relation, formatted as [\"<Entity_A>\", \"<RELATION_A_B>\", \"<Entity_B>\"]. If no relations can be found, please output an empty JSON array [].\n\nAbstract:\n\nEvaluation of flutamide genotoxicity in rats and in primary human hepatocytes. Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes. In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-glutamyltraspeptidase-positive foci were detected only in 3 of 10 rats. There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks. In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 microM. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic drug.", "role": "user" }, { "content": "[[\"Flutamide\", \"INHIBITOR\", \"androgen receptor\"]]", "role": "assistant" } ]

[ { "content": "Given a short query with keyphrases about a research idea in 2014 in the domain of artificial intelligence, recommend the relevant datasets to validate the research idea from the options provided. A short description of the datasets is also provided to help you.\n\nQuery: I want to use a fully supervised model for image classification.\n\nKeyphrases: image classification images\n\nDataset description:\nCIFAR-10: The CIFAR-10 dataset (Canadian Institute for Advanced Research, 10 classes) is a subset of the Tiny Images dataset and consists of 60000 32x32 color images. The images are labelled with one of 10 mutually exclusive classes: airplane, automobile (but not truck or pickup truck), bird, cat, deer, dog, frog, horse, ship, and truck (but not pickup truck).\nMulti Task Crowd: Multi Task Crowd is a new 100 image dataset fully annotated for crowd counting, violent behaviour detection and density level classification.\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.\nDCASE 2014: DCASE2014 is an audio classification benchmark.\n\nOptions: A: CIFAR-10 B: Multi Task Crowd C: Melinda D: DCASE 2014", "role": "user" }, { "content": "CIFAR-10", "role": "assistant" } ]

[ { "content": "You will be presented with a paragraph from a COVID-19 literature. Your task is to classify the topics of this piece of text by choosing from the following categories:\n\n- Epidemic Forecasting: The content relates to predictions about the spread of COVID-19.\n- Treatment: The paragraph discusses therapeutic methods or medication for COVID-19.\n- Prevention: The content covers measures to prevent the spread of COVID-19.\n- Mechanism: The paragraph explains the biological mechanisms of the virus.\n- Case Report: The content is a report of a COVID-19 case.\n- Transmission: The paragraph discusses how COVID-19 is transmitted.\n- Diagnosis: The content is about diagnosing COVID-19 in individuals.\n\nYour classification should be provided as an element within a JSON array. The array should be formatted with topics enclosed in double quotes and separated by commas, following the JSON format, for example: [\"Topic1\", \"Topic2\", ...]. Include all applicable categories within the array. \nYour output should be a valid JSON array, and no additional text should be included in your response.\n\nArticle:\n\nThe SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (M(pro)), and the peptidomimetic alpha-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys(145) and His(41) residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, alpha-ketoamide 13b, and ebselen, for their ability to interact with the M(pro). The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as alpha-ketoamide 13b in the M(pro) active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the M(pro) active site and any potential allosteric sites.", "role": "user" }, { "content": "[\"Treatment\", \"Mechanism\"]", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nThe Canadian Red Cross school meal study.\nAbstract 1:\nnan\n\n\nTitle 2:\nEvaluation of a ghetto school breakfast program.\nAbstract 2:\nA program was initiated to provide a free breakfast at a ghetto elementary school. Community support was achieved at the expense of randomization of study subjects. While no significantly greater increase in school attendance or performance was detected in comparison with a control school, none of the students was malnourished and diets of students in the control school were as adequate as those in the breakfast school. Thus, it cannot be concluded that school breakfast programs would not benefit malnourished children or teen-agers who most often go without breakfast.\n\n\nTitle 3:\nNutritional supplementation of disadvantaged elementary-school children.\nAbstract 3:\nnan\n\n\nTitle 4:\nEffect of mid-day meal programme on physical growth & mental function.\nAbstract 4:\nThe effect of food supplementation in rural primary school children was studied on physical growth and mental functions. Children (146) received 450-500 calories with 10-12 g of protein for an average of 172 days a year, for 2 yr (1984-1986). Height was found not to differ significantly in the supplemented group as compared to controls. However, there was marginally better weight gain. More children in the supplemented group remained in grade I in contrast to the controls who shifted to grade II nutritional status after 2 yr. Children receiving the supplementation showed marginal increment in full scale, verbal and performance IQ. The improvement was significant for all subtests except for comprehension and maze tests. The observations on unstructured Piagetian developmental tasks also indicated that the performance of children on task conservation of liquid was improved marginally after supplementation. However, on Bender Gestalt test, no change was observed. The scores on arithmetic achievement test showed improvement of 12-14 points in the supplementation group. It appears that nutrition supplementation is beneficial for better school attendance, and reduction in the drop out rate; it also improves intelligence and cognitive function to a marginal extent. However, as this age group falls in the slow growth period, no catch up was observed in physical growth.\n\n\nTitle 5:\nSchool breakfast improves verbal fluency in undernourished Jamaican children.\nAbstract 5:\nSchool feeding programs exist in many countries, but few have been properly evaluated. In this study, the short-term effects of breakfast on children's cognitive functions were examined. The subjects were 97 undernourished (weight-for-age < or = -1 SD of reference) and 100 adequately nourished (weight-for-age > -1 SD) children in four primary schools in rural Jamaica. The children were randomly assigned to a group provided with breakfast or a group given a quarter of an orange as a placebo, and then given a battery of four cognitive function tests. After a few weeks the treatments were reversed and the tests repeated. Undernourished children's performance improved significantly on a test of verbal fluency when they received breakfast, whereas that of the adequately nourished children did not change (breakfast x group interaction, P < 0.05). There were no other effects of breakfast on test scores. The findings extend those of a previous Jamaican study conducted under more controlled conditions, and support the targeting of school meals to undernourished children.\n\n\nTitle 6:\nAn evaluation of giving the Jamaican government school meal to a class of children.\nAbstract 6:\nWe evaluated the effects of giving the standard Jamaican government school meal to a class of school children. Unlike many other school-feeding studies, this project was carefully controlled and carried out with undernourished children who had low levels of school attendance and achievement. In spite of this, no improvement was found in the children's nutritional status as reflected by weight for age. However, small benefits were found in attendance and school achievement. These findings remained when sex, age, improvements over the previous term, and the effects of 'benevolent attention' were taken into account.\n\n\nTitle 7:\nNutrition and education: a randomized trial of the effects of breakfast in rural primary school children.\nAbstract 7:\nHunger during school may prevent children in developing countries from benefiting from education. Although many countries have implemented school feeding programs, few programs have been rigorously evaluated. We conducted a randomized, controlled trial of giving breakfast to undernourished and adequately nourished children. The undernourished group comprised 407 children in grades 2-5 in 16 rural Jamaican schools (weights-for-age < or = -1 SD of the National Center for Health Statistics references) and the adequately nourished group comprised 407 children matched for school and class (weights-for-age >-1 SD). Both groups were stratified by class and school, then randomly assigned to breakfast or control groups. After the initial measurements, breakfast was provided every school day for 1 school year. Children in the control group were given one-quarter of an orange and the same amount of attention as children in the breakfast group. All children had their heights and weights measured and were given the Wide Range Achievement Test before and after the intervention. School attendance was taken from the schools' registers. Compared with the control group, height, weight, and attendance improved significantly in the breakfast group. Both groups made poor progress in Wide Range Achievement Test scores. Younger children in the breakfast group improved in arithmetic. There was no effect of nutritional group on the response to breakfast. In conclusion, the provision of a school breakfast produced small benefits in children's nutritional status, school attendance, and achievement. Greater improvements may occur in more undernourished populations; however, the massive problem of poor achievement levels requires integrated programs including health and educational inputs as well as school meals.\n\n\nTitle 8:\nA randomised controlled trial of the effect of the provision of free school milk on the growth of children.\nAbstract 8:\nA randomised controlled study was carried out of the effect on growth of the provision of free milk supplements to schoolchildren aged 7 and 8. In selecting children for this study, the aim was to identify those whose socioeconomic circumstances might place them at a disadvantage for growth. Five hundred and eighty-one-children were selected from schools where a high proportion of the pupils received free school meals, and from families with four or more children. The subjects were randomly allocated to receive a third of a pint (190 ml) of free milk daily for six school terms or to a control group. The mean difference in height gain at the end of twenty-one-and-a-half months was 3% or 2.93 mm (P less than 0.05) in favour of the children provided with free milk. The mean difference in weight gain was 130 g (P greater than 0.05) in their favour. The height and weight gain associated with the provision of free mild was very small in the study population, and it is therefore likely that the benefit to growth of providing free milk for the whole unselected population of schoolchildren of these ages would be even smaller.\n\n\nTitle 9:\nA national evaluation of school breakfast clubs: evidence from a cluster randomized controlled trial and an observational analysis.\nAbstract 9:\nTo measure the health, educational and social impacts of breakfast club provision in schools serving deprived areas across England.\n A cluster randomized controlled trial and an observational analysis.\n England, the UK. Intervention: funding to establish a school-based breakfast club vs. control (no funding).\n Intention to treat analysis showed improved concentration (Trail Making Test Part A) amongst the intervention group at 3 months. Fewer pupils within the intervention group reported having skipped classes within the last month and fewer pupils within the intervention group reported having skipped 1 or more days of school within the last month at 1 year. Observational analysis at 1 year showed a higher proportion of primary-aged breakfast club attendees reported eating fruit for breakfast in comparison to non-attendees. A higher proportion of breakfast club attendees had borderline or abnormal conduct and total difficulties scores (primary-aged pupils) and prosocial score (secondary-aged pupils).\n Analyses revealed a mixed picture of benefit and apparent disbenefit. This study illustrated the challenges of evaluating a complex intervention in which the evaluators had less control than is usual in randomized trials over recruitment, eligibility checking and implementation. If the impact of new policy initiatives is to be assessed using the most robust forms of evaluation, social policy needs to be organized so that evaluations can be constructed as experiments. This is likely to prove most difficult where the perceived value of implementing an intervention rapidly is high.\n\n\nTitle 10:\nRural nutrition studies in Indonesia. IX. Feeding trial on schoolboys.\nAbstract 10:\nnan\n\n\nTitle 11:\nAnimal source foods improve dietary quality, micronutrient status, growth and cognitive function in Kenyan school children: background, study design and baseline findings.\nAbstract 11:\nA previous longitudinal three-country study in Egypt, Kenya and Mexico found significant positive associations between intake of animal source foods (ASF) and growth, cognitive development and physical activity. To test for a causal relationship, a controlled school feeding intervention study was designed to test the hypotheses that ASF would improve micronutrient status, growth and cognitive function in Kenyan primary school children. Twelve rural Kenyan schools with 554 children were randomized to four feeding interventions using a local vegetable stew as the vehicle. The groups were designated as Meat, Milk, Energy and Control, who received no feedings. Feeding was carried out on school days for seven terms during 21 mo. Preintervention baseline measures included nutritional status, home food intake, anthropometry, biochemical measures of micronutrient status, malaria, intestinal parasites, health status and cognitive and behavioral measures. The measurements of each child were repeated at intervals over 2 y. Baseline data revealed stunting and underweight in approximately 30% of children and widespread inadequate intakes and/or biochemical evidence of micronutrient deficiencies, particularly of iron, zinc, vitamins A and B-12, riboflavin and calcium. Little or no ASF were eaten and fat intake was low. Malaria was present in 31% of children, and hookworm, amebiasis and giardia were widely prevalent. The outcomes measured were rates of change or increase during the intervention in cognitive function, growth, physical activity and behavior and micronutrient status. Hierarchical linear random effects modeling was used for analysis of outcomes.", "role": "user" }, { "content": "School meals may have some small benefits for disadvantaged children. We recommend further well-designed studies on the effectiveness of school meals be undertaken, that results should be reported according to socio-economic status, and that researchers gather robust data on both processes and carefully chosen outcomes.", "role": "assistant" } ]

[ { "content": "You have to answer a biomedical question in binary format, i.e., only yes and no are acceptable answers. A list of paragraphs is provided as context to help you answer the question.\n\nQuestion: Is acid alpha-glucosidase the enzyme that causes Pompe disease when mutant?\n\nContext: Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA))\nPompe disease is a systemic metabolic disorder characterized by lack of acid-alpha glucosidase (GAA) resulting in ubiquitous lysosomal glycogen accumulation\nPompe disease is an autosomal recessive myopathic disorder caused by the deficiency of lysosomal acid α-glucosidase (GAA)\nAcid α-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available\nThe analysis revealed that the amino acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the acid alpha-glucosidase.\nPompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase.\nGlycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid alpha-glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness.\nStructural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease.\nThe nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease, consisting of 2 each of the infantile, childhood and adult types.\nPompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene.\nGlycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen.\nPompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA).\nDemonstration of acid alpha-glucosidase in different types of Pompe disease by use of an immunochemical method.\nAcid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists.\nDeficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy.\nAmbulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease.\nInfantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase.\nDetermination of acid alpha-glucosidase activity in blood spots as a diagnostic test for Pompe disease.\nThe pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease\nStructural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease\nGlycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme\nAlthough many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease\nThe nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease, consisting of 2 each of the infantile, childhood and adult types\nAs in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter\nGlycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome\nPompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene\nGlycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen\nGlycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme.\nStructural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease.\nReplacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers.\nThe pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease.\nPompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase.\nStructural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease.\nWe describe an improved method for detecting deficiency of the acid hydrolase, alpha-1,4-glucosidase in leukocytes, the enzyme defect in glycogen storage disease Type II (Pompe disease).\nAcid alpha-glucosidase (GAA) deficiency causes Pompe disease,\nInfantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase. Trials with recombinant human acid alpha-glucosidase enzyme replacement therapy (ERT) show a decrease in left ventricular mass and improved function.\nPompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. Due to virtual absence of acid alpha-glucosidase, patients with classical infantile Pompe disease develop progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy.\nPompe disease is caused by the congenital deficiency of the lysosomal enzyme acid alpha-glucosidase.\nThe nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease,\nPompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA). Recently, small molecule pharmacological chaperones have been shown to increase protein stability and cellular levels for mutant lysosomal enzymes and have emerged as a new therapeutic strategy for the treatment of LSDs.\nAcid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists.\nInfantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase.\nGlycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome.\nStructural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease.\nPompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA).\nStructural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease.\nAmbulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease.\nMutations in alpha-glucosidase cause accumulation of glycogen in lysosomes, resulting in Pompe disease, a lysosomal storage disorder.\nPompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase.\nInfantile Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme.", "role": "user" }, { "content": "yes", "role": "assistant" } ]

[ { "content": "You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should only include the abstract and no additional text.\n\nPaper text:\nrobertsonian translocation is one of the major chromosomal rearrangements with a prevalence rate of 0.1% of the general population and 1% of the infertile population . in this report\n, we present a nonhomologous robertsonian translocation in a female patient with a history of repeated abortions .\na couple with the complaint of repeated abortions was admitted in the institute of genetics and hospital for genetic diseases in begumpet , hyderabad , india for cytogenetic evaluation .\nchromosomal analysis of the couple revealed an abnormal karyotype in the female partner with 45 , xx , rob ( 14 , 15 ) ( q10 ; q10 ) chromosomal constitution , while the male partner showed normal 46 , xy karyotype .\nthe cytogenetic analysis of couples with repeated abortions is mandatory to identify any probable chromosomal aberrations .\nprenatal diagnosis should be offered to couples with repeated abortions in the case of future pregnancies .\nalthough the cause is unknown in many instances , but parental chromosomal abnormality is one of the possible causes for recurrence of miscarriages in the first three months of pregnancy ( 1 ) .\nrobertsonian translocations ( rts ) are recognized to be the most common structural chromosomal abnormalities in the population with an incidence of 1.23/1000 live births ( 2 ) .\nits incidence in neonates is estimated to be at about 1/1000 to 2/1000 live births ( 3 ) .\nrobertsonian translocation involves two acrocentric chromosomes , which fuse at the centromeric region and lose their short arms .\nthese chromosomal translocations are mainly observed in group d including 13 , 14 , 15 and group g including 21 and 22 chromosomes .\nthe most frequent type of d / d translocation includes 13 ; 14 translocation , whereas translocation rob ( 13 ; 15 ) and rob ( 14 ; 15 ) are rare structural rearrangements among robertsonian translocations ( 4 ) . in robertsonian translocation ,\nthe pericentric regions of two acrocentric chromosomes fuse to form a single centromere or two .\nthe resulting balanced karyotype has only 45 chromosomes including the translocated one , which is the result of a fusion of the long arms of two acrocentric chromosomes ( 5 ) . in the present study ,\nwe report a robertsonian translocation rob ( 14 ; 15 ) in a female patient with a history of repeated abortions .\na non - consanguineous couple ( a 27-year old male and a 25-year old female ) with the complaint of repeated abortions attended the aforementioned institute for cytogenetic evaluation .\nthey had a history of three repeated abortions in the past two years of their married life .\nthe first abortion was four months from pregnancy resulting in a fetus with anencephaly , kyphosis and cephalocele and the second was a blighted ovum at 3 month of pregnancy .\ntwo milliliters of peripheral blood was obtained from both partners in heparinised tubes to harvest white blood cells for karyotyping ( 6 , 7 ) .\ntwenty - five metaphases were analyzed and the karyotype was interpreted using the applied imaging software .\nthe chromosomes were identified and classified according to the guidelines by the international system for human cytogenetic nomenclature ( iscn , 1995 ) ( 8) .\nchromosomal analysis revealed an abnormality in the female partner with 45 , xx , rob ( 14 ; 15 ) ( q10 ; q10 ) chromosomal constitution .\nthe female karyotype revealed 45 chromosomes with missing chromosomes of 14 and 15 , along with an additional chromosome which did not fit into any group of the chromosomes in the karyotype .\nthe banding pattern of the short and long arms of the additional chromosome was similar to chromosome 14 and 15 , thereby indicating the presence of a non - homologous rt .\nthus , karyotype was confirmed as 45 , xx , rob ( 14;15 ) ( q10:q10 ) as depicted in fig 1 .\nkaryotype of the female with 45 , xx , rob ( 14;15 ) ( q10;q10 ) chromosomal constitution\nabout 15 to 20% of pregnancies end in spontaneous abortion , mostly in the first trimester , the most frequent cause being chromosomal abnormalities , with a prevalence of approximately 50% in spontaneous abortions .\nthe majority of chromosomal anomalies ( 95% ) are numerical , about 60% are trisomies , 20% are represented by x monosomy and another 15% by polyploidy , especially triploidy ( 9 ) . in the case of a numerical chromosomal aberration in the fetus ,\nparental chromosomes are usually normal ; therefore , cytogenetic analysis of the parents is not indicated .\napart from numerical aberrations , structural aberrations ( 5% ) of the chromosomes can also be the cause of pregnancy loss and subsequent infertility ( 10 ) .\nthe presence of a balanced chromosomal rearrangement in a parent results in an increased risk for structural chromosomal defects in future pregnancies .\nit is estimated that in about 70% of couples with at least two spontaneous abortions , one parent carries a balanced chromosomal rearrangement such as inversions , translocation , etc ( 11 ) . in the present study ,\nthe observed translocation could be due to either mutation or segregation in the offspring of a balanced carrier .\nthe carrier of a robertsonian translocation has a normal phenotype but is at risk of producing unbalanced gametes and , therefore , unbalanced offspring . in general , the prevalence of chromosomal abnormalities is higher in females than in males .\nfirst , it can result from the production of genetically unbalanced gametes , which lead to spontaneous abortions of unbalanced zygotes .\nsecond , it can be the consequence of the oogenic disturbances resulting in unviable zygotes ( 12 ) . in the present case ,\na trivalent configuration in metaphase i of meiosis could have resulted in a monosomic or trisomic condition . during pachytene stage in meiosis\ni , homologous pairing of robertsonian translocation is achieved by the formation of a trivalent structure .\n. nevertheless , adjacent segregations result in gametes , which are nullisomic or disomic for one of the chromosomes involved in the rearrangement and consequently a zygote with trisomy or monosomy for one of the involved chromosomes\n. zygotes with monosomy are not compatible with life and most translocated trisomy concepti are expected to result in early or first trimester losses .\nhowever , some survive beyond the second trimester or up to the term ( 13 ) .\ncytogenetic analysis of couples with recurrent abortions is mandatory to evaluate the probable presence of any chromosomal aberrations .\nphysicians should be aware of the condition as at least 5% of these couples with repeated abortions exhibit chromosomal abnormalities as the cause .\nsuch cases have to be analysed as early as possible to arrange for adequate genetic counseling and to allow couples to make an informed reproductive decision regarding subsequent pregnancies .", "role": "user" }, { "content": "introductionrobertsonian translocation is one of the major chromosomal rearrangements with a prevalence rate of 0.1% of the general population and 1% of the infertile population . in this report , we present a nonhomologous robertsonian translocation in a female patient with a history of repeated abortions.case presentationa couple with the complaint of repeated abortions \n was admitted in the institute of genetics and hospital for genetic diseases in begumpet , hyderabad , india for cytogenetic evaluation . \n chromosomal analysis of the couple revealed an abnormal karyotype in the female partner with 45 , xx , rob ( 14 , 15 ) ( q10 ; q10 ) chromosomal constitution , while the male partner showed normal 46 , xy karyotype.conclusionthe cytogenetic analysis of couples with repeated abortions is mandatory to identify any probable chromosomal aberrations . \n prenatal diagnosis should be offered to couples with repeated abortions in the case of future pregnancies .", "role": "assistant" } ]

[ { "content": "You will be shown a claim about public health and the abstract of a biomedical research paper. Each sentence from the abstract will be on a separate line. Your task is to return a JSON object with two fields:\n\n- \"verdict\": The fact-checking verdict. If the information in the abstract supports the claim, write \"SUPPORT\". If the abstract contradicts the claim, write \"CONTRADICT\". If the abstract does not provide enough information to arrive at a verdict, write \"NEI\" (for \"not enough information\").\n- \"evidence\": An array of sentences providing evidence for the verdict. Please copy all relevant sentences verbatim from the abstract. If the verdict was \"NEI\", then return an empty array.\n\nFor instance, if the model were given the claim \"wearing masks can prevent the spread of COVID\", the output might be:\n{\n \"verdict\": \"SUPPORT\",\n \"evidence\": [\"Our findings indicate that mass mask-wearing reduces the transmission rate for COVID-19.\"]\n}\n\nClaim: In general, people with diabetes are more likely to experience severe symptoms and complications when infected with a virus. \n\nAbstract:\nAIMS: To describe characteristics of COVID-19 patients with type 2 diabetes and to analyze risk factors for severity.\nMETHODS: Demographics, comorbidities, symptoms, laboratory findings, treatments and outcomes of COVID-19 patients with diabetes were collected and analyzed.\nRESULTS: Seventy-fourCOVID-19 patients with diabetes were included.\nTwenty-seven patients (36.5%) were severe and 10 patients (13.5%) died.\nHigher levels of blood glucose, serum amyloid A (SAA), C reactive protein and interleukin 6 were associated with severe patients compared to non-severe ones (P<0.05).\nLevels of albumin, cholesterol, high density lipoprotein, small and dense low density lipoprotein and CD4+T lymphocyte counts in severe patients were lower than those in non-severe patients (P<0.05).\nLogistic regression analysis identified decreased CD4+T lymphocyte counts (odds ratio [OR]=0.988, 95%Confidence interval [95%CI] 0.979-0.997) and increased SAA levels (OR=1.029, 95%CI 1.002-1.058) as risk factors for severity of COVID-19 with diabetes (P<0.05).\nCONCLUSIONS: Type 2 diabetic patients were more susceptible to COVID-19 than overall population, which might be associated with hyperglycemia and dyslipidemia.\nAggressive treatment should be suggested, especially when these patients had low CD4+T lymphocyte counts and high SAA levels.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "content": "You are presented with multiple paper abstracts, a literature review title, and a specific chapter title. Your task is to write a focused literature review chapter that aligns with the given chapter title. The review should synthesize the content from the provided abstracts, draw connections between different works, highlight major findings, and identify any gaps in the existing research.\nLiterature Review Title: Power system flexibility: an overview of emergence to evolution \nChapter Title: Inertia response \n1. Abstract of Cited Paper (BIB001): What does it mean to achieve a 100% renewable grid? Several countries already meet or come close to achieving this goal. Iceland, for example, supplies 100% of its electricity needs with either geothermal or hydropower. Other countries that have electric grids with high fractions of renewables based on hydropower include Norway (97%), Costa Rica (93%), Brazil (76%), and Canada (62%). Hydropower plants have been used for decades to create a relatively inexpensive, renewable form of energy, but these systems are limited by natural rainfall and geographic topology. Around the world, most good sites for large hydropower resources have already been developed. So how do other areas achieve 100% renewable grids? Variable renewable energy (VRE), such as wind and solar photovoltaic (PV) systems, will be a major contributor, and with the reduction in costs for these technologies during the last five years, large-scale deployments are happening around the world. \n2. Abstract of Cited Paper (BIB002): Preservation of the environment has become the main motivation to integrate more renewable energy sources (RESs) in electrical networks. However, several technical issues are prevalent at high level RES penetration. The most important technical issue is the difficulty in achieving the frequency stability of these new systems, as they contain less generation units that provide reserve power. Moreover, new power systems have small inertia constant due to the decoupling of the RESs from the AC grid using power converters. Therefore, the RESs in normal operation cannot participate with other conventional generation sources in frequency regulation. This paper reviews several inertia and frequency control techniques proposed for variable speed wind turbines and solar PV generators. Generally, the inertia and frequency regulation techniques were divided into two main groups. The first group includes the deloading technique, which allow the RESs to keep a certain amount of reserve power, while the second group includes inertia emulation, fast power reserve, and droop techniques, which is used to release the RESs reserve power at under frequency events.\n\nLiterature Review:", "role": "user" }, { "content": "In the case of highly proliferated VERs or equally the fading presence of conventional generation, the system would suffer from the inertia response issue . The result of Western Electricity Coordinating Council (WECC) system simulations in BIB001 reveals that under stress condition (e.g. low demand, high renewable generation, and absence of conventional generation), a significant drop in the system frequency response will occur while the system is facing a disturbance. The intensity of frequency response drop varies with respect to wind generation amount and number of offline fossil units. In addition, new resources such as VERs, storage, and flywheels can afford an inertia response as good as or even better than the frequency response when they have no contribution BIB002 BIB003 . Meanwhile, research on supplying the inertia response by means of market, or the required conditions for the network connection will continue. Although, when there is no more empirical evidence, the desired inertia response will be obtained via the required conditions for the network connection.", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"RNA\", \"CellType\", \"CellLine\", \"Protein\", \"DNA\"].\n\nPlease return the output as a JSON object of the format: {\"DNA\" : [\"TAL1\", ...], \"RNA\": [\"mRNAs\", ...], \"CellLine\": [\"T cells\", ...], \"CellType\": [\"monocytes\", ...], \"Protein\": [\"IL-2\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nMolecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance. Previous studies have implicated a role for intracellular thiols in the activation of nuclear factor-kappaB and transcriptional regulation of endothelial cell adhesion molecules. This study was designed to determine whether changes in endothelial cell glutathione (GSH) or oxidized glutathione (GSSG) can alter neutrophil adhesivity and to define the molecular mechanism that underlies this GSSG / GSH-induced adhesion response. Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0. 2 mmol / L diamide and 1 mmol / L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity. These redox changes are similar to those observed with anoxia / reoxygenation. Diamide plus BSO-induced thiol / disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2). N-Acetylcysteine treatment attenuated neutrophil adhesion in both phases, which indicated a role for GSH in the adhesion responses. Interestingly, phase 1 adhesion was inversely correlated with GSH levels but not with the GSSG / GSH ratio, whereas phase 2 neutrophil adhesion was positively correlated with GSSG / GSH ratio but not with GSH levels. Intercellular adhesion molecule-1 and P-selectin-specific monoclonal antibodies attenuated the increased neutrophil adhesion during both phases, whereas an anti-E-selectin monoclonal antibody also attenuated the phase 2 response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides that contained nuclear factor-kappaB or activator protein-1 cognate DNA sequences significantly attenuated the phase 2 response, which implicated a role for de novo protein synthesis. Surface expression of intercellular adhesion molecule-1, P-selectin, and E-selectin on HUVECs correlated with the phase 1 and 2 neutrophil adhesion responses. This study demonstrates that changes in endothelial cell GSSG / GSH cause transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules, which leads to a 2-phase neutrophil-endothelial adhesion response.", "role": "user" }, { "content": "{\"CellLine\": [\"HUVEC\", \"human umbilical vein endothelial cell (HUVEC) monolayers\", \"HUVECs\", \"human umbilical vein endothelial cell\"], \"CellType\": [\"neutrophil\"], \"DNA\": [], \"Protein\": [\"nuclear factor - kappaB\", \"P - selectin\", \"activator protein - 1\", \"P - selectin - specific monoclonal antibodies\", \"Intercellular adhesion molecule - 1\", \"intercellular adhesion molecule - 1\", \"E - selectin\", \"monoclonal antibody\", \"anti - E - selectin monoclonal antibody\", \"endothelial cell adhesion molecules\"], \"RNA\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.\n\nTitle: Profiling Synaptic Proteins Identifies Regulators of Insulin Secretion and Lifespan\nArticle:\nAbstract:\nCells are organized into distinct compartments to perform specific tasks with spatial precision. In neurons, presynaptic specializations are biochemically complex subcellular structures dedicated to neurotransmitter secretion. Activity-dependent changes in the abundance of presynaptic proteins are thought to endow synapses with different functional states; however, relatively little is known about the rules that govern changes in the composition of presynaptic terminals. We describe a genetic strategy to systematically analyze protein localization at Caenorhabditis elegans presynaptic specializations. Nine presynaptic proteins were GFP-tagged, allowing visualization of multiple presynaptic structures. Changes in the distribution and abundance of these proteins were quantified in 25 mutants that alter different aspects of neurotransmission. Global analysis of these data identified novel relationships between particular presynaptic components and provides a new method to compare gene functions by identifying shared protein localization phenotypes. Using this strategy, we identified several genes that regulate secretion of insulin-like growth factors( IGFs) and influence lifespan in a manner dependent on insulin/IGF signaling.\nIntroduction:\nDifferentiation and organization of eukaryotic cells require regulated localization of specific proteins into subcellular compartments where they perform discrete functions. Global analysis of protein localization in yeast revealed that >40% of proteins localize to specific subcellular compartments[1]. This large repertoire of localized proteins raises several questions. What genes or pathways orchestrate the subcellular abundance and distribution of these proteins? Is the protein composition of subcellular compartments static or plastic? What rules govern the composition of these structures? How do changes in protein localization alter the function of these structures, and ultimately organismal health? The large variety of proteins in subcellular compartments implies substantial genetic and biochemical complexity. Therefore, addressing these questions will require comprehensive and systematic approaches beyond the study of single genes or proteins. Such approaches have been successful in identifying groups of functionally related genes based on similarities in their expression patterns, or similarities in the phenotypic consequences of disrupting gene function[2]–[4]. Given recent advances in high-content imaging screens[1], it is now possible to do analogous studies linking gene function to changes in the global patterns of protein localization. In neurons, presynaptic specializations are estimated to contain approximately one thousand proteins that are configured into discrete compartments; these compartments contain different organelles and perform different cellular functions in neurotransmitter release[5]. Synaptic vesicles( SVs) contain neurotransmitters that are released upon SV fusion with the plasma membrane. The active zones are structures containing many scaffold proteins and calcium channels and are sites of SV fusion. Periactive zones are F-actin-rich areas where SV recycling occurs through endocytosis. Dense core vesicles( DCVs) are vesicles that release neuropeptides and peptide hormones[6], including insulin/IGF ligands implicated in metabolic diseases and the aging process[7],[8]. DCVs are a population of vesicles distinct from SVs that undergo differential regulated release at different locations in neurons[6]. DCVs have mostly been studied in cultured secretory cells; thus, genetic factors that regulate DCV secretion in vivo from neurons are poorly understood, despite their importance in health and disease. Synapses are able to operate over a broad range of functional states, which endow circuits with the capacity to store and process information. Relatively little is known about how the protein composition of synapses is altered across these functional states, nor how these changes contribute to differences in synaptic transmission. Is the abundance of proteins associated with the same subsynaptic structure( e. g. SVs) always correlated across physiological states? To what extent do the binary interactions between presynaptic proteins govern changes in presynaptic composition? Can changes in protein localization profiles be linked to changes in behavior and physiology of the whole animal? Here, we describe a genetic analysis of presynaptic structure in C. elegans by measuring in vivo changes in the abundance and distribution of a panel of fluorescently tagged presynaptic proteins. These proteins label distinct subsynaptic compartments and are involved in diverse aspects of neurotransmitter release( Table 1). Using these markers, we determined how synapse structure was altered in twenty-five mutants that alter various aspects of synaptic transmission. By comparing changes in protein localization caused by different mutations, we describe changes in protein composition of presynaptic terminals across a range of physiological states. In this manner, we identify several genes that regulate secretion of insulin/IGFs from neurons, and we show that these genes regulate lifespan, a physiological function of IGF signaling.\nDiscussion:\nRegulating the levels of a single presynaptic protein can be crucial in tuning neurotransmitter secretion. For example, increasing the levels of UNC-10 or its ortholog RIM1α can lead to increased neurotransmitter secretion[35],[75]. Several layers of regulation ensure that appropriate levels of UNC-10 or RIM1α are present at presynaptic specializations, including syd-2 α-Liprin-dependent and independent means of UNC-10 RIM1α recruitment[33; this work], as well as ubiquitin-mediated degradation of RIM1α[75]. We analyzed multiple synaptic markers, allowing us to detect trends and correlations not possible from studying individual markers. One theme that emerged was that markers localized to the same synaptic compartments could differ in their response to disruption of presynaptic function. For example, changes in the punctal fluorescence of active zone markers UNC-10 RIM1α and SYD-2 α-Liprin did not correlate when examined across a panel of neurotransmission mutants, suggesting that additional factors besides SYD-2 α-Liprin can exert a significant impact on UNC-10 RIM1α abundance. This result could represent changes in the ability or specificity of the proteins to localize to certain subcellular structures. Alternatively, this result may reflect altered rates of protein synthesis or turnover. Together, our data suggests that the composition of the active zone can be altered in response to changes in presynaptic function. The ability to independently regulate different components of the active zone could provide a mechanism to fine-tune neurotransmission. Detailed proteomic studies have revealed the protein components of SVs[76], some of which were studied here. We show that compositional changes among SV proteins can be observed when specific aspects of synaptic function are perturbed. Because SVs exist in functionally distinct pools that have been proposed to contain different molecular constituents[5], the compositional changes we observed might reflect shifts in the relative abundance of SV pools. For example, the abundance of SNN-1 synapsin was negatively correlated with both RAB-3 and SNB-1 synaptobrevin, possibly indicative of changes in their association with intermediates during the SV cycle. These relationships are consistent with the idea that different sets of proteins transiently associate with SVs as they traverse through different steps in the exocytosis/endocytosis cycle. Most work on DCV secretion has focused on cultured neurosecretory cells; less is known about the cell biology of DCV secretion in neurons of intact animals. We found a role for unc-36 α2δ VGCC in DCV secretion, which had not been previously implicated in this process. Prior work in Drosophila revealed that an α2δ VGCC subunit encoded by straitjacket is required for SV exocytosis[77],[78]. Thus, it is possible that α2δ VGCC subunits are involved in both SV and DCV secretion. The unc-2 α1 VGCC subunit[67] was a candidate for functioning in the same channel as unc-36 α2δ VGCC because they shared many behavioral and developmental phenotypes[56],[63],[68]. However, unc-2 α1 VGCC did not co-cluster with either unc-36 α2δ VGCC or unc-31 CAPS; furthermore, unc-2 α1 VGCC mutants did not show a detectable INS-22 insulin/IGF secretion defect. Thus, while unc-36 α2δ VGCC and unc-2 α1 VGCC may act together for certain processes, they may also participate in the formation of distinct channels, perhaps as a mechanism for increasing channel diversity in the nervous system. Our analysis was able to dissect the functions of these two VGCC subunits by separating them into two clusters. In Drosophila, straitjacket α2δ VGCC is required for proper localization of the cacophony α1 VGCC subunit required for SV secretion[77],[78]. This raises the possibility that UNC-36 α2δ VGCC might also localize another, presently unidentified, α1 VGCC subunit involved in DCV secretion. egl-8 PLCβ was also identified as a new positive regulator of INS-22 insulin/IGF secretion. Our previous work implicated pkc-1 PKCη/ε in DCV exocytosis and showed that an activated pkc-1 PKCη/ε mutation was epistatic to egl-8 PLCβ; this argued that pkc-1 PKCη/ε acts downstream of egl-8 PLCβ[53]. Here we showed that these two genes clustered together, indicating they have a similar spectrum of phenotypes, and are thus likely to act within the same pathway, rather than in parallel pathways. One model supported by our results is that EGL-8 PLCβ catalyzes the formation of a second messenger, DAG, to activate PKC-1 PKCη/ε, which in turn promotes DCV exocytosis[53]. This pathway appeared to be specific to DCV rather than SV secretion and may thus serve to regulate the types of transmitters secreted by a neuron. We identified goa-1 Gαo as a new negative regulator of insulin/IGF secretion. goa-1 Gαo also negatively regulates SV exocytosis in the same set of neurons[17],[20],[21],[69], consistent with a decrease in the punctal fluorescence of SNB-1 synaptobrevin in goa-1 Gαo mutants( Table S2). Together, this suggests that goa-1 may function as a regulator of secretion from both SVs and DCVs. The effect of GOA-1 Gαo on active zone components such as SYD-2 α-Liprin, UNC-10 RIM1α and UNC-13 likely contributes to its role to regulating SV secretion. Since DCV secretion does not occur at active zones[58], GOA-1 Gαo likely regulates DCV secretion through effectors in other compartments. Whether the same pools of GOA-1 Gαo act to coordinate SV and DCV secretion or are regulated distinctly for each of these functions also remains to be determined. Aging is modulated by a conserved insulin/IGF signaling pathway in C. elegans and other species[8]. Whereas much attention has been focused on the pathways and effectors downstream of insulin/IGF receptor in the regulation of lifespan, little is known about how insulin/IGF secretion is regulated to initiate this process. Mutations that disrupt the core DCV exocytic machinery lead to increased longevity[79], but the pathways that regulate insulin/IGF secretion in C. elegans lifespan control were previously unknown. Here, we identified G-protein and second messenger pathways that modulate insulin/IGF secretion and control C. elegans lifespan in an insulin/IGF signaling-dependent manner. Our results suggest that the bidirectional regulation of insulin/IGF secretion by these pathways are endogenous determinants of C. elegans lifespan. Elegant studies have indicated that communication between different tissues is required for proper regulation of lifespan[8]. The nervous system is the predominant locus of insulin/IGF expression in C. elegans[80] and may function as a signaling center in this process. Because the molecules identified here as regulators of insulin/IGF secretion are expressed throughout the C. elegans nervous system, they are likely to act as general rather than cell-specific factors. In this context, it is particularly interesting to identify signaling molecules such as G-proteins as regulators of insulin/IGF secretion. Since G-proteins mediate responses to extracellular signals, they provide an attractive mechanism for coupling changes in neuronal signaling to changes in lifespan. The proliferation of genomic and proteomic studies has provided substantial knowledge of cellular organization and function. Addressing how the genome regulates the proteome is a logical next step to link these two types of information. Our results demonstrate that even analyzing the relationship between a small, focused subset of genes and proteins can yield new and detailed information about a specific subcellular specialization. Thus, connecting gene function to protein localization can serve as a platform to understand detailed and global properties of subcellular compartments, the proteins that inhabit them and the genes that regulate these proteins. With advances in automated microscopy, we anticipate that extending our approach and analytical techniques to additional subcellular compartments across many genetically tractable systems will yield a wealth of biological information.", "role": "user" }, { "content": "Cells are divided into multiple subcellular compartments that perform diverse functions . In neurons , synapses mediate transmission of information between cells and they comprise hundreds of proteins dedicated for this purpose . Changes in the protein composition of synapses are thought to produce changes in synaptic transmission , such as those that occur during development , learning , and memory . Here , we describe a systematic genetic strategy for analyzing the protein composition of synapses . Using this strategy , we identified sets of genes that alter synapses in similar ways , and identified novel regulatory relationships between particular synaptic proteins . One set of genes regulated secretion of insulin-like hormones from neurons and had corresponding effects on lifespan , which is controlled by insulin signaling . These results illustrate how changes in synaptic composition can be utilized as a probe to explain changes in physiology . Our approach can be expanded to include a larger set of synaptic proteins or to analyze other subcellular compartments .", "role": "assistant" } ]

[ { "content": "You will be presented with a paragraph from a COVID-19 literature. Your task is to classify the topics of this piece of text by choosing from the following categories:\n\n- Epidemic Forecasting: The content relates to predictions about the spread of COVID-19.\n- Treatment: The paragraph discusses therapeutic methods or medication for COVID-19.\n- Prevention: The content covers measures to prevent the spread of COVID-19.\n- Mechanism: The paragraph explains the biological mechanisms of the virus.\n- Case Report: The content is a report of a COVID-19 case.\n- Transmission: The paragraph discusses how COVID-19 is transmitted.\n- Diagnosis: The content is about diagnosing COVID-19 in individuals.\n\nYour classification should be provided as an element within a JSON array. The array should be formatted with topics enclosed in double quotes and separated by commas, following the JSON format, for example: [\"Topic1\", \"Topic2\", ...]. Include all applicable categories within the array. \nYour output should be a valid JSON array, and no additional text should be included in your response.\n\nArticle:\n\nBACKGROUND: The coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been rapidly spreading nationwide and abroad. A serologic test to identify antibody dynamics and response to SARS-CoV-2 was developed. METHODS: The antibodies against SARS-CoV-2 were detected by an enzyme-linked immunosorbent assay based on the recombinant nucleocapsid protein of SARS-CoV-2 in patients with confirmed or suspected COVID-19 at 3-40 days after symptom onset. The gold standard for COVID-19 diagnosis was nucleic acid testing for SARS-CoV-2 by real-time reverse-transcription polymerase chain reaction (rRT-PCR). The serodiagnostic power of the specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against SARS-CoV-2 was investigated in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and consistency rate. RESULTS: The seroconversion of specific IgM and IgG antibodies were observed as early as the fourth day after symptom onset. In the patients with confirmed COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 77.3% (51/66), 100%, 100%, 80.0%, and 88.1%, respectively, and those of IgG were 83.3% (55/66), 95.0%, 94.8%, 83.8%, and 88.9%. In patients with suspected COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 87.5% (21/24), 100%, 100%, 95.2%, and 96.4%, respectively, and those of IgG were 70.8% (17/24), 96.6%, 85.0%, 89.1%, and 88.1%. Both antibodies performed well in serodiagnosis for COVID-19 and rely on great specificity. CONCLUSIONS: The antibodies against SARS-CoV-2 can be detected in the middle and later stages of the illness. Antibody detection may play an important role in the diagnosis of COVID-19 as a complementary approach to viral nucleic acid assays.", "role": "user" }, { "content": "[\"Diagnosis\"]", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nManagement of severe hypertension in the postpartum period with intravenous hydralazine or labetalol: a randomized clinical trial.\nAbstract 1:\nTo compare the safety and efficacy of intravenous labetalol and intravenous hydralazine for acutely lowering blood pressure in the puerperium.\n Randomized clinical trial.\n Critical care unit of gynecology and obstetrics department in the Complejo hospitalario \"Dr. AAM\" de la Caja de Seguro Social in Panama.\n Eighty-two women with severe hypertension during the postpartum period.\n Patients were randomized to receive hydralazine (5 mg as a slow bolus dose given intravenously, and repeated every 20 minutes to a maximum of five doses) or labetalol (20 mg in an intravenous bolus dose followed by 40 mg if not effective within 20 minutes, followed by 80 mg every 20 minutes to a maximum dose of 300 mg). The primary endpoint was the successful lowering of blood pressure. Secondary endpoints were maternal complications and side-effects.\n Forty-two women were enrolled in the hydralazine group and 40 in the labetalol group. Women were similar with respect to characteristics at randomization. No significant differences were observed for persistent severe hypertension or maternal side-effects. There was only one case of persistent severe hypertension in the labetalol group. There were no maternal deaths in any of the women studied.\n This randomized clinical trial shows that intravenous hydralazine and intravenous labetalol are effective and safe in the management of severe hypertension in the postpartum period.\n\n\nTitle 2:\nThe use of nifedipine during the postpartum period in patients with severe preeclampsia.\nAbstract 2:\nNifedipine is a calcium channel blocker that reduces blood pressure and increases renal blood flow. This double-blind investigation evaluated the effect of nifedipine in postpartum patients with severe preeclampsia. Thirty-one patients were randomized to receive either nifedipine (10 mg) or placebo every 4 hours beginning immediately after delivery. Data analysis revealed a significantly higher urine output in the nifedipine group during the first 24 hours after delivery (3834 versus 2057 ml; p less than 0.05). A significant reduction in mean arterial pressure was also noted in the nifedipine group between 18 and 24 hours postpartum (93.9 versus 100.2 mm Hg; p less than 0.05). There were no significant differences in the systolic or diastolic blood pressures, pulse, laboratory study results, or the need to administer hydralazine to control blood pressure. Nifedipine appears to have a beneficial effect on urinary output and mean arterial pressure during the first 24 hours post partum in patients with severe preeclampsia.\n\n\nTitle 3:\nEffect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial.\nAbstract 3:\nTo assess the benefit of l-arginine, the precursor to nitric oxide, on blood pressure and recovery of the glomerular lesion in preeclampsia.\n Forty-five women with preeclampsia were randomized to receive either l-arginine or placebo until day 10 postpartum. Primary outcome measures including mean arterial pressure, glomerular filtration rate, and proteinuria were assessed on the third and 10th days postpartum by inulin clearance and albumin-to-creatinine ratio. Nitric oxide, cyclic guanosine 3'5' monophosphate, endothelin-1, and asymmetric-dimethyl-arginine and arginine levels were assayed before delivery and on the third and 10th days postpartum. Healthy gravid women provided control values. Assuming a standard deviation of 10 mm Hg, the study was powered to detect a 10-mm Hg difference in mean arterial pressure (alpha .05, beta .20) between the study groups.\n No significant differences existed between the groups with preeclampsia before randomization. Compared with the gravid control group, women with preeclampsia exhibited significantly increased serum levels of endothelin-1, cyclic guanosine 3'5' monophosphate, and asymmetric-dimethyl-arginine before delivery. Despite a significant increase in postpartum serum arginine levels due to treatment, no differences were found in the corresponding levels of nitric oxide, endothelin-1, cyclic guanosine 3'5' monophosphate, or asymmetric-dimethyl-arginine between the two groups with preeclampsia. Further, there were no significant differences in any of the primary outcome measures with both groups demonstrating similar levels in glomerular filtration rate and equivalent improvements in both blood pressure and proteinuria.\n Blood pressure and kidney function improve markedly in preeclampsia by the 10th day postpartum. Supplementation with l-arginine does not hasten this recovery.\n I.\n\n\nTitle 4:\n[Management of severe pre-eclampsia in the puerperium. Comparative study of sublingual nifedipine and hydralazine].\nAbstract 4:\nAt random, two therapeutic schemes for severe preeclampsia during the puerperium, were evaluated. Group A (n = 20) was left without antihypertensive medication and sublingual nifedipine was used only in case of diastolic pressure of 110 mmHg or more. Group B (n = 18) receive Hydralazine 40 mlg. per os, every 6 hrs.; in this group also, nifedipine was administered in case of diastolic pressure of 110 mmHg or more. The only differences were that in group B the intervals for the administration of nifedipine were much shorter than in group A; also, in the same group the need for another antihypertensive was more frequent (5 of 18 vs 1 of 20 patients).\n\n\nTitle 5:\nA randomized study comparing timolol and methyldopa in hospital treatment of puerperal hypertension.\nAbstract 5:\nnan\n\n\nTitle 6:\nPostpartum preeclampsia management with furosemide: a randomized clinical trial.\nAbstract 6:\nThis investigation was undertaken to estimate whether a brief postpartum course of furosemide for patients with preeclampsia benefits recovery and shortens hospitalization by enhancing diuresis, lessening severe hypertension, and reducing the need for antihypertensive therapy.\n Two hundred sixty-four patients with preeclampsia were enrolled. After spontaneous onset of postpartum diuresis and discontinuation of intravenous magnesium sulfate, patients were randomly assigned to receive either no therapy or 20 mg oral furosemide daily for 5 days with oral potassium supplementation. Patient outcomes were compared between treatment groups with regard to classification of hypertensive disease.\n Only postpartum patients with severe preeclampsia (n = 70) who received furosemide compared with controls had significantly lower systolic blood pressure by postpartum day 2 (142 +/- 13 mm Hg compared with 153 +/- 19 mm Hg, P < .004) and required less antihypertensive therapy during hospitalization (14% compared with 26%, P = .371) and at discharge (6% compared with 26%, P = .045). No benefit was shown for patients with mild preeclampsia (n = 169) or superimposed preeclampsia (n = 25). Neither length of hospitalization nor frequency of delayed postpartum complications was positively affected by the intervention.\n Brief postpartum furosemide therapy for patients with severe preeclampsia seems to enhance recovery by normalizing blood pressure more rapidly and reducing the need for antihypertensive therapy. Shortening of hospitalization and reduction of delayed postpartum complications were not benefitted.\n\n\nTitle 7:\nA randomised placebo controlled trial of loop diuretics in moderate/severe pre-eclampsia, following delivery.\nAbstract 7:\nNineteen patients with pre-eclampsia were randomised to receive 40 mg of frusemide or placebo by mouth daily for 7 days in the first post-partum week. Outcome measures included mean and maximum blood pressure, the need for additional antihypertensive treatment during that period and mean length of hospital stay. There were no statistically significant differences in outcome between the treatment and placebo groups although there was a trend to more rapid lowering of blood pressure following delivery in those receiving frusemide.\n\n\nTitle 8:\nUtilization of hydralazine or alpha-methyldopa for the management of early puerperal hypertension.\nAbstract 8:\nDespite the importance of pregnancy-induced hypertension (PIH), there are few published investigations of therapeutic approaches for the postpartum management of such patients. Twenty-six gravida patients with PIH were prospectively studied during the first 24 hours after delivery while receiving intravenous magnesium sulfate. Each study subject was randomly assigned to a group also systemically administered either hydralazine or methyldopa. During the study interval, hourly measurements of blood pressure, pulse, fluid intake, and urine output were recorded. Hydralazine was found to be superior in its ability to effect more rapidly a lower mean arterial blood pressure. No significant differences in urine output or time until onset of diuresis were noted among treatment groups. No serious side effects were encountered with the use of either antihypertensive agent. Based on these preliminary findings, it appears that hydralazine is the less costly and more effective medication to lower mean arterial blood pressure in the immediate postpartum period.", "role": "user" }, { "content": "For women with pre-eclampsia, postnatal furosemide may decrease the need for postnatal antihypertensive therapy in hospital, but more data are needed on substantive outcomes before this practice can be recommended. There are no reliable data to guide management of women who are hypertensive postpartum. Any antihypertensive agent used should be based on a clinician's familiarity with the drug. Future studies should include data on postpartum analgesics, severe maternal hypertension, breastfeeding, hospital length of stay, and maternal satisfaction with care.", "role": "assistant" } ]

[ { "content": "You will be presented with a citation segment from the section of an NLP research paper, as well as the context surrounding that citation. Classify the intent behind this citation by choosing from one of the following categories:\n- Background: provides context or foundational information related to the topic.\n- Extends: builds upon the cited work.\n- Uses: applies the methods or findings of the cited work.\n- Motivation: cites the work as inspiration or rationale for the research.\n- CompareOrContrast: compares or contrasts the cited work with others.\n- FutureWork: cites the work as a direction for future research.\n\nYour answer should be a single word from the following list of options: [\"Background\", \"Extends\", \"Uses\", \"Motivation\", \"CompareOrContrast\", \"FutureWork\"]. Do not include any other text in your response.\n\nSection Title:\nNone\n\nContext before the citation:\nOther molecular biology databases We also included several model organism databases or nomenclature databases in the construction of the dictionary, i.e., mouse Mouse Genome Database (MGD) [18], fly FlyBase [19], yeast Saccharomyces Genome Database (SGD) [20], rat – Rat Genome Database (RGD) [21], worm – WormBase [22], Human Nomenclature Database (HUGO) [23], Online Mendelian Inheritance in Man (OMIM) [24], and Enzyme Nomenclature Database (ECNUM) [25, 26]. \u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0000 The Semantic Network contains information about the types or categories (e.g., “Disease or Syndrome”, “Virus”) to which all META concepts have been assigned. The SPECIALIST lexicon contains syntactic information for many terms, component words, and English words, including verbs, which do not appear in the META.\n\nCitation Sentence:\nOther molecular biology databases We also included several model organism databases or nomenclature databases in the construction of the dictionary , i.e. , mouse Mouse Genome Database ( MGD ) [ 18 ] , fly FlyBase [ 19 ] , yeast Saccharomyces Genome Database ( SGD ) [ 20 ] , rat -- Rat Genome Database ( RGD ) [ 21 ] , worm -- WormBase [ 22 ] , Human Nomenclature Database ( HUGO ) [ 23 ] , Online Mendelian Inheritance in Man ( OMIM ) [ 24 ] , and Enzyme Nomenclature Database ( ECNUM ) [ 25 , 26 ] .\n\nContext after the citation:", "role": "user" }, { "content": "Uses", "role": "assistant" } ]

[ { "content": "You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.\n\nTitle:\nPolyamine-containing etoposide derivatives as poisons of human type II topoisomerases: Differential effects on topoisomerase II\\xce\\xb1 and II\\xce\\xb2\n\nPaper sections:\n\n<p>Etoposide is one of the most widely prescribed anticancer drugs in the world.1–4 The cellular targets for the drug are the type II topoisomerases, topoisomerase IIα and topoisomerase IIβ.1–4 These enzymes alleviate torsional stress and remove knots and tangles from DNA by generating transient double-stranded breaks in the double helix.5–10 To maintain genomic integrity, type II topoisomerases covalently attach to the newly generated 5'-DNA termini. These covalent enzyme-cleaved DNA complexes are known as \"cleavage complexes.\"</p><p>Etoposide acts by stabilizing cleavage complexes,11–13 which ultimately generates un-ligatable DNA ends that need to be repaired by recombination pathways.2–6,9 When cells are overwhelmed by the drug, the accumulating strand breaks trigger cell death pathways.2–6,9 Because etoposide and other drugs that function by this mechanism convert type II topoisomerases into cellular toxins that fragment chromosomes, they are called \"topoisomerase II poisons.\"3,4,6,10 This is as opposed to \"topoisomerase II catalytic inhibitors,\" which kill cells by robbing them of the essential functions of these enzymes.3,4,6,10</p><p>Despite the importance of etoposide as a therapeutic agent for the treatment of cancer, the drug is associated with very serious side effects.4,14–18 Among the most dramatic of these are the generation of treatment-related acute myelogenous leukemias (AMLs) that involve rearrangements of the mixed lineage leukemia gene at chromosomal band 11q23,4,14–18 Although etoposide targets topoisomerase IIα and IIβ, the contributions of the two enzyme isoforms to the therapeutic and leukemogenic properties of the drug are not clear. Circumstantial evidence suggests that topoisomerase IIα may play a more prominent role in killing cancer cells, whereas topoisomerase IIβ may be more important in the induction of leukemic chromosomal translocations.4,14–18</p><p>In an effort to minimize off-target effects, the etoposide derivative F14512 (compound 2) was developed (Fig. 1).19 This drug, which is in clinical trials for human refractory/relapsing AMLs20 and canine lymphomas,21 replaces the C4 sugar moiety of etoposide with a spermine substituent.19 F14512 was designed to be taken up preferentially by cancer cells with active polyamine transport, thereby lessening off-target effects in non-cancer cells.19,22 Unexpectedly, F14512 turned out to be a much stronger topoisomerase II poison than etoposide.19,23 At least in part, this enhanced activity was believed to reflect the fact that the spermine moiety of F14512 interacts with DNA,19 whereas the parent drug does not.23–25 The linkage between the etoposide core and spermine is critical for the enhanced potency and efficacy of F14512.23 Thus, the increased activity is not due to the additive effects of a topoisomerase II poison and a separate DNA binding agent.</p><p>In order to assess the role of the polyamine moiety in promoting drug activity against type II topoisomerases, Palermo et al. synthesized a series of etoposide derivatives with varying C4 polyamine substituents (Fig. 1).26 In contrast to NMR studies carried out with F14512 and topoisomerase IIα, which indicated no interactions between the spermine substituent and the enzyme in the binary complex (enzyme•drug),23 modeling studies suggest that there are important polyamine-topoisomerase II contacts in the ternary complex (i.e. enzyme•DNA•drug).26 Furthermore, based on correlations with activity studies, the authors proposed that these polyamine-enzyme interactions in the ternary cleavage complex contributed to the enhanced ability of the etoposide-polyamine chimeras to poison topoisomerase IIα.26</p><p>In vitro, F14512 is more potent against topoisomerase IIβ than the α isoform.19, 23 In contrast, at least in A549 lung cancer cells, it has been suggested that topoisomerase IIα is the primary cytotoxic target of the drug.27 However, the level of topoisomerase IIα in the A549 cells used in the study was considerably higher than that of topoisomerase IIβ.27 Consequently, the relative roles of the two enzyme isoforms in the actions of F14512 in lung and other cancer cells remain an open question.</p><p>Therefore, to further understand how hybrid etoposide-polyamine drugs interact with type II topoisomerases and discriminate between the two enzyme isoforms, the abilities of compounds 2–7 (Fig. 1) to enhance DNA cleavage mediated by human topoisomerase IIα and IIβ were assessed and compared to those of etoposide. As seen in Fig. 2, all of the polyamine-based compounds displayed activities against topoisomerase IIα or IIβ that were equal to or greater than that of etoposide. The ability of compound 2 (F14512), which has the tetramine spermine side-chain, to induce double-stranded breaks was higher than the other derivatives examined, as described previously for topoisomerase IIα.19,23,26 The compounds displayed a modest decrease in their ability to induce enzyme-mediated DNA cleavage when the side-chain was substituted by the triamine spermidine (3), or by spermine that was methylated on the terminal amine (4) or that contained shortened methylene linkers between the inner amino groups (5 or 6). The lowest activity was seen with compound 7, in which the second and third amino groups were replaced with oxygens. Thus, the number of amines and their spacing all appear to contribute to the activity of this series of etoposide-polyamine hybrids.</p><p>Furthermore, as reported previously for compound 2,23,26 the etoposide-polyamine hybrids generally displayed a greater ability to induce double-stranded DNA breaks with topoisomerase IIβ than topoisomerase IIα (Fig. 2, top row). This is despite the fact that the parent drug etoposide induces higher levels of double-stranded breaks with the α isoform.23,26 To aid comparisons between the two enzyme isoforms, the bar graph (Fig. 2, top row, right) shows the induction of double-stranded DNA cleavage at 25 μM drug. This is the maximum concentration of compounds at which multiple cleavage events per plasmid were not observed. Similar effects were seen for the relative potencies of etoposide-polyamine hybrids as determined by levels required to induce 10% enzyme-mediated double-stranded DNA breaks (Table 1). All the compounds were considerably more potent than etoposide and, in general, were more potent against topoisomerase IIβ than IIα.</p><p>In contrast to results with double-stranded DNA cleavage, etoposide and the derivatives all induced considerably higher levels of single-stranded DNA breaks with topoisomerase IIα than with IIβ (Fig. 2 middle row). In general, the etoposide-polyamine hybrids induced levels of single-stranded breaks that were similar to or higher than that of the parent drug. However, with the exception of compound 7, all of the hybrid molecules maintained lower single-stranded to double-stranded ratios (i.e., they induced higher levels of double- as compared to single-stranded DNA breaks) than etoposide with both of the topoisomerase II isoforms (Fig. 3).</p><p>Taking both double- and single-stranded cleavage into account, the total percentage of the DNA molecules that are in cleavage complexes induced by the etoposide-polyamine hybrids were similar or higher than that seen for etoposide with topoisomerase IIα and considerably higher for topoisomerase IIβ (Fig. 2 bottom row).</p><p>Etoposide and F14512 increase topoisomerase II-mediated DNA scission by stabilizing cleavage complexes. This is reflected as an inhibition of the ability of the enzyme to religate cleaved DNA11,23 and an enhanced persistence of DNA cleavage complexes.23,28 This was also the case for all of the etoposide-polyamine hybrids examined. As seen in Fig. 4, they inhibited religation to an extent similar as that of etoposide. Furthermore, most of the cleavage complexes formed in the presence of the etoposide-polyamine hybrids persisted to a similar extent as etoposide following dilution with drug-free buffer (Fig. 5). As documented previously,23 cleavage complexes formed with topoisomerase IIα were more stable than those formed with the β isoform.</p><p>The abilities of etoposide-polyamine hybrids to induce DNA cleavage were generally greater than that of etoposide with topoisomerase IIα. However, the activities of these compounds against topoisomerase IIβ were dramatically higher than that of the parent compound (Table 2). Whereas the total levels of DNA cleavage for the hybrid compounds ranged from ~0.9 to 1.7 times that generated by etoposide with topoisomerase IIα, these cleavage ratios were ~3–8 times higher with topoisomerase IIβ (Table 2). To provide potential insight into the major differences in drug activity against the enzyme isoforms, the etoposide-polyamine hybrids were modeled into the DNA cleavage/ligation active sites of topoisomerase IIα and IIβ. Crystal structures obtained from the Protein Data Bank for the α (5GWK) and β (3QX3) isoforms were employed for these docking studies.13,29</p><p>Whereas the sugar moiety of etoposide is surrounded by a hydrophobic pocket comprised of three methionine residues in topoisomerase IIα, one of these amino acids (proximal to the C6 of the sugar) is a polar glutamine (Gln778) residue in the β isoform.13,29 On the basis of genetic studies, alterations in this amino acid affect biological sensitivity to etoposide.30 In the original data coordinates of the topoisomerase IIβ structure, Gln778 adopts two different conformations. Specifically, the side chain of the residue can point toward either etoposide or the protein. In the latter case, Gln778 points away from the bound ligand. Based on the highest occupancy of Gln778 in the crystal structure, we selected a starting conformation for docking in which the side chain of Gln778 is flipped away from the drug core, thus forming no interactions with etoposide.</p><p>As seen in Fig. 6, all of the etoposide-polyamine hybrids dock into the same active site pocket in the two enzyme isoforms. In our induced fit docking calculations with topoisomerase IIβ (Fig. 7, bottom), Gln778 (which is a polar residue) regularly flips to form stabilizing interactions either with the carbonyl group of the polyamine chain (panel C, H-bond length from 1.7–2.6 Å), or with the D-ring ether oxygen of the epipodophyllotoxin core (panel D, H-bond length from 1.9–2.5 Å). This implies that Gln778 changes its starting conformation to form electrostatic interactions with the etoposide-polyamine hybrid. In contrast, the corresponding methionine (Met762) in topoisomerase IIα (which is a non-polar residue) is unable to form electrostatic interactions with the ligand (Fig. 7, top). Although this methionine can adopt different conformations (compare panels A and B), Met762 never forms favorable interactions with the bound ligand. In our modeling studies, the methionine remained 3.5–9 Å away from the bound ligand. The differential effects of the glutamine versus methionine residue likely contribute to the fact that the etoposide-polyamine hybrids induce higher levels of DNA cleavage with the topoisomerase IIβ over the α isoform, especially when compared to the parent drug etoposide.</p><p>Finally, the amino groups of the polyamine conjugates of compounds 2–6 all appear to form stable hydrogen bonds with several DNA bases (Fig. 8 A). However, modeling studies suggest that the oxygen atoms in the polyamine tail of compound 7 are unable to form comparable hydrogen bonds (Fig. 8 B). This might explain the lower DNA cleavage activity observed for this compound with both etoposide. the α and β isoforms and the fact that its DNA cleavage profile more closely resembles that of</p><p>In conclusion, etoposide derivatives in which the C4 sugar moiety is replaced with a variety of polyamine tails induce higher levels of DNA cleavage with human topoisomerase IIα and IIβ than does the parent drug. These etoposide-polyamine hybrids display higher levels of activity against the β isoform, especially when compared to etoposide. Molecular docking studies suggest that this enhanced specificity may result from interactions with a glutamine residue that is present in topoisomerase IIβ, but not in topoisomerase IIα. The results of our enzymology and modeling studies form the basis of a testable hypothesis for the design of future drugs31 with enhanced specificity toward a single isoform of human topoisomerase II.</p>", "role": "user" }, { "content": "Etoposide is an anticancer drug that acts by inducing topoisomerase II-mediated DNA cleavage. Despite its wide use, etoposide is associated with some very serious side-effects including the development of treatment-related acute myelogenous leukemias. Etoposide targets both human topoisomerase II\\xce\\xb1 and II\\xce\\xb2. However, the contributions of the two enzyme isoforms to the therapeutic vs. leukemogenic properties of the drug are unclear. In order to develop an etoposide-based drug with specificity for cancer cells that express an active polyamine transport system, the sugar moiety of the drug has been replaced with a polyamine tail. To analyze the effects of this substitution on the specificity of hybrid molecules toward the two enzyme isoforms, we analyzed the activity of a series of etoposide-polyamine hybrids toward human topoisomerase II\\xce\\xb1 and II\\xce\\xb2. All of the compounds displayed an ability to induce enzyme-mediated DNA cleavage that was comparable to or higher than that of etoposide. Relative to the parent drug, the hybrid compounds displayed substantially higher activity toward topoisomerase II\\xce\\xb2 than II\\xce\\xb1. Modeling studies suggest that the enhanced specificity may result from interactions with Gln778 in topoisomerase II\\xce\\xb2. The corresponding residue in the \\xce\\xb1 isoform is a methionine.", "role": "assistant" } ]

[ { "content": "You have to answer a biomedical question in binary format, i.e., only yes and no are acceptable answers. A list of paragraphs is provided as context to help you answer the question.\n\nQuestion: Is patisiran currently (November 2017) in clinical phase II trials?\n\nContext: This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3).\npatisiran (phase 3)\nPhase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy\nEfficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study.", "role": "user" }, { "content": "no", "role": "assistant" } ]

[ { "content": "You will be presented with a sentence from biomedical research text. Extract all terms that correspond to chemical entities of biological interest (ChEBI).\nReturn your identified terms in a JSON array, formatted like this: [\"Entity1\", \"Entity2\", ...].\nIf no such entities are detected, respond by providing an empty JSON array [].\n\nBiomedical context:\nAcknowledgements", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "You will be shown a paragraph from a biomedical research article. Your task is to extract all drug combinations appearing in a specific sentence within the paragraph. Each drug combination should be assigned to one of the following three categories:\n\n- POS: Indicates a positive interaction between the drugs in the combination; for instance, drugs that have an additive or synergistic effect.\n- NEG: Indicates a negative interaction between the drugs in the combination; for instance, combining these drugs might result in adverse side effects, or might reduce their efficacy.\n- COMB: Indicates that the drugs are given in combination, but the type of interaction between the drugs cannot be determined based on the provided context.\n\nPlease format your answer as a JSON array. Each entry in the array should itself be an array formatted as [<drug_1>, <drug_2>, ..., <drug_n>, <category>] where <category> is one of the three categories listed above and <drug_1>, ..., <drug_n> are drug names copied verbatim from the input sentence. Different combinations may involve different numbers of drugs; in other words, the `n` in <drug_n> may vary.\n\nAs an example, the following output describes two extracted drug combinations; one between two drugs, and one between three drugs:\n\n[[\"artesunate\", \"artemether\", \"COMB\"], [\"Nifedipine\", \"Labetalol\", \"Prazosin\", \"POS\"]]\n\nThe paragraph and specific sentence are below. You should only extract relationships expressed in the specific sentence; the paragraph is provided for context.\n\nIn your output, return only the JSON array and no other text. If no drug combinations appear, return an empty array `[]`.\n\nparagraph: The effect of olprinone compared with milrinone on diaphragmatic muscle function in dogs. We compared the effect of olprinone with milrinone on the contractility of fatigued diaphragms in dogs. Animals were divided into four groups of 10 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, Group I received only maintenance fluids; Group II was given a bolus injection (50 microg/kg) followed by continuous infusion (0.5 microg x kg(-1) x min(-1)) of milrinone; Group III was infused with olprinone (10 microg/kg initial dose plus 0.3 microg x kg(-1) x min(-1) maintenance dose); Group IV was infused with nicardipine (5 microg x kg(-1) x min(-1)) during olprinone administration. After the fatigue-producing period in each group, transdiaphragmatic pressure (Pdi) at low-frequency (20 Hz) stimulation decreased from the prefatigued values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups II and III, during study drug infusion, Pdi at both stimuli increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group III than in Group II (P < 0.05). In Group IV , the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine . We conclude that olprinone is more effective than milrinone for the improvement of contractility in he fatigued diaphragm and that the potentiating mechanism of olprinone may be closely related to the transmembrane calcium movement. ### implications Diaphragmatic fatigue may contribute to the development of respiratory failure. Compared with milrinone, olprinone improves the contractility in fatigued diaphragm in dogs.\n\nsentence: In Group IV , the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine .", "role": "user" }, { "content": "[[\"olprinone\", \"nicardipine\", \"NEG\"]]", "role": "assistant" } ]

[ { "content": "You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.\n\nTitle:\nGenetically Encoded Tetrazine Amino Acid Directs Rapid Site-Specific In Vivo Bioorthogonal Ligation with trans-Cyclooctenes\n\nPaper sections:\n\n<p>Understanding protein networks and structural changes is key to revealing the secrets of biology. Currently available in vitro bioorthogonal ligation methods for site-specifically labeling proteins are limited by the reaction rates or bulk of reactive components. Also, no general method exists for in vivo site-specific labeling of proteins with a catalyst-free reaction or reactants that are stable, nontoxic and chemoselective.</p><p>A wide variety of functionalities have been genetically incorporated for the site-specific labeling of proteins, but these methods are not effective in vivo because they have modest coupling rates1. A robust but slow labeling reaction involves azides with unstrained alkynes and Cu+1 catalyst (k2=10−2−10−4 M−1s−1).2 Strained, fluorinated alkynes amino acids can be used without Cu+1 but still have modest coupling rates (k2=1 M−1s−1)1a,1c,3. Genetically encoded cyanobenzathiazole condensations and photo-click reactions have been developed with rate constants reaching 10 M−1s−1 but have side reactions in vivo or need short wavelengths of light.4 A wide variety of reactions have also been developed but show varying levels of side reactions in vivo (using cyclooctynes, aldehydes, phosphine labeling reagents)5. Alternative genetic incorporation methods such as self-labeling tag sequences6 and fluorescent protein fusions7 are non-toxic and can exhibit fast coupling rates, but the components are often bulky and can rarely be moved to multiple locations within the labeled protein without compromising the function of the system of interest.8 A bioorthogonal ligation reaction on proteins that is going to advance in vivo labeling will need i) components that are unreactive to cell culturing conditions, ii) to be rapid and quantitative, iii) to be encoded genetically for any site on the protein, iv) to result in a stable linkage facilitating labeling with diverse probes. In order to satisfy these labeling criteria and overcome current limitations we set out to develop a genetically encodable functionality based on the tetrazine-alkene coupling reaction.</p><p>Inverse electron-demand Diels-Alder reactions of s-tetrazines are venerable reactions in organic synthesis.9 Recently, we introduced the bioorthogonal reaction between tetrazines and trans-cyclooctene derivatives,10 a method of rapid bioconjugation which has been applied by a number of groups.11 The foundation of this bioorthogonal reaction is a photochemical, flow-chemistry method that provided the first general and scalable route to functionalized trans-cyclooctenes.12 These strained alkenes have allowed for tetrazines with reduced reactivities to be used that are more stable toward nucleophiles (ie water and thiols) but still yield fast coupling reactions (coupling rates with k2 >1000 M−1s−1).10,11,13</p><p>To develop an unnatural amino acid that could partner in the tetrazine ligation, one of the reactive partners needs to be attached to an amino acid, while the other needs to be attached to a useful label. The trans-cyclooctene functionality is stable under biological conditions and is relatively easy to functionalize.11a,b,11d,11f Accordingly, we set out to develop a tetrazine containing amino acid that is stable to cell culturing conditions but still sufficiently reactive with strained alkenes. The tetrazines that have been studied in conjugations with trans-cyclooctene, such as amido-substituted 3,6-di(2-pyridyl)-s-tetrazines and mono-aryl-s-tetrazines, are stable in biological milieu, but display slow background reactivity that would be incompatible with cellular growth conditions.11c,13–14 Thus, we aimed to design a tetrazine derivative that would be stable in cells, 4-(6-methyl-s-tetrazin-3-yl)aminophenylalanine, 1. Adding electron donating methyl and secondary amine substituents to the 3 and 6 position of the tetrazine should improve its stability against nucleophilic attack. The tetrazine-UAA 1 was synthesized in five steps from commercially available materials (see supporting information for details).</p><p>While the electron donating 3-amino substituent of 1 makes this tetrazine stable and soluble in biological conditions, it also decreases the rate of Diels-Alder reactions. Accordingly, we chose to combine this amino acid with derivatives of compound 2, a strained trans-cyclooctene (s-TCO) that we recently developed.13 With tetrazines, compound 2 displays relative rates that are significantly faster than our original system based on 5-hydroxy-trans-cyclooctene.10</p><p>We set out to evolve the Methanococcus jannaschii (Mj) tyrosyltRNA synthetase (RS)/tRNACUA pair since it has previously been used to incorporated UAAs of similar structure in response to an amber codon.15 To evolve the orthogonal MjTyrRS/tRNACUA pair capable of incorporating 1 in E. coli, we used a library of the synthetase (RS) gene that was randomized for the codons corresponding to six active-site residues within 7 Å of the bound tyrosine.15 We performed two rounds of alternating positive and negative selection on this library (see supporting information for details). Plasmids from surviving clones were transformed into cells with a plasmid containing a GFP gene interrupted with an amber codon.6g,16 96 colonies were assessed for UAA-dependent expression of GFP. The top 20 performing clones showed greater than 300 mg/L of GFP-1 expression in the presence of 1 and no detectable GFP fluorescence over background in the absence of 1 (Sup. Fig. 2). Sequencing these 20 clones revealed one unique RS sequence contain the mutations (Y32E, L65A, A107E, F108P, Q109S, D158G, L162G).</p><p>To further characterize the incorporation of 1 into proteins in response to the amber codon, the selected RS was cloned into a pDule vector that contains one copy of Mj tRNACUA to create pDule-mtaF.6g,16–17 Expression of GFP gene interrupted by an amber codon at site 150 in the presence of pDule-mtaF was efficient and dependent on the presence of 1 (Fig. 1b). Using 1 mM 1, 124 mg of GFP-1 was purified per liter of media, while GFP-wt yielded 220 mg/L under similar conditions (no GFP is produced in the absence of 1). To further demonstrate that 1 can be incorporated into recombinant proteins using pDule-mtaF, we compared the masses of GFP-1 to GFP-wt using ESI-Q-Tof mass analysis. The native GFP-wt has the expected mass of 27827 ±1 Da and GFP-1 exhibits the expected mass increase to 27971±1 Da verifying that 1 is incorporated at single site (Sup. Fig. 2). The site of 1 incorporation was confirmed by analysis of the tandem mass spectrometry (MS/MS) fragmentation series of the relevant tryptic peptide (Fig. 1C).18 Overall, the results of protein expression with affinity purification, SDS-PAGE, MS, and MS/MS analysis demonstrate the high fidelity and efficient incorporation of 1 at a genetically programmed site in GFP using pDule-mtaF. Since expressions contained 1 for 40 hrs in media at 37°C, this also confirms that stability of 1 to cell growth and protein purification conditions.</p><p>The conjugated pi systems of tetrazines cause them to absorb visible light between 510 and 550 nm, enabling them to quench many attached fluorescent probes.5g This quenching has proven useful because once the tetrazine undergoes cycloaddition with alkenes the conjugated system is removed and the coupled product ceases to quench nearby fluorophores. When 1 is encoded at site 150 in GFP, approximately 12 Å from the protein chromophore, the protein fluorescence is quenched 11 fold (Figure 2A,B). Incubating GFP-1 (3μM) with 39 μM 2 shows a complete return of fluorescence in less than 30 seconds indicating GFP-3 was formed. ESI-Q-Tof of the desalted reaction mixture confirmed the quantitative conversion of GFP-1 (expected 27971 Da; observed 27971±1 Da) into GFP-3 (expected 28094 Da; observed 28093 ±1 Da (Sup Figure 2).</p><p>It has been shown that tetrazine-alkene reaction rates are solvent dependent and are accelerated in polar solvents.10 In order to determine this rate constant for this reaction at a specific site in a protein the increase in GFP-3 fluorescence was followed in a PBS buffer at pH 7, 22°C. The kinetics of the reaction were performed under pseudo-first-order conditions as verified by a single exponential fit for product formation ([GFP] was 0.10μM and [2] ranged from 27.0 to 6.8 μM). The in vitro second order rate constant for GFP-1 with 2 is 880±10 M−1s−1 (Figure 3A). This verifies that this site-specific tetrazine-strained cyclooctene reaction is orders of magnitude faster than established site-specific labeling methods.</p><p>Thus far, tetrazine-alkene coupling reactions on engineered proteins have only been characterized in vitro and on cell surfaces. While it is possible to genetically encode ketone, azide and alkyne functionality site-specifically on amino acids, little labeling has been done on these engineered proteins in vivo with these amino acids. To determine if this bioorthogonal reaction is rapid and quantitative in vivo, E. coli cells containing expressed GFP-1 were incubated with 0.1 mM 2 in PBS buffer at room temperature. As expected, the fluorescence returned in less than a minute, indicating that GFP-3 had been formed. The cells were cooled and washed twice with PBS at 0°C to remove unreacted 2. ESI-Q-Tof MS of affinity purified his-tag protein resulted in a molecular mass matching only GFP-3 (Fig 2C). This verifies that 2 can be taken up by E. coli cells, the reaction is facile and the conjugated product is stable in vivo. This demonstrates the first site-specific in vivo reaction for this type of bioorthogonal ligation.</p><p>In vivo site-specific reaction rate constants have yet to be determined for bioorthogonal reactions. In order to determine the rate constant for this reaction inside living cells, E. coli expressing GFP-1 was pelleted and resus-pended in PBS buffer. In vivo kinetic studies were performed similarly to the in vitro studies and the five pseu-do-first-order rate constants were used to determine the bimolecular rate constant. The in vivo second order rate constant for GFP-1 with 2 is 330±20 M−1s−1 (Figure 3B). Since identical conditions were used for in vitro and in vivo kinetic measurements, the 60% rate constant reduction is most likely a result of the in vivo cellular environment or hampered uptake of 2. Limiting cellular uptake of 2 would result in non-exponential kinetics for the formation of GFP-3, which was not observed (Figure 3B). Also, the rate constant for the overall process measured in cells is comparable to the in vitro rate constants indicating the uptake step cannot be significantly slower than the reaction step. Molecular crowding or electrostatic changes induced by the internal cellular environment could account for the rate change. The in vivo coupling reaction was also verified in rich media and on live cells. No toxicity was evident as judge by comparing cell viability of cells harboring the sTCO reagent to those that did not (Sup. Fig. 5). While the in vivo reaction is slower than the in vitro, the coupling rate is still sufficient to label proteins in their native environment.</p><p>To verify that this labeling strategy is general, 2 was conjugated to a diacetyl-fluorescein dye forming 4 (Sup Scheme 2). The fluorescently labeled trans-cyclooctene, 4, was then reacted with GFP-1, similarly to reactions with 2. Quantitative labeling of GFP-1 would result in GFP-5 mass of 28653 Da (Figure 2D), but in aqueous conditions deacetylated products would be expected. While the fluorescein-labeled protein ionized poorly via ESI-MS, MALDI MS was used to confirm labeling (expected 28653 Da; observed 28635 ± 100 Da). This confirms that protein-containing 1 is reactive with labeled strained trans-cyclooctenes.</p><p>In conclusion, we report a general method for the site-specific incorporation of a novel, stable tetrazine containing amino acid, 1, into recombinant proteins in E. coli. We demonstrated that protein containing 1 can be quantitatively labeled with strained trans-cyclooctenes and that the resulting ligation product is stable to in vivo cellular conditions. We determined the in vitro and in vivo rate constants for this bioorthogonal coupling to be significantly faster than currently used site-specific labeling reactions.1a,2–4 The speed of this catalyst-free reaction and the stability of reacting components and ligation product will make it an advantageous tool for studying complex protein networks and conformational changes in vivo and in vitro. Our future efforts will focus on developing this reaction for use in labeling proteins in live yeast and mammalian cells, and engineering protein interactions.</p>", "role": "user" }, { "content": "Bioorthogonal ligation methods with improved reaction rates and less obtrusive components are needed for site-specifically labeling proteins without catalysts. Currently no general method exists for in vivo site-specific labeling of proteins that combines fast reaction rate with stable, nontoxic and chemoselective reagents. To overcome these limitations we have developed a tetrazine-containing amino acid, 1, that is stable inside living cells. We have site-specifically genetically encoded this unique amino acid in response to an amber codon allowing a single 1 to be placed at any location in a protein. We have demonstrated that protein containing 1 can be ligated to a conformationally strained trans-cyclooctene, 2, in vitro and in vivo with reaction rates significantly faster than most commonly used labeling methods.", "role": "assistant" } ]

[ { "content": "You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your response other than the answer.\n\nParagraph: It also acts as a peripheral membrane protein , as does the L protein [51] , an activity that could play a role in its presumed, but not yet demonstrated function as matrix [52] . Until recently, it had not been appreciated that N has a wide variety of other activities, some of which can be linked, not only to fundamental requirements of replication, but also to the interference with an array of the intracellular processes of the normal cell. Thus, an interaction between the amino terminus of the hantavirus N protein and the cellular protein Daxx has been proposed, with the suggestion of potential pro-apoptotic consequences [51] . N is also reported to interact with actin microfilaments, and the SUMO-1 protein [53, 54] . Using reporter-gene based assays, Connie Schmaljohn and her colleagues have reported that Hantaan virus' nucleocapsid protein has an inhibitory role in inflammatory responses mediated by NF kappa B (NF-B). The effects on NF-B expression appeared to be confined to prevention of its nuclear translocation after its attempted activation with lipopolysaccharide, LPS [55] . In the cytoplasm of infected cells, N protein can be found in cellular P bodies where it sequesters and protects 5' caps. It may locate the caps through its interaction with DCP1, a key constituent of P bodies. During hantavirus infection, the viral RNAs become concentrated in P bodies, through their interaction with N and DCP1. The N protein demonstrates preferential protection of mRNAs engineered to prematurely terminate their encoded protein in comparison to native mRNAs [56] . N protein has been increasingly linked to viral replication and translation, sometimes in previously unanticipated ways. It is among a growing family of diverse viral proteins that can serve as a nonspecific -RNA chaperone‖, an activity that should facilitate the L polymerase's access to vRNA for transcription and replication, in that it can transiently dissociate misfolded RNA structures [57] . Some of N protein's effects on translation might not immediately be recognized to be adaptive in nature. It can replace the entire EIF4F translational initiation complex, simultaneously presenting the ribosome with a replacement for the cap-binding activity of eIF 4E, binding to the 43S pre-initiation complex as does eIF 4G, while replacing the helicase activity of eIF 4A, which is presumed to be needed to dissociate higher-order RNA structure [56, 58] . These three factors normally work together to achieve translational initiation. In P bodies, N protein's ability to bind at high affinity to capped native cellular oligoribonucleotides, along with its activity in protecting capped RNAs from degradation likely facilitates the access of capped oligonucleotides for use in transcriptional initiation by L polymerase (-cap snatching‖). Trafficking of N for viral assembly: Classically, N protein in infected cells appears to be clustered or particulate in nature, with a heavy concentration at a single perinuclear location, widely considered to be the Golgi [27] . The N proteins of hantaviruses are found in association with particulate fractions, and confocal microscopy and biochemical-inhibitor studies have shown that N tracks along microtubules but not with actin filaments [52] . The ultimate destination for N, for its assembly into viral particles is the Golgi, and it traffics there via the endoplasmic reticulum-Golgi intermediate complex (ERGIC), also known as vesicular-tubular cluster [52] . A dominant negative inhibitor, dynamitin, associated with dynein-mediated transport, reduced N's accumulation in the Golgi. Later studies suggested that the specific dependence on microtubular transport is specific to Old World hantaviruses such as HTNV, but that the New World hantavirus ANDV is instead associated with actin filaments [59] . However, recent data indicates that microtubular transport is indeed utilized for the New World hantavirus SNV [60] . Hantavirus diseases of man have long been suspected of having an immunopathogenic basis in part because of their relatively long incubation period of 2-3 weeks and the observed temporal association between immunologic derangements and the first appearance of signs and symptoms of hantavirus illness. HFRS and HCPS share many clinical features, leading many investigators to consider them to be, in essence, different manifestations of a similar pathogenic process, differing mainly in the primary target organs of disease expression ( Table 2 ). The pathogenesis of hantavirus infections is the topic of a continuously-updated review in the series UpToDate [61] . By the time symptoms appear in HCPS, both strong antiviral responses, and, for the more virulent viral genotypes, viral RNA can be detected in blood plasma or nucleated blood cells respectively [63, 64] . At least three studies have correlated plasma viral RNA with disease severity for HCPS and HFRS, suggesting that the replication of the virus plays an ongoing and real-time role in viral pathogenesis [65] [66] [67] . Several hallmark pathologic changes have been identified that occur in both HFRS and HCPS. A critical feature of both is a transient (~ 1-5 days) capillary leak involving the kidney and retroperitoneal space in HFRS and the lungs in HCPS. The resulting leakage is exudative in character, with chemical composition high in protein and resembling plasma. The continued experience indicating the strong tissue tropism for endothelial cells, specifically, is among the several factors that make β3 integrin an especially attractive candidate as an important in vivo receptor for hantaviruses. It is likely that hantaviruses arrive at their target tissues through uptake by regional lymph nodes, perhaps with or within an escorting lung histiocyte. The virus seeds local endothelium, where the first few infected cells give rise, ultimately, to a primary viremia, a process that appears to take a long time for hantavirus infections [62, 63] . By the time that secondary viremia emerges, the agents of the more severe forms of HFRS and HCPS have begun to achieve sufficient mass as to induce, through PAMP-PRR interactions and other means, the expression of proinflammatory cytokines [64] . For HCPS, that expression favors the pulmonary bed and lymphoid organs, yet, for unknown reasons, spares the retroperitoneum and, in general, the kidney. In HFRS the situation is reversed, and yet it is often not appreciated that the expected preferential tissue tropism of HFRS-associated viruses and their HCPS-associated counterparts for the renal and pulmonary beds, respectively, is not as one would predict through the manifestations of the two diseases. Local elaboration of inflammatory and chemotactic mediators is considered to be a requirement for the development of systemic disease symptoms, with those abnormalities sometimes culminating in shock and death. Yet it is not hypoxemia, due to the prominent pulmonary edema, that leads to death in most fatal cases of HCPS, but rather intoxication of the heart by as-yet-undefined mediators that leads to the low cardiac output state and the associated shock syndrome [64, 65] . It is tempting to speculate that mediators produced in the lung in connection with the inflammatory infiltrate can percolate through the coronary circulation with minimal dilution in HCPS, a disadvantageous consequence of the close anatomic juxtaposition of the two organs. Thus, at least three classes of potential mechanisms, some overlapping and all certainly nonexclusive of the others, could be presumed to underlie the pathogenesis of HCPS. These include:\n\n(1) Innate immune mechanisms. The nature of interactions between hantavirus pathogen-associated molecular patterns (PAMP) with the pattern recognition receptors (PRR) of susceptible endothelial cells are beginning to be clarified. The prototypical HTNV appears to be recognized by TLR-3 [43] . Such an infection has consequences such as increased expression of HLA-DR in dendritic cells [66] and differentiation of monocytes toward dendritic cells [67] . (2) Direct viral effects. The observed correlation between viral load and disease severity leaves the possibility open that hantavirus particles or RNA can themselves have toxic effects on cells or on signaling. Some investigators have favored direct viral toxicity, acting through the inhibition of endothelial cell barrier function, as an explanation for much of the capillary leak, although there is widespread agreement that multiple mechanisms that mediate pathogenesis likely operate simultaneously in the affected patient [68] . A potentially important clue toward the mechanism by which hantavirus infections deplete blood platelets and, in some cases cause hemorrhagic manifestations, was advanced by the recent discovery that pathogenic hantaviruses are able to recruit platelets to adhere to endothelial cell surfaces, with β3 integrin used as a critical binding element [69] . (3) Pathogenic effects caused by the activities of specific viral macromolecules. We have reviewed some of the activities associated with the Gn, Gc and N, virally-encoded polypeptides in previous sections. Testing models of pathogenesis can be done more effectively when there is an animal model that mimics key aspects of the disease. There is no such model that closely mimics HFRS, but animal models exist for both the asymptomatic carriage of PUUV and SNV by their native carrier rodents, the bank vole Myodes glareolus and the deer mouse P. maniculatus; as well as a Syrian hamster model using ANDV or the related Maporal virus from Venezuela, for which an HCPS-mimetic disease is observed [70] [71] [72] [73] . The ANDV-Syrian hamster model has a number of features in common with the human disease, as well as some differences. Unlike the neurologic diseases that have been possible to elicit with HTNV, the hamster model for HCPS appears to be caused by capillary leak that results in pulmonary edema and the production of a pleural effusion with exudative characteristics. Typically the hamsters die between 11 and 14-d post-inoculation, reflecting a slightly accelerated incubation period in comparison to human infections. As with human HCPS, the microscopic examination of the lung reveals abundant fibrin deposition, thickened alveolar septa, and viral antigen expressed abundantly in the microvascular endothelium. ANDV-infected hamsters fitted with physiologic monitoring devices exhibited diminished pulse pressures, tachycardia, and hypotension that appear to closely mimic the shock that is believed to be the proximate cause of demise in patients who succumb to HCPS [65, 74] . Compared to the human disease, ANDV-infected hamsters exhibit exceptionally high titers of live ANDV in their tissues, with much of the viral replication occurring in hepatocytes, which are spared in the human disease. Titers of live ANDV in some cases exceed 10 8 /g, whereas hantavirus isolates from human tissues have been notoriously difficult to obtain. Despite the universal occurrence of mildly-elevated hepatic enzymes in patients with HCPS, hepatic enzymes do not appear to be present at elevated levels in the blood of diseased hamsters even immediately before death [75] . The protracted incubation period associated with hantavirus disease gives the host considerable time to mount a mature immune response against the virus. Thus, in contradistinction to infections of comparable severity and related symptomatology associated with arenaviruses and filoviruses, hantavirus infections of humans are associated with antibody responses of significant titer by the time symptoms commence. Despite this observation, it appears to be possible that natural variation in individual neutralizing antibody responses among patients with SNV infections can be linked to disease severity, suggesting that administration of antiviral antibodies could prove effective therapeutically [76] . In the case of ANDV infection, new evidence has emerged indicating that the apparent clearance of the virus from the blood does not result in the complete removal of antigenic stimulus by the virus, suggesting that the virus may persist, perhaps in some as-yet undetermined immunologically privileged site [77] . A role for T cell-mediated pathological responses in HFRS and HCPS has been the source of speculation for a variety of reasons. The severity of SNV-associated HCPS may have made it more apparent that the onset of pulmonary edema, tachycardia and hypertension seemed to be all but universally temporally associated with the appearance of a spectrum of highly-activated cells of the lymphoid lineage in the peripheral blood. Cells with a close morphologic similarity to these -immunoblasts‖ were detected in the congested, heavy lungs of patients who came to autopsy, as well as in lymphoid organs and in the portal triads [63, [78] [79] [80] . These observations led to speculation that some component of hantavirus pathogenesis could be linked to the appearance of antiviral T cells that could stimulate or contribute to the appearance of a -storm‖ of mediators and the associated capillary leak phenotype. Subsequent studies have borne out the expectation that a significant fraction of the immunoblast population in patients with HCPS are T cells with specificity for specific class I HLA-presented epitopes of viral antigens, including Gn, Gc and N [77, [81] [82] [83] . Presumably, the antiviral activities of such cells, manifested in part through their elaboration of mediators in the affected interstitium, can contribute to the endothelial/capillary leak that lies at the heart of hantavirus pathogenesis. Because early cases of HCPS often came to autopsy, it became possible to examine necropsied tissues for expression of cytokines. The study by Mori et al. (1999) revealed high relative expression of proinflammatory cytokines including TNF, IL-1, IL-6, providing evidence in favor of a -cytokine storm‖ model for pathogenesis [64] . The authors believed, based on the morphology of cytokine-secreting cells, that both monocytes and lymphocytes were contributing to the production of cytokines. That proinflammatory mediators are found in elevated levels in the plasma as well as the renal interstitium of patients with acute hantaviral illness has been recognized for some time as well [84, 85] . While diagnosis of HCPS as well as HFRS is best accomplished with IgM serology, in the acute stage of SNV infection, RT-PCR can also be used if blood cells or blood clot are used instead of plasma or serum, where sensitivity even using nested PCR primers drops to about 70% [86] [87] [88] . In a facility at which many cases of HCPS are treated, the University of New Mexico medical center in Albuquerque, a diagnostic service has long been offered in which the patient's hematologic findings are analyzed to establish the probability that a patient has HCPS.\n\nQuestion: What does the N-protein act as?", "role": "user" }, { "content": "a peripheral membrane protein", "role": "assistant" } ]

[ { "content": "You are provided with the abstract of a scientific paper and the abstracts of the papers it references. Your task is to write a Related Work section for the main paper. This section should concisely summarize and integrate the key points from the cited abstracts, reflecting how they relate to the main paper's contributions and context. In your summary, use numerical citation markers like [1], [2], etc., to refer to the corresponding papers.\n\nMain Abstract:\nData association-based multiple object tracking (MOT) involves multiple separated modules processed or optimized differently, which results in complex method design and requires non-trivial tuning of parameters. In this paper, we present an end-to-end model, named FAMNet, where Feature extraction, Affinity estimation and Multi-dimensional assignment are refined in a single network. All layers in FAMNet are designed differentiable thus can be optimized jointly to learn the discriminative features and higher-order affinity model for robust MOT, which is supervised by the loss directly from the assignment ground truth. We also integrate single object tracking technique and a dedicated target management scheme into the FAMNet-based tracking system to further recover false negatives and inhibit noisy target candidates generated by the external detector. The proposed method is evaluated on a diverse set of benchmarks including MOT2015, MOT2017, KITTI-Car and UA-DETRAC, and achieves promising performance on all of them in comparison with state-of-the-arts.\n\nCited Abstract(s):\n[1]: Tracking-by-detection has become a popular tracking paradigm in recent years. Due to the fact that detections within this framework are regarded as points in the tracking process, it brings data association ambiguities, especially in crowded scenarios. To cope with this issue, we extended the multiple hypothesis tracking approach by incorporating a novel enhancing detection model that included detection-scene analysis and detection-detection analysis; the former models the scene by using dense confidential detections and handles false trajectories, while the latter estimates the correlations between individual detections and improves the ability to deal with close object hypotheses in crowded scenarios. Our approach was tested on the MOT16 benchmark and achieved competitive results with current state-of-the-art trackers.\n\n[2]: We present a detection-based three-level hierarchical association approach to robustly track multiple objects in crowded environments from a single camera. At the low level, reliable tracklets (i.e. short tracks for further analysis) are generated by linking detection responses based on conservative affinity constraints. At the middle level, these tracklets are further associated to form longer tracklets based on more complex affinity measures. The association is formulated as a MAP problem and solved by the Hungarian algorithm. At the high level, entries, exits and scene occluders are estimated using the already computed tracklets, which are used to refine the final trajectories. This approach is applied to the pedestrian class and evaluated on two challenging datasets. The experimental results show a great improvement in performance compared to previous methods.\n\n[3]: \n\n[4]: We propose a network flow based optimization method for data association needed for multiple object tracking. The maximum-a-posteriori (MAP) data association problem is mapped into a cost-flow network with a non-overlap constraint on trajectories. The optimal data association is found by a min-cost flow algorithm in the network. The network is augmented to include an explicit occlusion model(EOM) to track with long-term inter-object occlusions. A solution to the EOM-based network is found by an iterative approach built upon the original algorithm. Initialization and termination of trajectories and potential false observations are modeled by the formulation intrinsically. The method is efficient and does not require hypotheses pruning. Performance is compared with previous results on two public pedestrian datasets to show its improvement.\n\n[5]: Data association is an essential component of any human tracking system. The majority of current methods, such as bipartite matching, incorporate a limited-temporal-locality of the sequence into the data association problem, which makes them inherently prone to IDswitches and difficulties caused by long-term occlusion, cluttered background, and crowded scenes.We propose an approach to data association which incorporates both motion and appearance in a global manner. Unlike limited-temporal-locality methods which incorporate a few frames into the data association problem, we incorporate the whole temporal span and solve the data association problem for one object at a time, while implicitly incorporating the rest of the objects. In order to achieve this, we utilize Generalized Minimum Clique Graphs to solve the optimization problem of our data association method. Our proposed method yields a better formulated approach to data association which is supported by our superior results. Experiments show the proposed method makes significant improvements in tracking in the diverse sequences of Town Center [1], TUD-crossing [2], TUD-Stadtmitte [2], PETS2009 [3], and a new sequence called Parking Lot compared to the state of the art methods.\n\n[6]: The main challenge of online multi-object tracking is to reliably associate object trajectories with detections in each video frame based on their tracking history. In this work, we propose the Recurrent Autoregressive Network (RAN), a temporal generative modeling framework to characterize the appearance and motion dynamics of multiple objects over time. The RAN couples an external memory and an internal memory. The external memory explicitly stores previous inputs of each trajectory in a time window, while the internal memory learns to summarize long-term tracking history and associate detections by processing the external memory. We conduct experiments on the MOT 2015 and 2016 datasets to demonstrate the robustness of our tracking method in highly crowded and occluded scenes. Our method achieves top-ranked results on the two benchmarks.\n\n[7]: This paper revisits the classical multiple hypotheses tracking (MHT) algorithm in a tracking-by-detection framework. The success of MHT largely depends on the ability to maintain a small list of potential hypotheses, which can be facilitated with the accurate object detectors that are currently available. We demonstrate that a classical MHT implementation from the 90's can come surprisingly close to the performance of state-of-the-art methods on standard benchmark datasets. In order to further utilize the strength of MHT in exploiting higher-order information, we introduce a method for training online appearance models for each track hypothesis. We show that appearance models can be learned efficiently via a regularized least squares framework, requiring only a few extra operations for each hypothesis branch. We obtain state-of-the-art results on popular tracking-by-detection datasets such as PETS and the recent MOT challenge.\n\n[8]: In this paper we show that multiple object tracking (MOT) can be formulated in a framework, where the detection and data-association are performed simultaneously. Our method allows us to overcome the confinements of data association based MOT approaches; where the performance is dependent on the object detection results provided at input level. At the core of our method lies structured learning which learns a model for each target and infers the best location of all targets simultaneously in a video clip. The inference of our structured learning is done through a new Target Identity-aware Network Flow (TINF), where each node in the network encodes the probability of each target identity belonging to that node. The proposed Lagrangian relaxation optimization finds the high quality solution to the network. During optimization a soft spatial constraint is enforced between the nodes of the graph which helps reducing the ambiguity caused by nearby targets with similar appearance in crowded scenarios. We show that automatically detecting and tracking targets in a single framework can help resolve the ambiguities due to frequent occlusion and heavy articulation of targets. Our experiments involve challenging yet distinct datasets and show that our method can achieve results better than the state-of-art.\n\n[9]: This paper explores a pragmatic approach to multiple object tracking where the main focus is to associate objects efficiently for online and realtime applications. To this end, detection quality is identified as a key factor influencing tracking performance, where changing the detector can improve tracking by up to 18.9 . Despite only using a rudimentary combination of familiar techniques such as the Kalman Filter and Hungarian algorithm for the tracking components, this approach achieves an accuracy comparable to state-of-the-art online trackers. Furthermore, due to the simplicity of our tracking method, the tracker updates at a rate of 260 Hz which is over 20x faster than other state-of-the-art trackers.\n\n[10]: We present an iterative approximate solution to the multidimensional assignment problem under general cost functions. The method maintains a feasible solution at every step, and is guaranteed to converge. It is similar to the iterated conditional modes (ICM) algorithm, but applied at each step to a block of variables representing correspondences between two adjacent frames, with the optimal conditional mode being calculated exactly as the solution to a two-frame linear assignment problem. Experiments with ground-truthed trajectory data show that the method outperforms both network-flow data association and greedy recursive filtering using a constant velocity motion model.", "role": "user" }, { "content": "Multiple object tracking (MOT) has been an active research area for decades, and many methods have been investigated for this topic. Recently, the most popular framework for MOT is the tracking-by-detection. Traditional methods primarily focus on solving the data association problem using such as Hungarian algorithm [9] [6] [2] , network flow [8] [5] [4] and multiple hypotheses tracking [1] [7] on various of affinity estimation schemes. Higher-order affinity provides the global and discriminative information that is not available in pairwise association. In order to utilize it, MOT is usually treated as the MDA problem. Collins [10] proposes a block ICM-like method for the MDA to incorporate higher-order motion model. The method iteratively solves bipartite assignments alternatively while keeping other assignments fixed. [3] , MDA is formulated as the rank-1 tensor approximation problem where a dedicated power iteration with unite @math normalization is proposed to find the optimal solution. Our work is closely related to the MDA formulation, especially [3] .", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"RNA\", \"CellType\", \"CellLine\", \"Protein\", \"DNA\"].\n\nPlease return the output as a JSON object of the format: {\"DNA\" : [\"TAL1\", ...], \"RNA\": [\"mRNAs\", ...], \"CellLine\": [\"T cells\", ...], \"CellType\": [\"monocytes\", ...], \"Protein\": [\"IL-2\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nGenes that regulate interleukin-4 expression in T cells. Interleukin-4 is an immunomodulatory cytokine which plays a central role in the regulation of allergic and atopic immune responses. Significant progress has been made in gaining a detailed understanding of the transcriptional regulation of the interleukin-4 gene. The recent identification and characterization of several key transcription factors has helped to elucidate the molecular mechanisms of T helper cell cytokine gene expression.", "role": "user" }, { "content": "{\"CellLine\": [], \"CellType\": [\"T cells\"], \"DNA\": [\"interleukin - 4 gene\", \"T helper cell cytokine gene\"], \"Protein\": [\"transcription factors\", \"an immunomodulatory cytokine\", \"interleukin - 4\", \"Interleukin - 4\", \"cytokine\", \"immunomodulatory cytokine\"], \"RNA\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nEffect of Lactobacillus rhamnosus GG in persistent diarrhea in Indian children: a randomized controlled trial.\nAbstract 1:\nTo evaluate the role of Lactobacillus rhamnosus GG (LGG) as probiotic in persistent diarrhea (PD) in children of North Bengal, India.\n Hospital-based study.\n Randomized, double-blind controlled trial.\n All patients of PD admitted over a period of 2 years were included in the study as per predefined inclusion criteria. They were randomized to receive oral rehydration solution (ORS) alone, or ORS plus LGG powder containing 60 million cells, twice daily for a minimum period of 7 days or till diarrhea has stopped along with correction of dehydration with ORS and/or intravenous fluids as per WHO protocol and antibiotics in culture positive patients. The duration and frequency of purge and vomiting were studied. Data were analyzed by SPSS-10 software. Statistical significance was calculated by Student t test and chi2 test.\n The study comprised of 235 patients randomized into 2 groups, cases (117) and controls (118). Both the groups were similar with respect to age, number of breastfed infants, presentation with dehydration, degree of protein energy malnutrition, and distribution of infections. Stool culture was positive in 90 (38.3%) patients, Escherichia coli being the commonest organism followed by Shigella spp. and Clostridium difficile. The mean duration of diarrhea was significantly lower in the cases than in controls (5.3 vs. 9.2 d). The average duration of hospital stay was also significantly lesser in cases. No complication was observed from the dose of LGG used.\n LGG (dose of 60 million cells) could decrease the frequency and duration of diarrhea and vomiting and reduced hospital stay in patients of PD.\n\n\nTitle 2:\nEffect of Lactobacillus strains and Saccharomyces boulardii on persistent diarrhea in children.\nAbstract 2:\nThe efficacy of probiotics on persistent diarrhea remains uncertain. The purpose of this study was to evaluate the effect of Lactobacillus sp and Saccharomyces boulardii on persistent diarrhea in children. In a double-blind trial eighty-nine children, aged 6-24 months were randomly distributed to receive pasteurized cow milk containing 2 viable lyophilized strains Lactobacillus casei and Lactobacillus acidophillus strains CERELA, (10(10)-10(12) colony-forming units per g) (n = 30), or lyophilized S. boulardii, (10(10)-10(12) colony forming units per g) (n = 30) or pasteurized cow milk as placebo (n = 29); on each diet 175 g was given twice a day for a 5 day period. Number of depositions, duration of illness and frequency of vomiting were considered. Enteric pathogens were isolated from stools in 40% of the patients, 27% had rotavirus. Lactobacillus and S. boulardii significantly reduced the number of depositions (p < 0.001) and diarrheal duration (p < 0.005). Similarly both significantly (p < 0.002) reduced vomiting as compared with placebo. There was no difference between treatments depending on rotavirus status. In conclusion, L. casei and L. acidophillus strains CERELA and S. boulardii are useful in the management of persistent diarrhea in children.\n\n\nTitle 3:\n[Clinical consequences of replacing milk with yogurt in persistent infantile diarrhea].\nAbstract 3:\nPersistent diarrhea is an episode of diarrhea that begins acutely but lasts longer than expected for this usually self-limited disease. Treatment of this ill-defined syndrome is not well standardized but immediate intervention is required to minimize the risk of malnutrition with its various consequences. This randomized clinical trial was undertaken to evaluate the clinical efficacy of substituting yogurt for milk, as the only treatment. After a one to two-day observation period during which a standard milk diet was given, 78 children aged 3 to 36 months with confirmed persistent diarrhea of more than 15 days but less than one month duration and negative tests for fecal blood were fed either milk (infant formula) or yogurt (infant formula fermented with Lactobacillus bulgaricus and Streptococcus thermophilus). At inclusion both groups were comparable for age, nutritional status, diarrhea, and lactose hydrogen breath test results. Clinical treatment failure (weight loss greater than 5% in one day or persistent diarrhea after 5 days) was significantly less common in children fed yogurt (15 +/- 6%) than in children fed milk (45 +/- 8%). The beneficial effects of feeding yogurt were apparent within 48 hours in 67 +/- 8% of infants. In conclusion, these data confirm the clinical efficacy of substituting yogurt for milk in young children with persistent diarrhea. They also suggest that yogurt may be a good alternative for the initial treatment of persistent diarrhea.", "role": "user" }, { "content": "There is limited evidence suggesting probiotics may be effective in treating persistent diarrhoea in children.", "role": "assistant" } ]

[ { "content": "You will be presented with a citation sentence from a research paper. Classify the intent behind this citation by choosing from one of the following categories:\n\n- Method: Cites the paper for its methodology or procedure.\n- Background: Cites the paper to provide background information.\n- Result: Cites the paper for its findings or results.\n\nYour answer should be a single word from the following list of options: [\"Method\", \"Background\", \"Result\"]. Do not include any other text in your response.\n\nCitation sentence:\n\nGene expression For quantification of mRNA expression in murine samples, cells/tissues were homogenized in TRIzol (Invitrogen), and RNA was extracted and cDNA was generated and quantified as previously described (91) using a Light Cycler 480 II (Roche).", "role": "user" }, { "content": "Method", "role": "assistant" } ]

[ { "content": "You will be shown sections from a scientific research paper, together with a question about the paper. This is an extractive question-answering task, where you must find and extract relevant text spans directly from the paper to answer the question. Your response should strictly be a `json` object with two fields:\n\n\"answer\": An array of strings extracted directly from the paper which, collectively, answer the question.\n\"evidence\": An array of strings. Each should be an excerpt from the paper, in which one or more of the extracted answers can be found.\n\nFor example, for the question \"What baselines did the authors compare against?\", a sample response might be:\n{\n \"answer\": [\"BERT\", \"RoBERTa\"],\n \"evidence\": [\"In our experiments, we compare the performance of our model against BERT and RoBERTa.\"]\n}\n\nDo not include any text in your response other than the json.\n\nIf the question is unanswerable given the provided excerpts, respond with the single word \"null\".\n\nPaper: Revealing the Dark Secrets of BERT\n\nBERT-based architectures currently give state-of-the-art performance on many NLP tasks, but little is known about the exact mechanisms that contribute to its success. In the current work, we focus on the interpretation of self-attention, which is one of the fundamental underlying components of BERT. Using a subset of GLUE tasks and a set of handcrafted features-of-interest, we propose the methodology and carry out a qualitative and quantitative analysis of the information encoded by the individual BERT's heads. Our findings suggest that there is a limited set of attention patterns that are repeated across different heads, indicating the overall model overparametrization. While different heads consistently use the same attention patterns, they have varying impact on performance across different tasks. We show that manually disabling attention in certain heads leads to a performance improvement over the regular fine-tuned BERT models.\n\nIntroduction\nOver the past year, models based on the Transformer architecture BIBREF0 have become the de-facto standard for state-of-the-art performance on many natural language processing (NLP) tasks BIBREF1, BIBREF2. Their key feature is the self-attention mechanism that provides an alternative to conventionally used recurrent neural networks (RNN).\nOne of the most popular Transformer-based models is BERT, which learns text representations using a bi-directional Transformer encoder pre-trained on the language modeling task BIBREF2. BERT-based architectures have produced new state-of-the-art performance on a range of NLP tasks of different nature, domain, and complexity, including question answering, sequence tagging, sentiment analysis, and inference. State-of-the-art performance is usually obtained by fine-tuning the pre-trained model on the specific task. In particular, BERT-based models are currently dominating the leaderboards for SQuAD BIBREF3 and GLUE benchmarks BIBREF4.\nHowever, the exact mechanisms that contribute to the BERT's outstanding performance still remain unclear. We address this problem through selecting a set of linguistic features of interest and conducting a series of experiments that aim to provide insights about how well these features are captured by BERT. This paper makes the following contributions:\nWe propose the methodology and offer the first detailed analysis of BERT's capacity to capture different kinds of linguistic information by encoding it in its self-attention weights.\nWe present the evidence of BERT's overparametrization and suggest a counter-intuitive yet frustratingly simple way of improving its performance, showing absolute gains of up to 3.2%.\n\nRelated work\nThere have been several recent attempts to assess BERT's ability to capture structural properties of language. BIBREF5 demonstrated that BERT consistently assigns higher scores to the correct verb forms as opposed to the incorrect one in a masked language modeling task, suggesting some ability to model subject-verb agreement. BIBREF6 extended this work to using multiple layers and tasks, supporting the claim that BERT's intermediate layers capture rich linguistic information. On the other hand, BIBREF7 concluded that LSTMs generalize to longer sequences better, and are more robust with respect to agreement distractors, compared to Transformers.\nBIBREF8 investigated the transferability of contextualized word representations to a number of probing tasks requiring linguistic knowledge. Their findings suggest that (a) the middle layers of Transformer-based architectures are the most transferable to other tasks, and (b) higher layers of Transformers are not as task specific as the ones of RNNs. BIBREF9 argued that models using self-attention outperform CNN- and RNN-based models on a word sense disambiguation task due to their ability to extract semantic features from text.\nOur work contributes to the above discussion, but rather than examining representations extracted from different layers, we focus on the understanding of the self-attention mechanism itself, since it is the key feature of Transformer-based models.\nAnother research direction that is relevant to our work is neural network pruning. BIBREF10 showed that widely used complex architectures suffer from overparameterization, and can be significantly reduced in size without a loss in performance. BIBREF5 observed that the smaller version of BERT achieves better scores on a number of syntax-testing experiments than the larger one. BIBREF11 questioned the necessity of computation-heavy neural networks, proving that a simple yet carefully tuned BiLSTM without attention achieves the best or at least competitive results compared to more complex architectures on the document classification task. BIBREF12 presented more evidence of unnecessary complexity of the self-attention mechanism, and proposed a more lightweight and scalable dynamic convolution-based architecture that outperforms the self-attention baseline. These studies suggest a potential direction for future research, and are in good accordance with our observations.\n\nMethodology\nWe pose the following research questions:\nWhat are the common attention patterns, how do they change during fine-tuning, and how does that impact the performance on a given task? (Sec. SECREF17, SECREF30)\nWhat linguistic knowledge is encoded in self-attention weights of the fine-tuned models and what portion of it comes from the pre-trained BERT? (Sec. SECREF25, SECREF34, SECREF36)\nHow different are the self-attention patterns of different heads, and how important are they for a given task? (Sec. SECREF39)\nThe answers to these questions come from a series of experiments with the basic pre-trained or the fine-tuned BERT models, as will be discussed below. All the experiments with the pre-trained BERT were conducted using the model provided with the PyTorch implementation of BERT (bert-base-uncased, 12-layer, 768-hidden, 12-heads, 110M parameters). We chose this smaller version of BERT because it shows competitive, if not better, performance while having fewer layers and heads, which makes it more interpretable.\nWe use the following subset of GLUE tasks BIBREF4 for fine-tuning:\nMRPC: the Microsoft Research Paraphrase Corpus BIBREF13\nSTS-B: the Semantic Textual Similarity Benchmark BIBREF14\nSST-2: the Stanford Sentiment Treebank, two-way classification BIBREF15\nQQP: the Quora Question Pairs dataset\nRTE: the Recognizing Textual Entailment datasets\nQNLI: Question-answering NLI based on the Stanford Question Answering Dataset BIBREF3\nMNLI: the Multi-Genre Natural Language Inference Corpus, matched section BIBREF16\nPlease refer to the original GLUE paper for details on the QQP and RTE datasets BIBREF4. We excluded two tasks: CoLa and the Winograd Schema Challenge. The latter is excluded due to the small size of the dataset. As for CoLa (the task of predicting linguistic acceptability judgments), GLUE authors report that the human performance is only 66.4, which is explained by the problems with the underlying methodology BIBREF17. Note also that CoLa is not included in the upcoming version of GLUE BIBREF18. All fine-tuning experiments follow the parameters reported in the original study (a batch size of 32 and 3 epochs, see devlin2018bert).\nIn all these experiments, for a given input, we extract self-attention weights for each head in every layer. This results in a 2D float array of shape $L\\times L$, where $L$ is the length of an input sequence. We will refer to such arrays as self-attention maps. Analysis of individual self-attention maps allows us to determine which target tokens are attended to the most as the input is processed token by token. We use these experiments to analyze how BERT processes different kinds of linguistic information, including the processing of different parts of speech (nouns, pronouns, and verbs), syntactic roles (objects, subjects), semantic relations, and negation tokens.\n\nExperiments\nIn this section, we present the experiments conducted to address the above research questions.\n\nExperiments ::: BERT's self-attention patterns\nManual inspection of self-attention maps for both basic pre-trained and fine-tuned BERT models suggested that there is a limited set of self-attention maps types that are repeatedly encoded across different heads. Consistently with previous observations, we identified five frequently occurring patterns, examples of which are shown in fig:atttypes:\nVertical: mainly corresponds to attention to special BERT tokens [CLS] and [SEP];\nDiagonal: formed by the attention to the previous/following tokens;\nVertical+Diagonal: a mix of the previous two types,\nBlock: intra-sentence attention for the tasks with two distinct sentences (such as, for example, RTE or MRPC),\nHeterogeneous: highly variable depending on the specific input and cannot be characterized by a distinct structure.\nWhereas the attention to the special tokens is important for cross-sentence reasoning, and the attention to the previous/following token comes from language model pre-training, we hypothesize that the last of the listed types is more likely to capture interpretable linguistic features, necessary for language understanding.\nTo get a rough estimate of the percentage of attention heads that may capture linguistically interpretable information, we manually annotated around 400 sample self-attention maps as belonging to one of the five classes. The self-attention maps were obtained by feeding random input examples from selected tasks into the corresponding fine-tuned BERT model. This produced a somewhat unbalanced dataset, in which the “Vertical” class accounted for 30% of all samples. We then trained a convolutional neural network with 8 convolutional layers and ReLU activation functions to classify input maps into one of these classes. This model achieved the F1 score of 0.86 on the annotated dataset. We used this classifier to estimate the proportion of different self-attention patterns for the target GLUE tasks using up to 1000 examples (where available) from each validation set.\n\nExperiments ::: Relation-specific heads in BERT ::: Results\nThe heatmap of averaged attention scores over all collected examples (fig:framenetresults) suggests that 2 out of 144 heads tend to attend to the parts of the sentence that FrameNet annotators identified as core elements of the same frame. fig:framenetresults shows an example of this attention pattern for these two heads. Both show high attention weight for “he” while processing “agitated” in the sentence “He was becoming agitated\" (the frame “Emotion_directed”).\n\nExperiments ::: Attention to linguistic features\nIn this experiment, we investigate whether fine-tuning BERT for a given task creates self-attention patterns which emphasize specific linguistic features. In this case, certain kinds of tokens may get high attention weights from all the other tokens in the sentence, producing vertical stripes on the corresponding attention maps (fig:atttypes).\nWe tested this hypothesis by checking whether there are vertical stripe patterns corresponding to certain linguistically interpretable features, and to what extent such features are relevant for solving a given task. In particular, we investigated attention to nouns, verbs, pronouns, subjects, objects, and negation words, and special BERT tokens across the tasks.\nFor every head, we compute the sum of self-attention weights assigned to the token of interest from each input token. Since the weights depend on the number of tokens in the input sequence, this sum is normalized by sequence length. This allows us to aggregate the weights for this feature across different examples. If there are multiple tokens of the same type (e.g. several nouns or negations), we take the maximum value. We disregard input sentences that do not contain a given feature.\nFor each investigated feature, we calculate this aggregated attention score for each head in every layer and build a map in order to detect the heads potentially responsible for this feature. We then compare the obtained maps to the ones derived using the pre-trained BERT model. This comparison enables us to determine if a particular feature is important for a specific task and whether it contributes to some tasks more than to others.\n\nExperiments ::: Attention to linguistic features ::: Results\nContrary to our initial hypothesis that the vertical attention pattern may be motivated by linguistically meaningful features, we found that it is associated predominantly, if not exclusively, with attention to [CLS] and [SEP] tokens (see Figure FIGREF32. Note that the absolute [SEP] weights for the SST-2 sentiment analysis task are greater than for other tasks, which is explained by the fact that there is only one sentence in the model inputs, i.e. only one [SEP] token instead of two. There is also a clear tendency for earlier layers to pay attention to [CLS] and for later layers to [SEP], and this trend is consistent across all the tasks. We did detect heads that paid increased (compared to the pre-trained BERT) attention to nouns and direct objects of the main predicates (on the MRPC, RTE and QQP tasks), and negation tokens (on the QNLI task), but the attention weights of such tokens were negligible compared to [CLS] and [SEP]. Therefore, we believe that the striped attention maps generally come from BERT pre-training tasks rather than from task-specific linguistic reasoning.\n\nExperiments ::: Disabling self-attention heads ::: Results\nOur experiments suggest that certain heads have a detrimental effect on the overall performance of BERT, and this trend holds for all the chosen tasks. Unexpectedly, disabling some heads leads not to a drop in accuracy, as one would expect, but to an increase in performance. This is effect is different across tasks and datasets. While disabling some heads improves the results, disabling the others hurts the results. However, it is important to note that across all tasks and datasets, disabling some heads leads to an increase in performance. The gain from disabling a single head is different for different tasks, ranging from the minimum absolute gain of 0.1% for STS-B, to the maximum of 1.2% for MRPC (see fig:disableheadsall). In fact, for some tasks, such as MRPC and RTE, disabling a random head gives, on average, an increase in performance. Furthermore, disabling a whole layer, that is, all 12 heads in a given layer, also improves the results. fig:disablelayers shows the resulting model performance on the target GLUE tasks when different layers are disabled. Notably, disabling the first layer in the RTE task gives a significant boost, resulting in an absolute performance gain of 3.2%. However, effects of this operation vary across tasks, and for QNLI and MNLI, it produces a performance drop of up to -0.2%.\n\nFigure 1: Typical self-attention classes used for training a neural network. Both axes on every image represent BERT tokens of an input example, and colors denote absolute attention weights (darker colors stand for greater weights). The first three types are most likely associated with language model pre-training, while the last two potentially encode semantic and syntactic information.\n\nTable 1: GLUE task performance of BERT models with different initialization. We report the scores on the validation, rather than test data, so these results differ from the original BERT paper.\n\nFigure 4: FrameNet annotation example for the “address” lexical unit with two core frame elements of different types annotated.\n\nFigure 5: Per-head cosine similarity between pre-trained BERT’s and fine-tuned BERT’s self-attention maps for each of the selected GLUE tasks, averaged over validation dataset examples. Darker colors correspond to greater differences.\n\nFigure 6: Per-task attention weights to the [SEP] (top row) and the [CLS] (bottom row) tokens averaged over input sequences’ lengths and over dataset examples. Darker colors correspond to greater absolute weights.\n\nQuestion: What handcrafter features-of-interest are used?", "role": "user" }, { "content": "{\"answer\": [\"nouns\", \"verbs\", \"pronouns\", \"subjects\", \"objects\", \"negation words\", \"special BERT tokens\"], \"evidence\": [\"We tested this hypothesis by checking whether there are vertical stripe patterns corresponding to certain linguistically interpretable features, and to what extent such features are relevant for solving a given task. In particular, we investigated attention to nouns, verbs, pronouns, subjects, objects, and negation words, and special BERT tokens across the tasks.\"]}", "role": "assistant" } ]

[ { "content": "You will be shown biomedical passages and your task is to answer the provided question. Provide a concise and accurate response and do not include any additional text in the response other than the answer.\n\nQuestion: Which virus is Cidofovir (Vistide) indicated for?\n\nContext: Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir.\nAt present, the antiviral drugs ganciclovir, foscarnet and cidofovir are commonly used in the treatment of CMV infection and disease.\nCidofovir can be considered as second-line therapy in patients with CMV disease failing previous antiviral therapy.\ndditional drugs like lobucavir and cidofovir have been used for specific indications.", "role": "user" }, { "content": "cytomegalovirus", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Participant\", \"Outcome\", \"Intervention\"].\n\nPlease return the output as a JSON object of the format: {\"Participant\": [\"patients with COPD\", ...], \"Intervention\": [\"Atenolol\", ...], \"Outcome\": [\"blood pressure\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\n[ Evaluation of Stepping Stones Triple P : Interims analysis of the Stepping-Stones-SPC-Multicentric Study ] . Stepping Stones Triple P is a behavioural parenting training for families with a handicapped child , which has already been successfully evaluated in its country of origin , Australia . Within a multicentric study of several Social Pediatric Centers ( SPCs ) and further clinics/institutions in Germany , it has been established as a group parenting training ( 3-7 families per training ) . Statistical analysis proved significant effects concerning dysfunctional parenting , parental stress and child behaviour problems as well as little side effects and a positive acceptance of stepping stones by the families .", "role": "user" }, { "content": "{\"Intervention\": [\"group parenting training\", \"Stepping Stones Triple P\"], \"Outcome\": [\"positive acceptance\", \"little side effects\", \"effects\", \"dysfunctional parenting , parental stress and child behaviour problems\"], \"Participant\": [\"child\"]}", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Gene\"].\n\nPlease return the output as a JSON object of the format: {\"Gene\": [\"SSX\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nMutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.", "role": "user" }, { "content": "{\"Gene\": [\"CHRNB1\", \"RAPSN\", \"rapsyn\", \"CHRNG\", \"acetylcholine receptor-related genes\", \"CHRNA1\", \"CHRND\", \"embryonal acetylcholine receptor g subunit\"]}", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nRole of flies and provision of latrines in trachoma control: cluster-randomised controlled trial.\nAbstract 1:\nEye-seeking flies have received much attention as possible trachoma vectors, but this remains unproved. We aimed to assess the role of eye-seeking flies as vectors of trachoma and to test provision of simple pit latrines, without additional health education, as a sustainable method of fly control.\n In a community-based, cluster-randomised controlled trial, we recruited seven sets of three village clusters and randomly assigned them to either an intervention group that received regular insecticide spraying or provision of pit latrines (without additional health education) to each household, or to a control group with no intervention. Our primary outcomes were fly-eye contact and prevalence of active trachoma. Frequency of child fly-eye contact was monitored fortnightly. Whole communities were screened for clinical signs of trachoma at baseline and after 6 months. Analysis was per protocol.\n Of 7080 people recruited, 6087 (86%) were screened at follow-up. Baseline community prevalence of active trachoma was 6%. The number of Musca sorbens flies caught from children's eyes was reduced by 88% (95% CI 64-100; p<0.0001) by insecticide spraying and by 30% (7-52; p=0.04) by latrine provision by comparison with controls. Analysis of age-standardised trachoma prevalence rates at the cluster level (n=14) showed that spraying was associated with a mean reduction in trachoma prevalence of 56% (19-93; p=0.01) and 30% with latrines (-81 to 22; p=0.210) by comparison with the mean rate change in the controls.\n Fly control with insecticide is effective at reducing the number of flies caught from children's eyes and is associated with substantially lower trachoma prevalence compared with controls. Such a finding is consistent with flies being important vectors of trachoma. Since latrine provision without health education was associated with a significant reduction in fly-eye contact by M sorbens, studies of their effect when combined with other trachoma control measures are warranted.\n\n\nTitle 2:\nHealth education and antibiotic therapy in trachoma control.\nAbstract 2:\nThe objective of this study was to confirm whether the combination of a health education programme with a mass treatment campaign was able to improve the effectiveness of trachoma control. An open controlled clinical trial with a 2 x 2 factorial design was carried out. Four villages, matched for size and epidemiological, economic and social conditions, were included in the study. The first village received mass treatment with 1% oxytetracycline eye drops combined with a specific health education programme. The second village received only a health education programme. The third village received only mass treatment and the fourth village did not receive any intervention during the study (control village). 1810 subjects were enrolled of whom 76% were successfully followed for 6 months. The incidence of new cases ranged between 1.6% and 14.2%. In this study the combination of a health education programme with mass treatment failed to increase the cure rate. There was even a negative interaction (P = 0.03). The best results were obtained in the village where antibiotic treatment was used alone, both in terms of cure rate (82%) and reduction of C trachomatis transmission. These results suggest that the addition of a health education programme does not systematically improve the performances of a mass treatment campaign. The efficacy of this combination depends essentially on the capacity of the community to modify its hygiene behaviour.\n\n\nTitle 3:\nEfficacy of latrine promotion on emergence of infection with ocular Chlamydia trachomatis after mass antibiotic treatment: a cluster-randomized trial.\nAbstract 3:\nThe World Health Organization (WHO) recommends environmental improvements such as latrine construction in the integrated trachoma control strategy, SAFE. We report a cluster-randomized trial assessing the effect of intensive latrine promotion on emergence of infection with ocular Chlamydia trachomatis after mass treatment with antibiotics.Twenty-four communities in Goncha Seso Enesie woreda, Amhara Regional State, Ethiopia, were enumerated, and a random selection of 60 children aged 0- 9 years in each was monitored for clinical signs of trachoma and ocular chlamydial infection at baseline, 12 and 24 months. All community members were offered treatment with a single dose of oral azithromycin or topical tetracycline. After treatment, 12 subkebeles were randomized to receive intensive latrine promotion. Mean cluster ocular infection in the latrine and the non-latrine arms were reduced from 45.5% (95% CI 34.1-56.8%) and 43.0% (95% CI 31.1-54.8%) respectively at baseline to 14.6% (95% CI 7.4-21.8%) and 14.8% (95% CI 8.9-20.8%) respectively at 24 months (P=0.93). Clinical signs fell from 72.0% (95% CI 58.2-85.5%) and 61.3% (95% CI 44.0-78.5%) at baseline to 45.8% (36.0-55.6%) and 48.5% (34.0-62.9%) respectively at 24 months (P=0.69). At 24 months, estimated household latrine coverage and use were 80.8% and 61.7% respectively where there had been intensive latrine promotion and 30.0% and 25.0% respectively in the single treatment only arm. We were unable to detect a difference in the prevalence of ocular chlamydial infection in children due to latrine construction.\n\n\nTitle 4:\nEffect of fly control on trachoma and diarrhoea.\nAbstract 4:\nDomestic flies are accepted vectors of diarrhoea, but their role in trachoma transmission has never been quantified and no study has shown that fly control decreases the prevalence of trachoma. We assessed the effect of fly control on public health in a pilot study in Gambian villages.\n We studied two pairs of villages--one pair in the 1997 wet season, and one pair in the 1998 dry season. For each pair, deltamethrin was sprayed for 3 months to control flies in one village whilst the other was used as a control. Fly populations were monitored with traps. We surveyed trachoma at baseline and at 3 months, and collected daily data on diarrhoea in children aged between 3 months and 5 years.\n Fly control decreased numbers of muscid flies by around 75% in the intervention villages compared with controls. Trachoma prevalence was similar at baseline (wet season, prevalence in intervention village 8.8% vs control 12.2%; dry season, 18.0% vs 16.0%), but after 3 months of fly control there were 75% fewer new cases of trachoma in the intervention villages (wet season 3.7% vs 13.7%; dry season 10.0% vs 18.9%; rate ratio and relative risk of pooled data 0.25 [adjusted 95% CI 0.09-0.64], p=0.003). There was 22% less childhood diarrhoea in the wet season (14% vs 19%, period prevalence ratio 0.78 [0.64-0.95], p=0.01), and 26% less diarrhoea in the dry season (6% vs 8%; 0.74 [0.34-1.59], p=0.60) compared with controls.\n Muscid flies are important vectors of trachoma and childhood diarrhoea in The Gambia. Deltamethrin spray is effective for fly control and may be useful for reducing trachoma and diarrhoea in some situations, but further research on sustainable fly-control methods is needed.\n\n\nTitle 5:\nIntensive insecticide spraying for fly control after mass antibiotic treatment for trachoma in a hyperendemic setting: a randomised trial.\nAbstract 5:\nThere are no data on the cumulative effect of fly control and antibiotic distribution on trachoma in hyperendemic communities. We sought to determine whether insecticide spray intervention after mass antibiotic treatment could reduce trachoma and ocular infection with Chlamydia trachomatis in hyperendemic neighbourhoods in Tanzania.\n We did a single-blind, randomised clinical trial in 16 neighbourhoods (balozi) in Kongwa, Tanzania. All children aged 1-7 years were enrolled, with 119 children in the eight balozi of the intervention group and 183 in the eight control balozi. Children were examined at baseline, 6 months, and 1 year for clinical trachoma and ocular C trachomatis infection. One dose of azithromycin was offered to all residents of both intervention and control balozi after the baseline survey. Households (and surrounding areas) in the intervention group were then sprayed with insecticide throughout the ensuing year and monitored for reductions in fly counts. This study is registered at ClinicalTrials.gov, number NCT00347763.\n The intervention balozi had significantly lower fly counts than controls at all monitored weeks (p<0.05), apart from weeks 7-9. The trachoma rate did not differ significantly in the intervention and control balozi at 6 months post-treatment (20%vs 33%, p=0.07), nor did it at 1 year (43%vs 44%, p=0.90). Infection with C trachomatis did not differ between groups at 6 months post-treatment (9%vs 7%, p=0.45).\n Intensive insecticide spraying reduced flies in the environment, but our results suggest that fly reduction after mass antibiotic treatment has no added benefit on reduction of trachoma.", "role": "user" }, { "content": "There is some evidence from two trials that insecticides are effective in reducing trachoma, however, this effect was not demonstrated in another trial that used insecticides. Two trials on latrine provision as a fly control measure have not demonstrated significant trachoma reduction. Health education had shown significant reduction of trachoma in one study but another study did not demonstrate similar findings. Generally there is a dearth of data to determine the effectiveness of all aspects of environmental sanitation in the control of trachoma.", "role": "assistant" } ]

[ { "content": "You are provided with the abstract of a scientific paper and the abstracts of the papers it references. Your task is to write a Related Work section for the main paper. This section should concisely summarize and integrate the key points from the cited abstracts, reflecting how they relate to the main paper's contributions and context. In your summary, use numerical citation markers like [1], [2], etc., to refer to the corresponding papers.\n\nMain Abstract:\nThe DEPAS (Decentralized Probabilistic Auto-Scaling) algorithm assumes an overlay network of computing nodes where each node probabilistically decides to shut down, allocate one or more other nodes or do nothing. DEPAS was formulated, tested, and theoretically analyzed for the simplified case of homogenous systems. In this paper, we extend DEPAS to heterogeneous systems.\n\nCited Abstract(s):\n[1]: We address the problem of resource management for a large-scale cloud environment that hosts sites. Our contribution centers around outlining a distributed middleware architecture and presenting one of its key elements, a gossip protocol that meets our design goals: fairness of resource allocation with respect to hosted sites, efficient adaptation to load changes and scalability in terms of both the number of machines and sites. We formalize the resource allocation problem as that of dynamically maximizing the cloud utility under CPU and memory constraints. While we can show that an optimal solution without considering memory constraints is straightforward (but not useful), we provide an efficient heuristic solution for the complete problem instead. We evaluate the protocol through simulation and find its performance to be well-aligned with our design goals.", "role": "user" }, { "content": "Another decentralized auto-scaling approach was proposed by [1] . They aim to develop a Platform as a Service for hosting sites in the cloud. In their approach, each virtual machine is managed by a VM manager which is connected through a custom overlay network to other VM managers that store instances of the same sites. The utility of a site instance is computed as the ratio between the allocated CPU capacity and the CPU demand. The utility of the system is the minimum utility of all instances of all sites. A decentralized heuristic algorithm is used to maximize the utility of the system while minimizing the cost of adaptation. The resulting system is scalable with respect to the number of virtual machines and the number of sites, but it is not scalable with respect to the number of instances of a site.", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Gene\"].\n\nPlease return the output as a JSON object of the format: {\"Gene\": [\"SSX\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nTumor associated antigen recognition by autologous serum in patients with breast cancer. Breast cancer accounts for 30-40% of all deaths from cancers in females. In an effort to identify tumor associated antigens that may be useful for immunotherapy, we utilized serological analysis of recombinant cDNA expression libraries (SEREX) technique to identify breast cancer-associated antigens. SEREX screening of cDNA expression libraries derived from 3 breast cancer patients identified a total of 88 positive clones (bcg-1 to bcg-88), including 27 hitherto unknown sequences. The cDNA sequences and mRNA expression patterns were characterized. Seroreactivity of the SEREX clones were determined in sera from 75 breast cancer patients, 75 colon cancer patients, and 25 healthy donors. Expression analysis on a cDNA panel from 17 different normal tissues by reverse transcription-PCR (RT-PCR) revealed tissue restricted mRNA expression of 2 of the 27 unknown antigens. Bcg-72 is expressed only in breast, prostate and thymus, while bcg-84 is expressed at moderate levels in testis, spleen and breast. The other 25 unknown antigens were expressed in most other tissues. Serologic assay revealed that 7 out of the 88 clones showed reactivity to at least one serum from either 75 breast or 75 colon cancer patients. These clones did not react with sera from a panel of 25 healthy adult individuals. Our results demonstrate the utility of the SEREX approach for the identification of potential tumor associated antigens in human breast cancer.", "role": "user" }, { "content": "{\"Gene\": [\"bcg-1\"]}", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a research paper and a corresponding research question. Determine the answer to the research question based on the context provided. Your answer should be one of: \"YES\", \"NO\", or \"MAYBE\".\n\nAbstract:\n(BACKGROUND) To evaluate the role of clinical assessment with selective use of imaging studies in the management of suspected acute appendicitis in children.\n(PATIENTS AND METHODS) Medical records of children referred to Emergency Room in 2010 for suspected appendicitis were retrospectively reviewed. Diagnostic investigations divided by age and sex were related to pathological findings. Negative appendectomy and complication rates were calculated.\n(RESULTS) 923 children needed surgical assessment : In 75.7% of them surgical indication was excluded and 24.3% were admitted to surgical ward for observation. Appendectomy was eventually performed in 137 patients (61.9%), 82.4% of them without any preoperative imaging while 17.6% underwent selective studies, mainly abdominal ultrasonography (14.6%). Imaging was requested twice as frequently in not operated admitted children (39.3%) than in the operated ones (17.5%, P<0.001). Overall complicated appendicitis rate (peritonitis and abscess) resulted 26.4% and negative appendectomy rate 8.8%. Females older than 10 years presented histologically not-confirmed appendicitis in 22.2% of cases, while the younger ones presented more frequently complicated appendicitis (29.3%).\n\nQuestion:\nDo we need imaging to diagnose appendicitis in children?\n\nAnswer:", "role": "user" }, { "content": "MAYBE", "role": "assistant" } ]

[ { "content": "Given a short query with keyphrases about a research idea in 2017 in the domain of artificial intelligence, recommend the relevant datasets to validate the research idea from the options provided. A short description of the datasets is also provided to help you.\n\nQuery: We propose a novel adversarial learning approach to unsupervised domain adaptation in NLP. It consists of a discriminator,\n\nKeyphrases: unsupervised domain adaptation text\n\nDataset description:\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.\nGTA5: The GTA5 dataset contains 24966 synthetic images with pixel level semantic annotation. The images have been rendered using the open-world video game Grand Theft Auto 5 and are all from the car perspective in the streets of American-style virtual cities.\nVisDA-2017: VisDA-2017 is a simulation-to-real dataset for domain adaptation with over 280,000 images across 12 categories in the training, validation and testing domains. The training images are generated from the same object under different circumstances, while the validation images are collected from MSCOCO..\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\nOptions: A: TableBank B: GTA5 C: VisDA-2017 D: CelebA", "role": "user" }, { "content": "CelebA", "role": "assistant" } ]

[ { "content": "You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should only include the abstract and no additional text.\n\nPaper text:\nalternative medicine refer to a broad set of health care practices that are not part of that country s own tradition or conventional medicine and are not fully integrated into the dominant health - care system . according to who they are used interchangeably with traditional medicine in some countries .\nhomeopathic medicine , herbal medicine and acupuncture are the most common , albeit not the unique , cam forms in european countries .\nhomeopathy is a method of medical practice that aims to improve the level of health of an organism through the administration of medicinal products selected individually according to the principle of similarity ( see text ) . since homeopathy is strictly individualized and takes into account the physical , emotional , mental , constitutional , biographical and environmental state , it is a medicine of the whole person .\nthe term homeopathy comes from the greek ( omoios = similar , pathos = suffering ) .\nintegrative medicine is not simply the combination of conventional medicine with complementary and alternative medicine .\nthe consortium of academic health centers for integrative medicine defines it as the practice of medicine that reaffirms the importance of the relationship between practitioner and patient , focuses on the whole person , is informed by evidence , and makes use of all appropriate therapeutic approaches , healthcare professionals and disciplines to achieve optimal health and healing .\nalternative medicine refer to a broad set of health care practices that are not part of that country s own tradition or conventional medicine and are not fully integrated into the dominant health - care system . according to who they are used interchangeably with traditional medicine in some countries .\nhomeopathic medicine , herbal medicine and acupuncture are the most common , albeit not the unique , cam forms in european countries .\nhomeopathy is a method of medical practice that aims to improve the level of health of an organism through the administration of medicinal products selected individually according to the principle of similarity ( see text ) . since homeopathy is strictly individualized and takes into account the physical , emotional , mental , constitutional , biographical and environmental state , it is a medicine of the whole person .\nthe term homeopathy comes from the greek ( omoios = similar , pathos = suffering ) .\nintegrative medicine is not simply the combination of conventional medicine with complementary and alternative medicine .\nthe consortium of academic health centers for integrative medicine defines it as the practice of medicine that reaffirms the importance of the relationship between practitioner and patient , focuses on the whole person , is informed by evidence , and makes use of all appropriate therapeutic approaches , healthcare professionals and disciplines to achieve optimal health and healing .", "role": "user" }, { "content": "some physicians have incorporated some forms of complementary and alternative medicine ( cam ) or related medicinal products in their clinical practices , suggesting that an unconventional treatment approach might be seen as an integration rather than as an alternative to standard medical practice . among the various cams , \n homeopathy enjoys growing popularity with the lay population , but it is not acknowledged by academia or included in medical guidelines . the major problem is to establish the effectiveness of this clinical approach using the strict criteria of evidence - based medicine . \n this issue of the journal of medicine and the person collects contributions from some of the most prestigious centers and research groups working in the field of homeopathy and integrative medicine . \n these contributions are not specialized information but are of general interest , focusing on this discipline as one of the emerging fields of personalized medical treatment .", "role": "assistant" } ]

[ { "content": "You will be shown biomedical passages and your task is to answer the provided question. Provide a concise and accurate response and do not include any additional text in the response other than the answer.\n\nQuestion: Gene silencing can be achieved by RNA interference (RNAi) in eukaryotic organisms. What is the name of the analogous process in prokaryotic organisms?\n\nContext: he CRISPR-Cas (clustered regularly interspaced short palindromic repeats, CRISPR-associated genes) is an adaptive immunity system in bacteria and archaea that functions via a distinct self-non-self recognition mechanism that is partially analogous to the mechanism of eukaryotic RNA interference (RNAi).\nRNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex.\nCompelling evidence indicates that the CRISPR-Cas system protects prokaryotes from viruses and other potential genome invaders.\nRNA in defense: CRISPRs protect prokaryotes against mobile genetic elements.\nn this article, we discuss our current understanding of this fascinating adaptive and heritable defense system, and describe functional similarities and differences with RNAi in eukaryotes.\nBacteria have developed several defense mechanisms against bacteriophages over evolutionary time, but the concept of prokaryotic RNA interference mediated defense mechanism against phages and other invading genetic elements has emerged only recently. Clustered regularly interspaced short palindromic repeats (CRISPR) together with closely associated genes (cas genes) constitute the CASS system that is believed to provide a RNAi-like defense mechanism against bacteriophages within the host bacterium.\nIn many prokaryotes, noncoding RNAs that arise from the clustered regularly interspaced short palindromic repeat (CRISPR) loci are now thought to mediate defense against viruses and other molecular invaders by an RNAi-like pathway.", "role": "user" }, { "content": "CRISPR-Cas", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Chemical\"].\n\nPlease return the output as a JSON object of the format: {\"Chemical\": [\"Arsenic\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nHigh-Resolution Direct-Absorption Spectroscopy of Hydroxymethyl Radical in the CH Symmetric Stretching Region. High-resolution, fully rotationally resolved direct absorption spectra of hydroxymethyl radical, CH2OH, are presented in the infrared CH stretching region. As a result of low rotational temperatures and sub-Doppler linewidths obtained in the slit supersonic expansion, the Ka = 0 ← 0 band of the symmetric CH stretch for CH2OH has been unambiguously identified and analyzed. By way of chemical confirmation, hydroxymethyl radical is generated via two different slit jet discharge syntheses: (i) direct dissociation of CH3OH to form CH2OH and (ii) dissociation of Cl2 followed by the radical H atom extraction reaction Cl + CH3OH → HCl + CH2OH. The identified transitions are fit to a Watson A-reduced symmetric top Hamiltonian to yield first precision experimental values for the ground state rotational constants as well as improved values for the symmetric stretch rotational constants and vibrational band origin. The results both complement and substantially improve upon spectral efforts via previous double resonance ionization detected infrared methods by Feng et al. [J. Phys. Chem. A, 2004, 108, 7093], as well as offer high-resolution predictions for laboratory and astronomical detection of hydroxymethyl radical in the millimeter-wave region.", "role": "user" }, { "content": "{\"Chemical\": [\"Cl2\", \"hydroxymethyl\", \"CH\", \"H\", \"HCl\", \"CH3OH\", \"Cl\", \"Hydroxymethyl\", \"CH2OH\"]}", "role": "assistant" } ]

[ { "content": "Below are the Abstract, Introduction, and Conclusion sections of a computer science research paper. Please summarize the main contribution of the work in a single sentence. Your response should include the summary sentence and no additional text.\n\nPaper text:\n\nIn learning to rank, one is interested in optimising the global ordering of a list of items according to their utility for users.\nPopular approaches learn a scoring function that scores items individually (i.e. without the context of other items in the list) by optimising a pointwise, pairwise or listwise loss.\nThe list is then sorted in the descending order of the scores.\nPossible interactions between items present in the same list are taken into account in the training phase at the loss level.\nHowever, during inference, items are scored individually, and possible interactions between them are not considered.\nIn this paper, we propose a context-aware neural network model that learns item scores by applying a self-attention mechanism.\nThe relevance of a given item is thus determined in the context of all other items present in the list, both in training and in inference.\nFinally, we empirically demonstrate significant performance gains of self-attention based neural architecture over Multi-Layer Perceptron baselines.\nThis effect is consistent across popular pointwise, pairwise and listwise losses on datasets with both implicit and explicit relevance feedback.\nLearning to rank (LTR) is an important area of machine learning research, lying at the core of many information retrieval (IR) systems.\nIt arises in numerous industrial applications like search engines, recommender systems, question-answering systems, and others.\nA typical machine learning solution to the LTR problem involves learning a scoring function, which assigns real-valued scores to each item of a given list, based on a dataset of item features and human-curated or implicit (e.g. clickthrough logs) relevance labels.\nItems are then sorted in the descending order of scores [19] .\nPerformance of the trained scoring function is usually evaluated using an Permission to make digital or hard copies of part or all of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page.\nCopyrights for third-party components of this work must be honored.\nFor all other uses, contact the owner/author(s).\nThe Web Conference, April, 2020, Taipei, Taiwan © 2019 Copyright held by the owner/author(s).\nACM ISBN 978-x-xxxx-xxxx-x/YY/MM.\nhttps://doi.org/10.1145/nnnnnnn.nnnnnnn IR metric like Mean Reciprocal Rank (MRR) [29] , Normalised Discounted Cumulative Gain (NDCG) [16] or Mean Average Precision (MAP) [4] .\nIn contrast to other classic machine learning problems like classification or regression, the main goal of a ranking algorithm is to determine relative preference among a group of items.\nScoring items individually is a proxy of the actual learning to rank task.\nUsers' preference for a given item on a list depends on other items present in the same list: an otherwise preferable item might become less relevant in the presence of other, more relevant items.\nCommon learning to rank algorithms attempt to model such inter-item dependencies at the loss level.\nThat is, items in a list are still scored individually, but the effect of their interactions on evaluation metrics is accounted for in the loss function, which usually takes a form of a pairwise (RankNet [6] , LambdaLoss [30] ) or a listwise (ListNet [9] , ListMLE [31] ) objective.\nFor example, in LambdaMART [8] the gradient of the pairwise loss is rescaled by the change in NDCG of the list which would occur if a pair of items was swapped.\nPointwise objectives, on the other hand, do not take such dependencies into account.\nIn this work, we propose a learnable, context-aware, self-attention [27] based scoring function, which allows for modelling of interitem dependencies not only at the loss level but also in the computation of items' scores.\nSelf-attention is a mechanism first introduced in the context of natural language processing.\nUnlike RNNs [14] , it does not process the input items sequentially but allows the model to attend to different parts of the input regardless of their distance from the currently processed item.\nWe adapt the Transformer [27] , a popular self-attention based neural machine translation architecture, to the ranking task.\nWe demonstrate that the obtained ranking model significantly improves performance over Multi-Layer Perceptron (MLP) baselines across a range of pointwise, pairwise and listwise ranking losses.\nEvaluation is conducted on MSLR-WEB30K [24] , the benchmark LTR dataset with multi-level relevance judgements, as well as on clickthrough data coming from Allegro.pl, a large-scale e-commerce search engine.\nWe provide an open-source Pytorch [22] implementation of our self-attentive context-aware ranker available at url_removed.\nThe rest of the paper is organised as follows.\nIn Section 2 we review related work.\nIn Section 3 we formulate the problem solved in this work.\nIn Section 4 we describe our self-attentive ranking model.\nExperimental results and their discussion are presented in Section 5.\nIn Section 6 we conduct an ablation study of various hyperparameters of our model.\nFinally, a summary of our work is given in Section 7.\nIn this work, we addressed the problem of constructing a contextaware scoring function for learning to rank.\nWe adapted the selfattention based Transformer architecture from the neural machine translation literature to propose a new type of scoring function for LTR.\nWe demonstrated considerable performance gains of proposed neural architecture over MLP baselines across different losses and types of data, both in ranking and re-ranking setting.\nThese experiments provide strong evidence that the gains are due to the ability of the model to score items simultaneously.\nAs a result of our empirical study, we observed the strong performance of models trained to optimise ordinal loss function.\nSuch models outperformed models trained with well-studied losses like LambdaLoss or LambdaMART, which were previously shown to provide tight bounds on IR metrics like NDCG.\nOn the other hand, we observed the surprisingly poor performance of models trained to optimise RankNet and ListMLE losses.\nIn future work, we plan to investigate the reasons for both good and poor performance of the aforementioned losses, in particular, the relation between ordinal loss and NDCG.", "role": "user" }, { "content": "Learning to rank using the Transformer architecture.", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Participant\", \"Outcome\", \"Intervention\"].\n\nPlease return the output as a JSON object of the format: {\"Participant\": [\"patients with COPD\", ...], \"Intervention\": [\"Atenolol\", ...], \"Outcome\": [\"blood pressure\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nChronic fatigue syndrome versus neuroendocrineimmune dysfunction syndrome : differential attributions . Since 1988 , when the term chronic fatigue syndrome ( CFS ) was coined , considerable discussion has occurred about stigma associated with this diagnostic term . In particular , patients with CFS have felt that this term trivializes the serious nature of this disorder . A Name Change Work group , appointed by the CFS Coordinating Committee , developed an umbrella term : chronic neuroendocrineimmune dysfunction syndrome ( CNDS ) , and proposed that there would be sub-types under this term , one being CFS . The present study examined attributions of this new umbrella term when compared with CFS . Nurses and physician assistants ( PAs ) were presented a case study of a patient with symptoms of CFS . They were told that the patient had either \" chronic fatigue syndrome , \" \" chronic neuroendocrineimmune dysfunction syndrome , \" or \" chronic neuroendocrineimmune dysfunction syndrome , which had formerly been called chronic fatigue syndrome . \" The different terms led to different attributions , with PA respondents rating the \" CNDS \" label as more severe . Results suggest that a more medical sounding term ( CNDS ) may lead to attributions that this syndrome is a more serious , disabling illness . The policy implications of these findings are discussed .", "role": "user" }, { "content": "{\"Intervention\": [\"syndrome : differential attributions\", \"medical sounding term ( CNDS )\", \"case study of a patient with symptoms of CFS\"], \"Outcome\": [\"attributions\", \"medical sounding term\"], \"Participant\": [\"patients with CFS\"]}", "role": "assistant" } ]

[ { "content": "You will be presented with a sentence from biomedical research text. Extract all terms that correspond to chemical entities of biological interest (ChEBI).\nReturn your identified terms in a JSON array, formatted like this: [\"Entity1\", \"Entity2\", ...].\nIf no such entities are detected, respond by providing an empty JSON array [].\n\nBiomedical context:\nSryexpressionisdetectedinbothSox9flox/DeltaandSox9Delta/Deltagonadsat11.5dpc(GandH),whereasFgf9expressionismarkedlydecreasedorabsentinSox9Delta/Deltagonadsat11.5dpc(IandJ).", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "You will be presented with a citation sentence from a research paper. Classify the intent behind this citation by choosing from one of the following categories:\n\n- Method: Cites the paper for its methodology or procedure.\n- Background: Cites the paper to provide background information.\n- Result: Cites the paper for its findings or results.\n\nYour answer should be a single word from the following list of options: [\"Method\", \"Background\", \"Result\"]. Do not include any other text in your response.\n\nCitation sentence:\n\nHaruno & Kawato, 2006), it is important to note that there is ample evidence from functional magnetic imaging experiments that in humans prediction errors are indeed encoded in the dorsal striatum (e.g. Valentin & O’Doherty, 2009; Cooper et al., 2011), including regions of dorsal putamen most comparable to rat DLS (e.", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "content": "You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.\n\nTitle:\nPromoting the Outgrowth of Neurites on Electrospun Microfibers by Functionalization with Electrosprayed Microparticles of Fatty Acids\n\nPaper sections:\n\n<p>Controlling the outgrowth of neurites is of great importance for enhancing the repair of injured nerves.[1–3] The neuron utilizes the so-called growth cone, a highly motile structure at the end of the neurite, to sense the surrounding environment. The growth cone can be approximately 10–760 μm2 in area depending on the type of the neuron and the extracellular matrix.[4–8] Through interactions with the surroundings, including the topographic features on a substrate[9–12] and the diffusible guidance molecules in a medium,[13,14] neuritis can undertake different path-finding behaviors. The correlation between the neuronal behavior and the topographic cue on a substrate was initially investigated using lithographically fabricated structures[15] and electrospun aligned fibers.[16] In parallel, substrates decorated with Au[11,17] or Ag nanoparticles,[18] anodized aluminum oxide membranes,[19] silica beads,[8,20] and electrosprayed poly(lactic-co-glycolic acid) (PLGA) microparticles,[21] have all been shown to be able to drastically affect neuronal responses. The optimization of the topographical features holds the key to achieve the desired neural behaviors. In order to stimulate neurons in a controllable and systematic manner, it is necessary to fabricate substrates with reproducible and rigid topographical features. To this end, electrospray offers a simple and effective method for producing and depositing particles on a surface to construct substrates with controllable topographical features by simply varying the density of the particles.[21]</p><p>Topographical cues often act in concert with biochemical cues, working synergistically to control the neural behaviors. The outgrowth of neurites from the cell body requires the generation of an additional plasma membrane, involving the activation of phospholipases to produce soluble fatty acids.[22,23] It has been demonstrated that medium-chain saturated fatty acids (e.g., octanoic, nonanoic, decanoic, and lauric acids) can enhance never growth factor (NGF)-induced neurite outgrowth from PC12 cells by activating the mitogen-activated protein kinases.[24] In a completely different application, fatty acids have been explored as a new class of gating materials for controlled release by leveraging their well-defined, sharp melting points.[25–29] In principle, solid microparticles of fatty acids can be used as a multi-functional platform to present topographic guidance while offering a chemical cue and serving as a gating material for controlled release.</p><p>Herein, we utilized electrospray to fabricate solid microparticles from a mixture of lauric acid and stearic acid, which was formulated with a sharp melting point at 39°C to ensure structural integrity when cultured with cells.[25–27] We varied the densities of the microparticles on glass slides to construct substrates with controllable topographical cues to optimize the outgrowth of neurites from PC12 cells. We also examined the influences of the microparticles on neurite outgrowth by benchmarking against free fatty acids at different concentrations. Furthermore, we deposited the microparticles on uniaxially aligned, electrospun microfibers at an optimal density to direct the outgrowth of neurites from both PC12 multicellular spheroids and chick embryonic dorsal root ganglia (DRG) bodies.</p><p>First, we performed electrospraying to fabricate microparticles of fatty acids. Figure S1, A and B in the Supporting Information, shows scanning electron microscopy (SEM) images of the as-deposited particles, indicating that they were more or less spherical in shape, together with a rough surface. The average diameter of the particles was 4.36 ± 0.33 μm (Figure S2). Since the microparticles are deposited randomly on the glass slide, we could easily tailor the densities of the particles on the glass slides by changing the collection time to construct substrates with different degrees of surface roughness.[21]\nFigure S1, C–F, shows SEM images of the particles on glass slides collected for 1, 2, 5, and 8 min. The extension of collection time resulted in an increase in density for the microparticles and thus an increase in average surface roughness for the substrate.</p><p>We then investigated the influence of the deposited microparticles on the outgrowth of neurites from PC12 cells. The substrates did not cause any major cytotoxicity until a collection time of 8 min for the particles (Figure S3). From Figure S4A, neurites were extended in a random orientation. Both the average and the longest lengths of the neurites increased when the surface roughness of the substrate increased from low (with a collection time of 1 or 2 min for the microparticles) to moderate (with a collection time of 5 min) and subsequently decreased when the surface roughness was further increased from moderate to high (with a collection time of 8 min; Figure S4B). On the substrate with a collection time of 5 min, the average length of the neurites was the greatest (154.4 ± 32.7 μm), which was about six-times longer than that of cells cultured on the glass slide without microparticles, and the largest number of neurites were extended from cells (Figure S4C). As shown in Figure S5, the cells cultured on the substrate with moderate density of particles expressed the highest levels of three types of genes related to neurite outgrowth (growth associated protein 43, GAP43; neurofilament heavy, NEFH; and tubulin beta-3, TUBB3) among all groups. Thus, the density of the microparticles, that is, the topographic feature on the substrate, had a major impact on the outgrowth of neurites. The size polydispersity of the electrosprayed particles should not cause significant changes to the neurite outgrowth.</p><p>To understand the modulation of neural behaviors by the density of the microparticles, we investigated how the particles dispersed in a culture medium affected the neurite outgrowth. The microparticles had no cytotoxicity at concentrations of 10 and 50 μg mL−1 (Figure S6A). At a concentration of 100 μg mL−1, the cell viability was decreased. From Figures S6, B and C, as the concentration of the microparticles was increased, both the average and the longest lengths of the neurites were increased, indicating that the dispersed microparticles could still promote neurite outgrowth. Since lauric acid and stearic acid can be slightly dissolved into the medium, we hypothesized that the promotion of neurite outgrowth could be attributed to the dissolved free fatty acids. In this regard, we studied the influence of free fatty acids (a mixture made of lauric acid and stearic acid at a mass ratio of 4:1) at different concentrations on the outgrowth of neurites. As shown in Figure S7A, free fatty acids showed cytotoxicity until at concentrations of 50 and 100 μg mL−1. With regard to the neurite outgrowth, the cells incubated in the medium containing 10 μg mL−1 of free fatty acids projected significantly longer neurites (58.7 ± 4.0 μm) than those incubated in the media with 1 μg mL−1 of free fatty acids (P < 0.01) and without free fatty acids (P < 0.01) (Figure S7, B and C). When the free fatty acids were used at 50 μg mL−1, the average length of the neurites was 54.2 ± 3.1 μm, showing no significant difference from the group with the free fatty acids at 10 μg mL−1.</p><p>Our results show that the cells incubated in the medium supplemented with 10 μg mL−1 of free fatty acids projected longer neurites than those in the media supplemented with 50 and 100 μg mL−1 microparticles. This observation also indicates that the effect provided by the chemical cue of the soluble fatty acids was rather limited as the neurites could only be increased by about two times in terms of length. In comparison, when the microparticles were deposited on glass slides, the length of the neurites could be enhanced by almost six times. Taken together, it is clear that the surface roughness of the substrate also greatly contributed to the outgrowth of neurites. The neurites extending from PC12 cells that were cultured on substrates with moderate roughness were notably longer than those on substrates with both low and high surface roughness. These results agree with a previous report in that the moderate roughness of a substrate constructed from electrosprayed PLGA microparticles resulted in the longest neurite outgrowth from DRG bodies.[21] On a substrate, the neurites utilize growth cones to guide their pathways, and the adjacent surface features may work as points of adhesion for the growth cones. On the substrate with moderate surface roughness, the neurites use the microparticles as anchoring points to further support the growth cones for moving and finding pathways, resulting in elongation with little structural disruption for the extending neurites. In comparison, on the substrate with a high density of microparticles, there are many available points of adhesion, resulting in short and multi-directional turns for the neurites in order to navigate across the tortuous surface. Besides, a high density of microparticles could cause cytotoxicity to the cells, thus inhibiting the outgrowth of neurites.</p><p>For repairing injured nerves, it is important to guide the outgrowth of neurites along one direction. Uniaxially aligned fibers fabricated by electrospinning have been widely used to guide the outgrowth of neurites along the fiber alignment.[30–32] Herein we utilized aligned poly-(ε-caprolactone) (PCL) microfibers to collect the microparticles for 1, 2, 5, and 8 min, respectively (Figure 1). The average diameter of the fibers was 987 ± 72 nm, and the fiber density was approximately 336 fibers per mm (or with an average separation of 1989 nm between adjacent fibers). The electrosprayed particles could adhere strongly to the fibers or glass slide as a result of the presence of residual solvent. The particles tended to be localized both on the fiber and between the fibers, and the percentages of particles located at different positions did not vary with the collection time.</p><p>To better demonstrate the directional outgrowth of neurites, we cultured PC12 multicellular spheroids with a diameter of about 200–400 μm on the different substrates. From Figure S8, the substrates did not cause any major cytotoxicity until a collection time of 8 min for the particles. From the fluorescence micrographs in Figure 2A and Figure S9, in the presence of uniaxially aligned fibers, the neurites were guided to extend along the fiber alignment. As shown in Figure 2B, in comparison with those on the bare fibers, longer neurites were extended from the multicellular spheroids for the substrates comprising of aligned fibers and decorated with the microparticles. On the substrates with a collection time of 5 min, the average length of the neurites was the longest (430.6 ± 22.9 μm). The neurites were extended along the fibers and across the particles. The aligned fibers guided the directional outgrowth of the neurites while the particles provided anchoring points to further support the growth cones for finding pathways. Since the growth cone at the tip of a growing neurite can cover a relatively wide angle, the exact locations of the particles relative to the fibers should not have a major impact on the extension of neurites. Regardless of the substrates utilized to collect the microparticles, glass slides or aligned fibers, their topographic features showed a similar impact on the outgrowth of neurites, with the best performance corresponding to a moderate density of microparticles. Meanwhile, the fatty acids offered the chemical cue to accelerate the neurite outgrowth. Furthermore, the multicellular spheroids on the substrates with a collection time of 5 min expressed the highest levels of genes related to neurite outgrowth among all groups (Figure 2C). The influence of the substrates on the expression levels of genes showed the same correlation to the length of the neurites.</p><p>We also utilized chick embryonic DRG as another neuron model to investigate the influence of the different substrates on neurite outgrowth. As shown in Figure 3, the neurites extending from the DRG cultured on the different substrates were parallel to the alignment direction of the fibers. From Figure 4, on the bare fibers, the average length of the neurites was 869.6 ± 19.1 μm. On the aligned fibers deposited with microparticles for 2 min, both the average and the longest lengths of the neurites were slightly increased (P < 0.05). By further increasing the collection time to 5 min, the average length of the neurites was significantly increased to 1202.3 ± 29.7 μm (P < 0.01). Taken together, the electrospun fibers functionalized with microparticles of fatty acids could also promote the outgrowth of neurites from DRG bodies.</p><p>In summary, we have fabricated microparticles of fatty acids by electrospray and varied their density on a collector to construct a substrate with the optimal topographical features to promote neurite outgrowth. On the substrates constructed by varying the densities of microparticles deposited on glass slides, PC12 cells showed sensitivity to the topographical features. By functionalizing uniaxially aligned, electrospun microfibers with a moderate density of the microparticles, we could maximally guide the directional outgrowth of neurites from both PC12 multicellular spheroids and DRG bodies. The neurite outgrowth could be attributed to the surface roughness of the substrates and the chemical cue offered by the fatty acids. The fiber density together with the surface coating can also be varied to control the growth direction of the neurites.[30] For translational use, the uniaxially aligned fibers can be placed a on non-woven mat of random fibers prior to electrospray of microparticles. The bi-layer structure can then be rolled-up to form a conduit for peripheral nerve repair.[32] In addition, known for their reversible solid–liquid phase transition in response to temperature variation, fatty acids have been used as a class of thermosensitive materials for the controlled release of various bioactive agents.[25–29] This unique capability can be combined with various types of growth factors to further enhance neurite outgrowth.</p>", "role": "user" }, { "content": "Controlling the outgrowth of neurites is important for enhancing the repair of injured nerves and understanding the development of nervous systems. Herein we report a simple strategy for enhancing the outgrowth of neurites through a unique integration of topographical guidance and a chemical cue. We use electrospray to easily functionalize the surface of a substrate with microparticles of natural fatty acids at a controllable density. Through a synergistic effect from the surface roughness arising from the microparticles and the chemical cue offered by the fatty acids, the outgrowth of neurites from PC12 cells is greatly enhanced. We also functionalize the surfaces of uniaxially aligned, electrospun microfibers with the microparticles and further demonstrate that the substrates can guide and enhance directional outgrowth of neurites from both PC12 multicellular spheroids and chick embryonic dorsal root ganglia bodies.", "role": "assistant" } ]

[ { "content": "You will be shown a claim about public health and the abstract of a biomedical research paper. Each sentence from the abstract will be on a separate line. Your task is to return a JSON object with two fields:\n\n- \"verdict\": The fact-checking verdict. If the information in the abstract supports the claim, write \"SUPPORT\". If the abstract contradicts the claim, write \"CONTRADICT\". If the abstract does not provide enough information to arrive at a verdict, write \"NEI\" (for \"not enough information\").\n- \"evidence\": An array of sentences providing evidence for the verdict. Please copy all relevant sentences verbatim from the abstract. If the verdict was \"NEI\", then return an empty array.\n\nFor instance, if the model were given the claim \"wearing masks can prevent the spread of COVID\", the output might be:\n{\n \"verdict\": \"SUPPORT\",\n \"evidence\": [\"Our findings indicate that mass mask-wearing reduces the transmission rate for COVID-19.\"]\n}\n\nClaim: Obesity Ups Severe COVID-19 Risk in Young Patients\n\nAbstract:\nBACKGROUND: The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).\nWhile systemic inflammation and pulmonary complications can result in significant morbidity and mortality, cardiovascular complications may also occur.\nOBJECTIVE: This brief report evaluates cardiovascular complications in the setting of COVID-19 infection.\nDISCUSSION: The current COVID-19 pandemic has resulted in over one million infected worldwide and thousands of death.\nThe virus binds and enters through angiotensin-converting enzyme 2 (ACE2).\nCOVID-19 can result in systemic inflammation, multiorgan dysfunction, and critical illness.\nThe cardiovascular system is also affected, with complications including myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and venous thromboembolic events.\nCurrent therapies for COVID-19 may interact with cardiovascular medications.\nCONCLUSIONS: Emergency clinicians should be aware of these cardiovascular complications when evaluating and managing the patient with COVID-19.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "content": "You are provided with the abstract of a scientific paper and the abstracts of the papers it references. Your task is to write a Related Work section for the main paper. This section should concisely summarize and integrate the key points from the cited abstracts, reflecting how they relate to the main paper's contributions and context. In your summary, use numerical citation markers like [1], [2], etc., to refer to the corresponding papers.\n\nMain Abstract:\nMultivariate time series (MTS) arise when multiple interconnected sensors record data over time. Dealing with this high-dimensional data is challenging for every classifier for at least two aspects: First, a MTS is not only characterized by individual feature values, but also by the co-occurrence of features in different dimensions. Second, this typically adds large amounts of irrelevant data and noise. We present our novel MTS classifier WEASEL+MUSE (Word ExtrAction for time SEries cLassification + MUltivariate Symbols and dErivatives) which addresses both challenges. WEASEL+MUSE builds a multivariate feature vector, first using a sliding-window approach applied to each dimension of the MTS, then extracts discrete features per window and dimension. The feature vector is subsequently fed through feature selection, removing non-discriminative features, and analysed by a machine learning classifier. The novelty of WEASEL+MUSE lies in its specific way of extracting and filtering multivariate features from MTS by encoding context information into each feature, resulting in a small, yet very discriminative feature set useful for MTS classification. Based on a popular benchmark of @math MTS datasets, we found that WEASEL+MUSE is the most accurate domain agnostic classifier, when compared to the state of the art. The outstanding robustness of WEASEL+MUSE is further confirmed based on motion gesture recognition data, where it out-of-the-box achieved similar accuracies as domain-specific methods.\n\nCited Abstract(s):\n[1]: We propose in this work a new family of kernels for variable-length time series. Our work builds upon the vector autoregressive (VAR) model for multivariate stochastic processes: given a multivariate time series x, we consider the likelihood function p_ (x) of different parameters in the VAR model as features to describe x. To compare two time series x and x', we form the product of their features p_ (x) p_ (x') which is integrated out w.r.t using a matrix normal-inverse Wishart prior. Among other properties, this kernel can be easily computed when the dimension d of the time series is much larger than the lengths of the considered time series x and x'. It can also be generalized to time series taking values in arbitrary state spaces, as long as the state space itself is endowed with a kernel . In that case, the kernel between x and x' is a a function of the Gram matrices produced by on observations and subsequences of observations enumerated in x and x'. We describe a computationally efficient implementation of this generalization that uses low-rank matrix factorization techniques. These kernels are compared to other known kernels using a set of benchmark classification tasks carried out with support vector machines.\n\n[2]: Time series data mining has received much greater interest along with the increase in temporal data sets from different domains such as medicine, finance, multimedia, etc. Representations are important to reduce dimensionality and generate useful similarity measures. High-level representations such as Fourier transforms, wavelets, piecewise polynomial models, etc., were considered previously. Recently, autoregressive kernels were introduced to reflect the similarity of the time series. We introduce a novel approach to model the dependency structure in time series that generalizes the concept of autoregression to local autopatterns. Our approach generates a pattern-based representation along with a similarity measure called learned pattern similarity (LPS). A tree-based ensemble-learning strategy that is fast and insensitive to parameter settings is the basis for the approach. Then, a robust similarity measure based on the learned patterns is presented. This unsupervised approach to represent and measure the similarity between time series generally applies to a number of data mining tasks (e.g., clustering, anomaly detection, classification). Furthermore, an embedded learning of the representation avoids pre-defined features and an extraction step which is common in some feature-based approaches. The method generalizes in a straightforward manner to multivariate time series. The effectiveness of LPS is evaluated on time series classification problems from various domains. We compare LPS to eleven well-known similarity measures. Our experimental results show that LPS provides fast and competitive results on benchmark datasets from several domains. Furthermore, LPS provides a research direction and template approach that breaks from the linear dependency models to potentially foster other promising nonlinear approaches.", "role": "user" }, { "content": "[2] extracts segments from an MTS. It then trains regression trees to identify structural dependencies between segments. The regression trees trained in this manner represent a non-linear AR model. LPS next builds a BOW representation based on the labels of the leaf nodes similar to SMTS. Finally a similarity measure is defined on the BOW representations of the MTS. LPS showed better performance than DTW in a benchmark using 15 MTS datasets. [1] proposes an AR kernel-based distance measure for MTSC.", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Disease\"].\n\nPlease return the output as a JSON object of the format: {\"Disease\": [\"COVID-19\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nHepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome. Hepatoblastoma is a rare neoplasm of infants and children only recently documented in association with hereditary adenomatous polyposis of the colon [Kingston et al., 1983]. We report four children with hepatoblastoma from four unrelated families with Gardner syndrome (GS). One child, now 19 years old, survived after a resection of a hepatoblastoma in infancy and recently was found to have GS. He has an associated odontoma and pigmented ocular fundus lesions, both of which have been shown to be clinical markers of GS. Many individuals in these four GS families, both affected and at risk, have osteomatous jaw lesions and pigmented ocular fundus lesions. A search for colonic polyps should be made in families of infants and children with hepatoblastoma. If the child survives, he or she should be monitored for the later appearance of colonic polyps. The finding of jaw lesions and/or pigmented ocular fundus lesions in relatives at risk are indications of the possible presence of the GS gene.", "role": "user" }, { "content": "{\"Disease\": [\"odontoma\", \"pigmented ocular fundus lesions\", \"Hepatoblastoma\", \"Gardner syndrome\", \"jaw lesions\", \"hereditary adenomatous polyposis of the colon\", \"GS\", \"hepatoblastoma\", \"neoplasm\", \"colonic polyps\", \"osteomatous jaw lesions\"]}", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nDiffusion tensor imaging predictors of treatment outcomes in major depressive disorder.\nAbstract 1:\nBACKGROUND Functional neuroimaging studies implicate anterior cingulate and limbic dysfunction in major depressive disorder ( MDD ) and responsiveness to antidepressants . Diffusion tensor imaging ( DTI ) enables characterisation of white matter tracts that relate to these regions . AIMS To examine whether DTI measures of anterior cingulate and limbic white matter are useful prognostic biomarkers for MDD . METHOD Of the 102 MDD out- patients from the International Study to Predict Optimized Treatment for Depression ( iSPOT-D ) who provided baseline magnetic resonance imaging ( MRI ) data , 74 completed an 8-week course of antidepressant medication ( r and omised to escitalopram , sertraline or extended-release venlafaxine ) and were included in the present analyses . Thirty-four matched controls also provided DTI data . Fractional anisotropy was measured for five anterior cingulate-limbic white matter tracts : cingulum cingulate and hippocampus bundle , fornix , stria terminalis and uncinate fasciculus . ( Trial registered at Clinical Trials.gov : NCT00693849 . ) RESULTS A cross-vali date d logistic regression model demonstrated that altered connectivity for the cingulum part of the cingulate and stria terminalis tracts significantly predicted remission independent of demographic and clinical measures with 62 % accuracy . Prediction improved to 74 % when age was added to this model . CONCLUSIONS Anterior cingulate-limbic white matter is a useful predictor of antidepressant treatment outcome in MDD\n\n\nTitle 2:\nQuantification of brain maturation and growth patterns in C57BL/6J mice via computational neuroanatomy of diffusion tensor images.\nAbstract 2:\nDiffusion Tensor magnetic resonance imaging and computational neuroanatomy are used to quantify postnatal developmental patterns of C57BL/6J mouse brain . Changes in neuronal organization and myelination occurring as the brain matures into adulthood are examined , and a normative baseline is developed , against which transgenic mice may be compared in genotype-phenotype studies . In early postnatal days , gray matter-based cortical and hippocampal structures exhibit high water diffusion anisotropy , presumably reflecting the radial neuronal organization . Anisotropy drops rapidly within a week , indicating that the underlying brain tissue becomes more isotropic in orientation , possibly due to formation of a complex r and omly intertwined web of dendrites . Gradual white matter anisotropy increase implies progressively more organized axonal pathways , likely reflecting the myelination of axons forming tightly packed fiber bundles . In contrast to the spatially complex pattern of tissue maturation , volumetric growth is somewhat uniform , with the cortex and the cerebellum exhibiting slightly more pronounced growth . Temporally , structural growth rates demonstrate an initial rapid volumetric increase in most structures , gradually tapering off to a steady state by about 20 days . Fiber maturation reaches steady state in about 10 days for the cortex , to 30 - 40 days for the corpus callosum , the hippocampus , and the internal and external capsules\n\n\nTitle 3:\nDelineation of Early and Later Adult Onset Depression by Diffusion Tensor Imaging\nAbstract 3:\nBackground Due to a lack of evidence , there is no consistent age of onset to define early onset ( EO ) versus later onset ( LO ) major depressive disorder ( MDD ) . Fractional anisotropy ( FA ) , derived from diffusion tensor imaging ( DTI ) , has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry , abnormalities of which might facilitate the delineation of EO versus LO MDD . Method In this study , 61 pairs of untreated , non-elderly , first-episode MDD patients and healthy controls ( HCs ) aged 18–45 years old received DTI scans . The voxel-based analysis method ( VBM ) , classification analysis , using the Statistical Package for the Social Sciences ( SPSS ) , and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms . Results Classification analysis suggested in the best model that there were two subgroups of MDD patients , delineated by an age of onset of 30 years old , by which MDD patients could be divided into EO ( 18–29 years old ) and LO ( 30–45 years old ) groups . LO MDD was characterized by decreased FA , especially in the white matter ( WM ) of the fronto-occipital fasciculus and posterior limb of internal capsule , with a negative correlation with the severity of depressive symptoms ; in marked contrast , EO MDD showed increased FA , especially in the WM of the corpus callosum , corticospinal midbrain and inferior fronto-occipital fasciculus , while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms . Conclusion Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old , as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms . This DTI study supported the evidence of an exact age for the delineation of MDD , which could have broad multidisciplinary importance . Trial Registration Clinical Trials.gov\n\n\nTitle 4:\nDisrupted Brain Connectivity Networks in Drug-Naive, First-Episode Major Depressive Disorder\nAbstract 4:\nBACKGROUND Neuroimaging studies have shown that major depressive disorder ( MDD ) is accompanied by structural and functional abnormalities in specific brain regions and connections ; yet , little is known about alterations of the topological organization of whole-brain networks in MDD patients . METHODS Thirty drug-naive , first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan . The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions , and their topological properties ( e.g. , small-world , efficiency , and nodal central ity ) were analyzed using graph theory-based approaches . Nonparametric permutation tests were further used for group comparisons of topological metrics . RESULTS Both the MDD and control groups showed small-world architecture in brain functional networks , suggesting a balance between functional segregation and integration . However , compared with control subjects , the MDD patients showed altered quantitative values in the global properties , characterized by lower path length and higher global efficiency , implying a shift toward r and omization in their brain networks . The MDD patients exhibited increased nodal central ities , predominately in the cau date nucleus and default-mode regions , including the hippocampus , inferior parietal , medial frontal , and parietal regions , and reduced nodal central ities in the occipital , frontal ( orbital part ) , and temporal regions . The altered nodal central ities in the left hippocampus and the left cau date nucleus were correlated with disease duration and severity . CONCLUSIONS These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients\n\n\nTitle 5:\nBDNF val66met polymorphism, white matter abnormalities and remission of geriatric depression.\nAbstract 5:\nOBJECTIVE The polymorphism BDNF val66met of the brain derived neurotrophic factor ( BDNF ) is common , may increase the risk for depression , and affects BDNF secretion , critical for neuronal survival , plasticity , neurogenesis , and synaptic connectivity . Our objectives were : 1 ) to test the hypothesis that BDNF(val/met ) status influences the remission rate of geriatric depression ; 2 ) to explore whether the relationship between BDNF allelic status to remission is influenced by the presence of microstructural white matter abnormalities . METHOD Non-demented older subjects with major depression had a 2-week placebo period , after which those with a Hamilton Depression Rating Scale ( HDRS ) of 18 or greater received escitalopram 10 mg daily for 12 weeks . Fractional anisotropy was determined in specific regions using the Reproducible Object Quantification Scheme ( ROQS ) software that operates on non-normalized data . RESULTS BDNF(met ) carriers were more likely to achieve remission than BDNF(val/val ) homozygotes after 12 weeks of treatment with escitalopram 10 mg daily . Microstructural abnormalities in the corpus callosum , left superior corona radiata , and right inferior longitudinal fasciculum were also associated with lower remission rate . However , there were no significant interactions between BDNF(val66met ) status and microstructural abnormalities in predicting remission . LIMITATIONS Small number of subjects , focus on a single BDNF polymorphism , fixed antidepressant dose . CONCLUSIONS Depressed older BDNF(met ) carriers had a higher remission rate than BDNF(val/val ) homozygotes . This effect was not related to microstructural white matter abnormalities , which predicted remission independently . We speculate that the relationship between BDNF(val66met ) and remission is due to different effects of BDNF in brain structures related to mood regulation\n\n\nTitle 6:\nEffects of Electroconvulsive Therapy on Frontal White Matter in Late-Life Depression: A Diffusion Tensor Imaging Study\nAbstract 6:\nThis study was conducted to eluci date the effects of electroconvulsive therapy ( ECT ) on frontal white matter in late-life depressed patients . Diffusion tensor imaging was performed on 8 late-life depressed patients and 12 healthy age-matched controls . The patients were scanned before and after a course of ECT . Fractional anisotropy ( FA ) was determined in the frontal and temporal regions and the corpus callosum . A significant white matter FA reduction was found in widespread frontal and temporal brain regions in patients with depression before ECT treatment compared with controls . A significant increase in frontal white matter FA was seen following ECT treatment . A course of bilateral ECT ameliorated white matter integrity in frontal brain regions . This suggests a strong relationship with the antidepressant action of ECT\n\n\nTitle 7:\nHigh-frequency rTMS treatment increases white matter FA in the left middle frontal gyrus in young patients with treatment-resistant depression.\nAbstract 7:\nBACKGROUND Repetitive transcranial magnetic stimulation ( rTMS ) is an effective treatment for treatment-resistant depression ( TRD ) , but its therapeutic mechanisms are unclear . White matter abnormalities are thought to cause network dysfunction underlying TRD . Diffusion tensor imaging ( DTI ) is an ideal tool for examining neural connections and the integrity of white matter . Few studies have used DTI to investigate the impact of rTMS on alterations of whiter matter in TRD . METHOD 30 young treatment-resistant unipolar depression patients ( 19 males and 11 females ) were enrolled in a double-blind , r and omized high-frequency ( 15 Hz ) rTMS treatment study . Seventeen patients were treated with real stimulation , and 13 were treated with sham stimulation . White-matter fractional anisotropy ( FA ) was evaluated using voxel-based analysis ( VBA ) of FA maps derived from DTI before and after treatment . Twenty-five age- and gender-matched subjects were examined as a control group . RESULTS In an exploratory VBA method , clusters of fifty voxels or greater that survived a family-wise error (FWE)-corrected threshold of p<0.05 were considered significant . The results revealed significantly reduced FA in the left middle frontal gyrus , with peak coordinates [ -18 46 -14 ] in TRD patients . This reduced FA was significantly improved after active rTMS treatment , but not sham stimulation . FA increases were correlated with decreased depressive symptoms . LIMITATIONS This study requires replication and further clarification in a larger patient population , and optimization of stimulation locations and methods . CONCLUSIONS These results suggest that the efficacy of rTMS on TRD is related to increased white-matter FA in the left middle frontal gyrus", "role": "user" }, { "content": "Results Both pooled and subgroup meta-analyses in medication washout patients showed robust fractional anisotropy ( FA ) reductions in white matter of the right cerebellum hemispheric lobule , body of the corpus callosum ( CC ) and bilateral superior longitudinal fasciculus III ( SLF III ) , whereas FA reductions in the genu of the CC and right anterior thalamic projections were seen in only medication-naive patients .\nFibre tracking showed that the main tracts with observed FA reductions included the right cerebellar tracts , body of the CC , bilateral SLF III and arcuate fascicle .\nConclusion By excluding the confounding influences of current medication status , findings from the present study may provide a better underst and ing of the underlying neuropathology of MDD", "role": "assistant" } ]

[ { "content": "You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.\n\nTitle:\nTime-resolved dimerization of a PAS-LOV protein measured with photocoupled small angle x-ray scattering\n\nPaper sections:\n\n<p>Here, we report the coupling of photoexcitation with time-resolved SAXS to monitor conformational changes accompanying light activation of the blue-light signal transduction protein Vivid (VVD). Solution small angle X-ray scattering (SAXS) reports the size and shape of soluble biomolecules. Previously, SAXS was used in conjunction with rapid mixing techniques to time resolve macromolecular folding1,2. SAXS studies have also been used to determine large scale differences between the dark and light excited states of proteins3,4. Flash-flow devices have been used for time-resolved IR spectroscopy5; integration with SAXS expands the technique, enabling exploration of global kinetics. While time dependent processes in different blue-light sensors have been revealed by a variety of techniques6,7, this method elucidates previously unknown association dynamics of the long-lived VVD light-adapted state.</p><p>VVD, a so-called LOV (for Light Oxygen Voltage sensing) protein of the PAS family, regulates blue-light responses in the filamentous fungus Neurospora crassa 8. Photon absorption by the VVD flavin cofactor drives conformational changes within the LOV domain. In the absence of light, the protein is monomeric. Recent measurements suggest the establishment of a rapidly exchanging monomer:dimer equilibrium in the light-activated state9, thus VVD (like other LOV domains10,11) changes association state in response to light-stimulated structural modifications. PAS:PAS dimerization is believed to be a key regulatory event in signal transduction12, and is likely important for a close VVD homolog, WC-1, to activate transcription13. Because of the challenge of characterizing structural intermediates in these processes, little is known about how cofactor chemical state relates to association mode, and ultimately, the engagement of targets.</p><p>To time-resolve changes in the structure of VVD resulting from photoexcitation, we employed a microfluidic cell coupled to both laser and x-ray sources (Figure 1). The cell consists of a thin wall polyester tube (Advanced Polymers, VT)14 which is optically transparent and scatters x-rays minimally. A 473 nm laser beam (Holograms & Lasers International, Texas) is directed at 90° to a focused x-ray beam. The location where the x-ray and light beams intersect defines the time-equals-zero position for the experiment. Offsetting the two beams creates a controllable delay between laser excitation and SAXS measurement. This average delay time is calculated by dividing the distance between the two beams, x, by the flow speed of the protein solution, u (Figure 1). Use of a flow cell eliminates radiation damage to the protein and enables long x-ray exposures, which increase signal-to-noise without loss of time resolution. Temporal precision is restricted by the laminar flow boundary condition at the channel wall where u=0, but can be improved by employing a flow of sheath buffer which confines the protein-containing solution to a thin jet that travels along the tube axis with relatively uniform speed. The transit time of each molecule through either the laser or x-ray incident spot was 160 ms on average. The laser spot was continuously illuminated for all light-state measurements and the x-ray exposure time ranged from 20 to 30 sec.</p><p>The intensity of the scattered x-rays is typically plotted as a function of the momentum transfer q = 4π sin(θ)/λ where θ is half the scattering angle and λ is the x-ray wavelength. Following standard analysis procedures17 the zero angle intensity, I(0), and the radius of gyration, (Rg), were extracted from the low q data (see supplemental information). A Kratky plot18 places emphasis on data acquired at large q, which provides detail about macromolecular conformation.</p><p>SAXS measurements of the dark state of VVD are in good agreement with the computed signal from the monomeric crystal structure 2PD7 (supplementary information)4. Upon light illumination, the low angle scattering intensity from VVD is increased relative to the dark state (Fig. 2 and supplementary information). The increase occurs rapidly, and appears finished by the earliest time detected, 20 ms after photoexcitation. Such an increase in I(0) is consistent with dimerization. Inline multi-light scattering (MALS), dynamic light scattering (DLS), size exclusion chromatography and equilibrium ultracentrifugation confirm the presence of a rapidly dissociating dimer in the light adapted state9. Complete dimerization in 20 msec is consistent with a diffusion controlled association rate constant in the range of 105–106 M−1 s−1 9, and demonstrates that the conformational change which precedes dimerization is unlikely to be rate limiting. This association rate exceeds that reported for other LOV domain proteins11. Importantly, we also evaluated the time-dependent SAXS profile of a VVD point mutant (Cys71Ser) that cannot undergo light-induced dimerization, but otherwise has normal photochemical properties4. Cys71Ser VVD undergoes no change in scattering upon illumination; thus, laser heating or radiation damage cannot be the cause of the scattering changes we observe with wild-type VVD.</p><p>Scattering data acquired at longer times after photoexcitation show variation in the high q region of the profile, suggesting that the conformational changes continue for several seconds after dimerization is complete (Figure 3). As VVD remains in the light-adapted state for several hours19 this phenomenon reflects additional changes post dimerization that may be essential for engaging targets and propagating signals.</p><p>While these time-resolved SAXS measurements show a consistent pattern of oligomerization after light excitation, the magnitude of the change varies depending on the specific sample and experiment. The affinity of the VVD dimer is known to be highly sensitive to modifications at the N-terminus as well as protein oxidation at currently unspecified sites9. We suspect differences in dimer yield result from such subtle changes in protein chemistry; we are exploring the phenomenon in more detail. Measurements on millisecond (or sub-millisecond) time scales will be required to directly detect light-induced conformational differences in the monomeric state which must precede and gate access to the dimeric state</p><p>Time-resolved measurements of global structural states are critical for unraveling the protein dynamics that underlie LOV protein light sensing; SAXS is an ideal tool for studying both the conformational changes and protein association that accompany such events. Application of a continuous flow cell to couple SAXS and photoexcitation, as demonstrated here, can elucidate ~millisecond conformational changes without signal averaging by photocycle repetition, thus avoiding the sample damage associated with repeat exposures and facilitating measurement of samples with slow photocycles. Notably, this method will resolve diffusion-limited association rates and it is generally applicable to many photoreceptors, even those with transient light-adapted states much less stable than that of VVD.</p><p>Supporting Information Available: Quantitative results of a Guinier analysis on the data and comparison of scattering data to an existing crystal structure.</p><p>A schematic of the continuous flow setup that enables time-resolved SAXS measurements following photoexcitation of protein. An x-ray beam, incident from the right, passes through a focusing capillary15,16 to obtain sufficient x-ray flux in a small spot. Guard slits are used to decrease the scattering background. The excitation laser beam is directed perpendicular to the axis of the flow cell and the x-ray beam. A magnified illustration of the flow cell demonstrates how time-resolution is achieved.</p><p>Left: Scattering profiles for wild-type VVD before (blue) and 0.02 s after excitation (green) display an increase in zero angle intensity, consistent with light induced dimerization. No further change is measured 0.3 s after excitation (cyan). Right: Scattering profiles of the inactive Cys71Ser mutant are not changed by light excitation.</p><p>Kratky plots of data collected hundreds of milliseconds to seconds after photoexcitation. Variations in scattering profiles become evident at q>0.08 Å−1 after 8 s indicating conformational changes of the dimer.</p>", "role": "user" }, { "content": "Time-resolved small angle x-ray scattering (SAXS) has been used to probe photoexcitation of the blue-light signal transduction protein Vivid (VVD). Laser excitation of sample in a continuous flow cell enables time-resolved measurement of the initial response of VVD to illumination. Good signal-to-noise is achieved without relying on multiple exposures of the same sample or limiting exposure times to prevent radiation damage. The SAXS data demonstrate that VVD dimerizes within tens of milliseconds of light-state activation. Time-resolved SAXS in a flow cell format is a general method for connecting chemical changes in photoreceptors to conformationally driven output signals.", "role": "assistant" } ]

[ { "content": "You will be presented with a citation sentence from a research paper. Classify the intent behind this citation by choosing from one of the following categories:\n\n- Method: Cites the paper for its methodology or procedure.\n- Background: Cites the paper to provide background information.\n- Result: Cites the paper for its findings or results.\n\nYour answer should be a single word from the following list of options: [\"Method\", \"Background\", \"Result\"]. Do not include any other text in your response.\n\nCitation sentence:\n\nTransanal minimally invasive surgery (TAMIS) has emerged as an important alternative to transanal endoscopic microsurgery (TEM) capable of providing highquality local excision for rectal neoplasia [1–10].", "role": "user" }, { "content": "Background", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Finding\", \"Bacterium\", \"ProfessionalOrOccupationalGroup\", \"InjuryOrPoisoning\", \"Eukaryote\", \"BodySystem\", \"Virus\", \"ResearchActivity\", \"BodySubstance\", \"PopulationGroup\", \"Chemical\", \"AnatomicalStructure\", \"SpatialConcept\", \"HealthCareActivity\", \"Organization\", \"BiomedicalOccupationOrDiscipline\", \"Food\", \"ClinicalAttribute\", \"MedicalDevice\", \"BiologicFunction\", \"IntellectualProduct\"].\n\nPlease return the output as a JSON object of the format: {\"Virus\": [\"HIV\", ...], \"Bacterium\": [\"MRSA\", ...], \"AnatomicalStructure\": [\"Lung\", ...], \"BodySystem\": [\"CNS\", ...], \"BodySubstance\": [\"Serum\", ...], \"Finding\": [\"Headache\", ...], \"InjuryOrPoisoning\": [\"Fracture\", ...], \"BiologicFunction\": [\"Death\", ...], \"HealthCareActivity\": [\"Biopsy\", ...], \"ResearchActivity\": [\"Clinical trial\", ...], \"MedicalDevice\": [\"Lenses\", ...], \"SpatialConcept\": [\"Camps\", ...], \"BiomedicalOccupationOrDiscipline\": [\"Forensic medicine\", ...], \"Organization\": [\"WHO\", ...], \"ProfessionalOrOccupationalGroup\": [\"Provider\", ...], \"PopulationGroup\": [\"Swimmers\", ...], \"Chemical\": [\"Gold\", ...], \"Food\": [\"Rice\", ...], \"IntellectualProduct\": [\"RPAM\", ...], \"ClinicalAttribute\": [\"Biomarker\", ...], \"Eukaryote\": [\"Dogs\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nElevated Serum Krebs von den Lungen-6 in Early Disease Predicts Subsequent Deterioration of Pulmonary Function in Patients with Systemic Sclerosis and Interstitial Lung Disease To identify predictors of poor prognosis in patients with systemic sclerosis (SSc) associated with interstitial lung disease (ILD). Fifty patients with early-stage SSc - ILD who had never received disease - modifying drugs and were either observed for ≥ 10 years or died from ILD -related causes were enrolled. The baseline variables of patients who developed endstage lung disease (ESLD) were compared with those of patients who remained ESLD - free, and the Cox proportional hazard model was used to identify initial factors that correlated with ESLD development. Sixteen patients (32%) developed ESLD during 173.5 ± 64.7 months of followup. Elevated serum Krebs von den Lungen-6 (KL-6) at initial assessment was highly correlated with ESLD development (p = 0.0002). Receiver-operating characteristic curve analysis revealed that a KL-6 value of 1273 U/ml effectively discriminated patients who developed ESLD from those who did not. Patients with KL-6 > 1273 U/ml were less likely to remain ESLD - free compared with those with lower KL-6 levels (p < 0.0001). Multivariate analysis showed that KL-6 > 1273 U/ml was the most reliable predictor of ESLD development (OR 51.2, 95% CI 7.6-343, p < 0.0001). Finally, the initial KL-6 level correlated with the forced vital capacity (FVC) decline rate (r = 0.58, p < 0.0001). The natural course of SSc - ILD is highly variable. Baseline serum KL-6 is a biomarker potentially useful for predicting FVC decline.", "role": "user" }, { "content": "{\"AnatomicalStructure\": [], \"Bacterium\": [], \"BiologicFunction\": [\"disease\", \"systemic sclerosis\", \"interstitial lung disease\", \"Interstitial Lung Disease\", \"Systemic Sclerosis\", \"Disease\", \"SSc\", \"died\", \"ESLD\", \"endstage lung disease\", \"ILD\", \"Pulmonary Function\"], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [\"Serum\", \"serum\"], \"BodySystem\": [], \"Chemical\": [\"Krebs von den Lungen-6\", \"KL-6\", \"drugs\"], \"ClinicalAttribute\": [\"biomarker\"], \"Eukaryote\": [], \"Finding\": [\"FVC\", \"causes\", \"forced vital capacity\"], \"Food\": [], \"HealthCareActivity\": [\"followup\", \"prognosis\"], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"Cox proportional hazard model\"], \"MedicalDevice\": [], \"Organization\": [], \"PopulationGroup\": [], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [\"Receiver-operating characteristic curve analysis\"], \"SpatialConcept\": [], \"Virus\": []}", "role": "assistant" } ]

[ { "content": "You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your response other than the answer.\n\nParagraph: A membrane-less organelle originally described as the ''Ribosome Factory'', the nucleolus is dedicated to RNA-polymerase-I-directed rDNA transcription, rRNA processing mediated by small nucleolar ribonucleoproteins (soRNPs) and ribosome assembly . Ribosome biogenesis is essential for protein synthesis and cell viability [2] and ultimately results in the separate large (60S) and small (40S) ribosomal subunits, which are subsequently exported to the cytoplasm. This fundamental cellular process, to which the cell dedicates most of its energy resources, is tightly regulated to match dynamic changes in cell proliferation, growth rate and metabolic activities [3] . The nucleolus is the site of additional RNA processing, including mRNA export and degradation, the maturation of uridine-rich small nuclear RNPs (U snRNPs), which form the core of the spliceosome, biogenesis of t-RNA and microRNAs (miRNAs) [4] . The nucleolus is also involved in other cellular processes including cell cycle control, oncogenic processes, cellular stress responses and translation [4] . The concept of a multifunctional and highly dynamic nucleolus has been substantiated by several studies combining organellar proteomic approaches and quantitative mass spectrometry, and describing thousands of proteins transiting through the nucleolus in response to various metabolic conditions, stress and cellular environments [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16] . Collectively, the aforementioned studies represent landmarks in understanding the functional complexity of the nucleolus, and demonstrated that nucleolar proteins are in continuous exchange with other nuclear and cellular compartments in response to specific cellular conditions. Of importance, the nucleolus is also the target of viruses including HIV-1, hCMV, HSV and KSHV, as part of their replication strategy [2, 17] . Proteomics studies analysing the nucleoli of cells infected with Human respiratory syncytial virus (HRSV), influenza A virus, avian coronavirus infectious bronchitis virus (IBV) or adenovirus highlighted how viruses can distinctively disrupt the distribution of nucleolar proteins [2, 17, 18, 19, 20, 21, 22, 23, 24] . Interestingly, both HIV-1 regulatory proteins Tat and Rev localise to the nucleoplasm and nucleolus. Both their sequences encompass a nucleolar localisation signal (NoLS) overlapping with their nuclear localisation signal (NLS), which governs their nucleolar localisation [25, 26, 27, 28, 29, 30, 31] . Furthermore, Tat and Rev interact with the nucleolar antigen B23, which is essential for their nucleolar localisation [25, 26, 27, 28, 29, 30] . Nevertheless, a recent study described that in contrast to Jurkat T-cells and other transformed cell lines where Tat is associated with the nucleus and nucleolus, in primary T-cells Tat primarily accumulates at the plasma membrane, while trafficking via the nucleus where it functions [32] . While the regulation of their active nuclear import and/or export, as mediated by the karyopherin/importin family have been well described, the mechanisms distributing Tat and Rev between the cytoplasm, nucleoplasm and the nucleolus remains elusive [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48] . Importantly, two major studies by Machienzi et al. have revealed important functional links between HIV-1 replication and the nucleolus [49, 50] . First, they could inhibit HIV-1 replication and Tat transactivation function employing a TAR decoy specifically directed to the nucleolus. Furthermore, using a similar approach, with an anti-HIV-1 hammerhead ribozyme fused to the U16 small nucleolar RNA and therefore targeted to the nucleolus, they could dramatically suppress HIV-1 replication. Collectively, these findings strongly suggest that HIV-1 transcripts and Tat nucleolar trafficking are critical for HIV-1 replication. However the nature of these contributions remains to be elucidated. In this report, we systematically analysed the nucleolar proteome perturbations occurring in Jurkat T-cells constitutively expressing HIV-1 Tat, using a quantitative mass spectrometry approach. Following the detailed annotation of the quantitative abundance changes in the nucleolar protein composition upon Tat expression, we focussed on the Tat-affected cellular complexes and signalling pathways associated with ribosome biogenesis, spliceosome, molecular chaperones, DNA replication and repair and metabolism and discuss their potential involvement in HIV-1 pathogenesis. In this study, we investigated the quantitative changes in the nucleolar proteome of Jurkat T cells constitutively expressing HIV-1 Tat (86aa) versus their Tat-negative counterpart, using stable isotope labelling with amino acids in cell culture (SILAC) technology, followed by ESI tandem mass spectrometry and implemented the experimental approach described in Figure 1A . First, using retroviral gene delivery, we transduced HIV-1 Tat fused to a tandem affinity purification (TAP) tag (consisting of two protein G and a streptavidin binding peptide) or TAP tag alone (control vector) in Jurkat leukemia T cell clone E6-1 and sorted the transduced cells (GFP positive) by FACS. This resulted in a highly enriched population of polyclonal transduced cells presenting different expression levels of the transgene ( Figure 1B) . The functionality of TAP-Tat was confirmed by transfecting Jurkat TAP-Tat and TAP cells with a luciferase reporter gene vector under the control of the HIV-1 LTR (pGL3-LTR) [36] . TAP-Tat up regulated gene expression from the HIV-1 LTR by up to 28 fold compared to control ( Figure 1C ). To further address the functionality of Tat fused to TAP, we compared Jurkat TAP-Tat with Jurkat-tat, a cell line stably expressing untagged Tat [51] . Both cell line exhibited comparable HIV-1 LTR activity following transfection with pGL3-LTR ( Figure S1 ). Next, Tat expression and subcellular localization was verified by subcellular fractionation followed by WB analysis ( Figure 1E ). TAP-Tat displayed a prominent nuclear/nucleolar localization but could also be detected in the cytoplasm. These observations were further validated by immunofluorescence microscopy ( Figure 1E ). Of note, Jurkat-tat presented similar patterns for Tat subcellular distribution as shown by immunofluorescence microscopy and subcellular fractionation followed by WB analysis (Figure S2 and S3). We next compared the growth rate and proliferation of the Jurkat TAP and TAP-Tat cell lines (Materials and Methods S1), which were equivalent ( Figure S4A ). Similarly, FACS analysis confirmed that the relative populations in G1, S, and G2/M were similar for Jurkat TAP-Tat and TAP cells ( Figure S4B ). We labeled Jurkat TAP-Tat and Jurkat TAP cells with light (R0K0) and heavy (R6K6) isotope containing arginine and lysine, respectively. Following five passages in their respective SILAC medium, 85 million cells from each culture were harvested, pooled and their nucleoli were isolated as previously described ( Figure 1A ) [52] . Each step of the procedure was closely monitored by microscopic examination. To assess the quality of our fractionation procedure, specific enrichment of known nucleolar antigens was investigated by Western Blot analysis ( Figure 1D ). Nucleolin (110 kDa) and Fibrillarin (FBL) (34 kDa), two major nucleolar proteins known to localise to the granular component of the nucleolus, were found to be highly enriched in the mixed nucleolar fraction. Of note, nucleolin was equally distributed between the nuclear and cytoplasmic fractions. This distribution pattern for nucleolin appears to be specific for Jurkat T-cells as show previously [52, 53] . The nuclear protein PARP-1 (Poly ADPribose polymerase 1) (113 kDa) was present in the nuclear and nucleoplasmic fraction but was depleted in the nucleolar fraction. Alpha-tubulin (50 kDa) was highly abundant in the cytoplasmic fraction and weakly detected in the nuclear fractions. Collectively, these results confirmed that our methods produced a highly enriched nucleolar fraction without significant cross contamination. Subsequently, the nucleolar protein mixture was trypsindigested and the resulting peptides were analysed by mass spectrometry. Comparative quantitative proteomic analysis was performed using MaxQuant to analyse the ratios in isotopes for each peptide identified. A total of 2427 peptides were quantified, representing 520 quantified nucleolar proteins. The fully annotated list of the quantified nucleolar proteins is available in Table S1 and the raw data from the mass spectrometry analysis was deposited in the Tranche repository database (https:// proteomecommons.org/tranche/), which can be accessed using the hash keys described in materials and methods. We annotated the quantified proteins using the ToppGene Suite tools [54] and extracted Gene Ontology (GO) and InterPro annotations [55] . The analysis of GO biological processes ( Figure 1F ) revealed that the best-represented biological processes included transcription (24%), RNA processing (23%), cell cycle process (13%) and chromosome organisation (15%), which reflects nucleolar associated functions and is comparable to our previous characterisation of Jurkat T-cell nucleolar proteome [52] . Subcellular distribution analysis ( Figure 1F ) revealed that our dataset contained proteins known to localise in the nucleolus (49%), in the nucleus (24%) while 15% of proteins were previously described to reside exclusively in the cytoplasm. The subcellular distribution was similar to our previous analysis of the Jurkat T-cell nucleolar proteome [52] . Table S1 . The distribution of protein ratios are represented in Figure 1G as log 2 (abundance change). The SILAC ratios indicate changes in protein abundance in the nucleolar fraction of Jurkat TAP-Tat cells in comparison with Jurkat TAP cells. The distribution of the quantified proteins followed a Gaussian distribution ( Figure 1G ). A total of 49 nucleolar proteins exhibited a 1.5 fold or greater significant change (p,0.05) upon Tat expression (Table 1) . Of these, 30 proteins were enriched, whereas 19 proteins were depleted. Cells displayed no changes in the steady state content of some of the major and abundant constituents of the nucleolus, including nucleophosmin (NPM1/ B23), C23, FBL, nucleolar protein P120 (NOL1), and nucleolar protein 5A (NOL5A). The distinct ratios of protein changes upon Tat expression could reflect specific nucleolar reorganization and altered activities of the nucleolus. We performed WB analysis to validate the SILAC-based results obtained by our quantitative proteomic approach ( Figure 2 ). 15 selected proteins displayed differential intensity in the nucleolar fractions upon Tat expression, including 9 enriched (HSP90b, STAT3, pRb, CK2a, CK2a', HSP90a, Transportin, ZAP70, DDX3), and 3 depleted (ILF3, BOP1, and SSRP1) proteins. In addition, we also tested by WB analysis, protein abundance not affected by Tat expression (Importin beta, FBL, B23, C23). These results highlight the concordance in the trend of the corresponding SILAC ratios, despite some differences in the quantitative ranges. Of note, using WB, we could observe a change of intensity for protein with a SILAC fold change as low as 1.25-fold. Of note, the question remains as to which fold change magnitude might constitute a biologically relevant consequence. On the one hand, the threshold of protein abundance changes can be determined statistically and would then highlight the larger abundance changes as illustrated in Table 1 . Alternatively, the coordinated enrichment or depletion of a majority of proteins belonging to a distinct cellular complex or pathway would allow the definition of a group of proteins of interest and potential significance. Therefore, we next focused on both enriched or depleted individual proteins with activities associated with HIV-1 or Tat molecular pathogenesis, and on clustered modifications affecting entire cellular signaling pathways and macromolecular complexes. We initially focused on signaling proteins interacting with Tat and/or associated HIV-1 molecular pathogenesis and whose abundance in the nucleolus was modulated by Tat expression. Phospho-protein phosphatases. Phospho-protein phosphatase PP1 and PP2A are essential serine/threonine phosphatases [56, 57] . Importantly, PP1 accounts for 80% of the Ser/Thr phosphatase activity within the nucleolus. In our study, PP1 was found to be potentially enriched by 1.52-fold in the nucleolus of Jurkat cells expressing Tat, which supports previous studies describing the nuclear and nucleolar targeting of PP1a by HIV-1 Tat and how PP1 upregulates HIV-1 transcription [58, 59, 60, 61, 62] . PP1 c was also identified as part of the in vitro nuclear interactome [63] . Similarly, PPP2CA, the PP2A catalytic subunit (1.29-fold) and its regulatory subunit PP2R1A (1.27-fold) were similarly enriched upon Tat expression. Interestingly, Tat association with the PP2A subunit promoters results in the overexpression and up regulation of PP2A activity in lymphocytes [64, 65] . Furthermore, PP2A contributes to the regulation of HIV-1 transcription and replication [61, 66] . Retinoblastoma Protein. The tumour suppressor gene pRb protein displayed a 1.4-fold change in the nucleolus upon Tat expression [67] . Furthermore, WB analysis confirmed the distinct translocation of pRb from the nucleoplasm to the nucleolus by Tat ( Figure 2 ). Depending on the cell type, pRb can be hyperphosphorylated or hypophosphorylated upon Tat expression and can negatively or positively regulate Tat-mediated transcription respectively [68, 69, 70] . Interestingly, the hyperphosphorylation of pRB triggers in its translocation into the nucleolus [71] . Phosphorylation of pRB is also associated with an increase in ribosomal biogenesis and cell growth [72] . STAT3. The transcription factor signal transducer and activator of transcription 3 (STAT3) was significantly enriched (1.86-fold) in the nucleolar fraction by Tat constitutive expression. Furthermore, WB analysis indicated that Tat expression could promote the relocalisation of STAT3 from the cytoplasm to the nucleus, with a distinct enrichment in the nucleolus ( Figure 2) .\n\nQuestion: What cellular processes occur in the nucleolus?", "role": "user" }, { "content": "RNA-polymerase-I-directed rDNA transcription, rRNA processing mediated by small nucleolar ribonucleoproteins (soRNPs) and ribosome assembly", "role": "assistant" } ]

[ { "content": "You will be shown biomedical passages and your task is to answer the provided question. Provide a concise and accurate response and do not include any additional text in the response other than the answer.\n\nQuestion: The drug JTV519 is derivative of which group of chemical compounds?\n\nContext: In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca²⁺ leak.\nThe 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex.\nIn this article, we synthesize derivatives of the channel activator 4-chloro-3-methyl phenol (4-CmC) and the 1,4-benzothiazepine channel inhibitor 4-[-3{1-(4-benzyl) piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (K201, JTV519) with enhanced electron donor properties.\nK201 (JTV519), a benzothiazepine derivative, has been shown to possess anti-arrhythmic and cardioprotective properties, but the mechanism of its action is both complex and controversial.\nK201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker.\nA derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias.\nWe report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury.\nIn conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.\nA newly synthesized 1,4-benzothiazipine derivate, 4-[3-(4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2,3,4,5-tetrahydro-1, 4-benzothiazepine monohydrochloride (JTV-519) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) mediated multidrug resistance (MDR) in K562/MDR and KB/MRP cells, respectively.\nJTV-519, which has potential use as an antiarrhythmic [285800]. The drug is a novel cardioprotectant derivative of 1,4-benzothiazepine for which phase I trials were completed in the third quarter of 1998\nThe 1,4-benzothiazepine derivative JTV-519 is a new type of calcium ion channel modulator.\nA new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury.\nA newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective.\nProtective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation\nA new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury.\nWe report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process.\nProtective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation.\nA new 1,4-benzothiazepine derivative, JTV519 (JTV), has strong protective effects against isoproterenol-induced myocardial injury.\nA new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury.\nIn these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca?⁺ leak.\nThe cardioprotective effects of a new 1,4-benzothiazepine derivative, JTV519, on ischemia/reperfusion-induced Ca2+ overload in isolated rat hearts.\nWe report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process", "role": "user" }, { "content": "1,4-benzothiazepine", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nEffect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck.\nAbstract 1:\nPURPOSE A subset of head and neck cancers is associated with the human papillomavirus ( HPV ) . Viral infection is closely correlated with expression of p16(INK4A ) in these tumors . We evaluated p16(INK4A ) as a prognostic marker of treatment response and survival in a well-defined and prospect ively collected cohort of patients treated solely with conventional radiotherapy in the Danish Head and Neck Cancer Group ( DAHANCA ) 5 trial . PATIENTS AND METHODS Immunohistochemical expression of p16(INK4A ) was analyzed in pretreatment paraffin-embedded tumor blocks from 156 patients treated with conventional primary radiotherapy alone . The influence of p16(INK4A ) status on locoregional tumor control , disease-specific survival , and overall survival after radiotherapy was evaluated . RESULTS p16(INK4A ) positivity was found in 35 tumors ( 22 % ) . Tumor-positivity for p16(INK4A ) was significantly correlated with improved locoregional tumor control ( 5-year actuarial values 58 % v 28 % ; P = .0005 ) , improved disease-specific survival ( 72 % v 34 % ; P = .0006 ) , and improved overall survival ( 62 % v 26 % ; P = .0003 ) . In multivariate analysis , p16(INK4A ) remained a strong independent prognostic factor for locoregional failure ( hazard ratio [ HR ] , 0.35 ; 95 % CI , 0.19 to 0.64 ) , disease-specific death ( HR , 0.36 ; 95 % CI , 0.20 to 0.64 ) , and overall death ( HR , 0.44 ; 95 % CI , 0.28 to 0.68 ) . CONCLUSION Expression of p16(INK4A ) has a major impact on treatment response and survival in patients with head and neck cancer treated with conventional radiotherapy\n\n\nTitle 2:\nSentinel node dissection is safe in the treatment of early-stage vulvar cancer.\nAbstract 2:\nPURPOSE To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients . PATIENTS AND METHODS A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 ( < 4 cm ) squamous cell cancer of the vulva . When the sentinel node was found to be negative at pathologic ultrastaging , inguinofemoral lymphadenectomy was omitted , and the patient was observed with follow-up for 2 years at intervals of every 2 months . Stopping rules were defined for the occurrence of groin recurrences . RESULTS From March 2000 until June 2006 , a sentinel node procedure was performed in 623 groins of 403 assessable patients . In 259 patients with unifocal vulvar disease and a negative sentinel node ( median follow-up time , 35 months ) , six groin recurrences were diagnosed ( 2.3 % ; 95 % CI , 0.6 % to 5 % ) , and 3-year survival rate was 97 % ( 95 % CI , 91 % to 99 % ) . Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy ( wound breakdown in groin : 11.7 % v 34.0 % , respectively ; P < .0001 ; and cellulitis : 4.5 % v 21.3 % , respectively ; P < .0001 ) . Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy ( recurrent erysipelas : 0.4 % v 16.2 % , respectively ; P < .0001 ; and lymphedema of the legs : 1.9 % v 25.2 % , respectively ; P < .0001 ) . CONCLUSION In early-stage vulvar cancer patients with a negative sentinel node , the groin recurrence rate is low , survival is excellent , and treatment-related morbidity is minimal . We suggest that sentinel node dissection , performed by a quality -controlled multidisciplinary team , should be part of the st and ard treatment in selected patients with early-stage vulvar cancer\n\n\nTitle 3:\nImproved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial.\nAbstract 3:\nBACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma ( HNSCC ) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospect i ve clinical trial . METHODS We prospect ively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group ( ECOG ) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and st and ard fractionation radiation therapy . The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction ( PCR ) and in situ hybridization . Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis . The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age , ECOG performance status , stage , and other covariables was estimated by use of a multivariable Cox proportional hazards model . All statistical tests were two-sided . RESULTS Genomic DNA of oncogenic HPV types 16 , 33 , or 35 was located within tumor cell nuclei of 40 % ( 95 % confidence interval [ CI ] = 30 % to 50 % ) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR . Compared with patients with HPV-negative tumors , patients with HPV-positive tumors had higher response rates after induction chemotherapy ( 82 % vs 55 % , difference = 27 % , 95 % CI = 9.3 % to 44.7 % , P = .01 ) and after chemoradiation treatment ( 84 % vs 57 % , difference = 27 % , 95 % CI = 9.7 % to 44.3 % , P = .007 ) . After a median follow-up of 39.1 months , patients with HPV-positive tumors had improved overall survival ( 2-year overall survival = 95 % [ 95 % CI = 87 % to 100 % ] vs 62 % [ 95 % CI = 49 % to 74 % ] , difference = 33 % , 95 % CI = 18.6 % to 47.4 % , P = .005 , log-rank test ) and , after adjustment for age , tumor stage , and ECOG performance status , lower risks of progression ( hazard ratio [ HR ] = 0.27 , 95 % CI = 0.10 to 0.75 ) , and death from any cause ( HR = 0.36 , 95 % CI = 0.15 to 0.85 ) than those with HPV-negative tumors . CONCLUSION For patients with HNSCC of the oropharynx , tumor HPV status is strongly associated with therapeutic response and survival\n\n\nTitle 4:\nLymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study.\nAbstract 4:\nPURPOSE To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer . PATIENTS AND METHODS Eligible women had squamous cell carcinoma , at least 1-mm invasion , and tumor size ≥ 2 cm and ≤ 6 cm . The primary tumor was limited to the vulva , and there were no groin lymph nodes that were clinical ly suggestive of cancer . All women underwent intraoperative lymphatic mapping , sentinel lymph node biopsy , and inguinal femoral lymphadenectomy . Histologic ultra staging of the sentinel lymph node was prescribed . RESULTS In all , 452 women underwent the planned procedures , and 418 had at least one sentinel lymph node identified . There were 132 node-positive women , including 11 ( 8.3 % ) with false-negative nodes . Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node . The sensitivity was 91.7 % ( 90 % lower confidence bound , 86.7 % ) and the false-negative predictive value ( 1-negative predictive value ) was 3.7 % ( 90 % upper confidence bound , 6.1 % ) . In women with tumor less than 4 cm , the false-negative predictive value was 2.0 % ( 90 % upper confidence bound , 4.5 % ) . CONCLUSION Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva", "role": "user" }, { "content": "Implementation of sentinel lymph node biopsy in patients with tumours not exceeding 4 cm is safe and efficiently eliminates redundant groin dissections .", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Chemical\", \"Disease\"].\n\nPlease return the output as a JSON object of the format: {\"Chemical\": [\"Naloxone\", ...], \"Disease\": [\"Hypotensive\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nAntithymocyte globulin in the treatment of D-penicillamine-induced aplastic anemia. A patient who received antithymocyte globulin therapy for aplastic anemia due to D-penicillamine therapy is described. Bone marrow recovery and peripheral blood recovery were complete 1 month and 3 months, respectively, after treatment, and blood transfusion or other therapies were not necessary in a follow-up period of more than 2 years. Use of antithymocyte globulin may be the optimal treatment of D-penicillamine-induced aplastic anemia.", "role": "user" }, { "content": "{\"Chemical\": [\"D-penicillamine\", \"Antithymocyte globulin\", \"antithymocyte globulin\"], \"Disease\": [\"aplastic anemia\"]}", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nSublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial.\nAbstract 1:\nBACKGROUND There are presently no available therapeutic options for patients with peanut allergy . OBJECTIVE We sought to investigate the safety , efficacy , and immunologic effects of peanut sublingual immunotherapy ( SLIT ) . METHODS After a baseline oral food challenge ( OFC ) of up to 2 g of peanut powder ( approximately 50 % protein ; median successfully consumed dose [ SCD ] , 46 mg ) , 40 subjects , aged 12 to 37 years ( median , 15 years ) , were r and omized 1:1 across 5 sites to daily peanut or placebo SLIT . A 5-g OFC was performed after 44 weeks , followed by unblinding ; placebo-treated subjects then crossed over to higher dose peanut SLIT , followed by a subsequent crossover Week 44 5-g OFC . Week 44 OFCs from both groups were compared with baseline OFCs ; subjects successfully consuming 5 g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders . RESULTS After 44 weeks of SLIT , 14 ( 70 % ) of 20 subjects receiving peanut SLIT were responders compared with 3 ( 15 % ) of 20 subjects receiving placebo ( P < .001 ) . In peanut SLIT responders , median SCD increased from 3.5 to 496 mg . After 68 weeks of SLIT , median SCD significantly increased to 996 mg ( compared with Week 44 , P = .05 ) . The median SCD at the Week 44 Crossover OFC was significantly higher than baseline ( 603 vs 71 mg , P = .02 ) . Seven ( 44 % ) of 16 crossover subjects were responders ; median SCD increased from 21 to 496 mg among responders . Of 10,855 peanut doses through the Week 44 OFCs , 63.1 % were symptom free ; excluding oral-pharyngeal symptoms , 95.2 % were symptom free . CONCLUSIONS Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared with placebo . Longer duration of therapy showed statistically significant increases in the SCD\n\n\nTitle 2:\nA randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.\nAbstract 2:\nBACKGROUND Open-label oral immunotherapy ( OIT ) protocol s have been used to treat small numbers of patients with peanut allergy . Peanut OIT has not been evaluated in double-blind , placebo-controlled trials . OBJECTIVE To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind , placebo-controlled study . METHODS In this multicenter study , children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo . Initial escalation , build-up , and maintenance phases were followed by an oral food challenge ( OFC ) at approximately 1 year . Titrated skin prick tests ( SPTs ) and laboratory studies were performed at regular intervals . RESULTS Twenty-eight subjects were enrolled in the study . Three peanut OIT subjects withdrew early in the study because of allergic side effects . During the double-blind , placebo-controlled food challenge , all remaining peanut OIT subjects ( n = 16 ) ingested the maximum cumulative dose of 5000 mg ( approximately 20 peanuts ) , whereas placebo subjects ( n = 9 ) ingested a median cumulative dose of 280 mg ( range , 0 - 1900 mg ; P < .001 ) . In contrast with the placebo group , the peanut OIT group showed reductions in SPT size ( P < .001 ) , IL-5 ( P = .01 ) , and IL-13 ( P = .02 ) and increases in peanut-specific IgG(4 ) ( P < .001 ) . Peanut OIT subjects had initial increases in peanut-specific IgE ( P < .01 ) but did not show significant change from baseline by the time of OFC . The ratio of forkhead box protein 3 (FoxP3)(hi ) : FoxP3(intermediate ) CD4 + CD25 + T cells increased at the time of OFC ( P = .04 ) in peanut OIT subjects . CONCLUSION These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation . The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance\n\n\nTitle 3:\nSublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization.\nAbstract 3:\nBACKGROUND There are no treatments currently available for peanut allergy . Sublingual immunotherapy ( SLIT ) is a novel approach to the treatment of peanut allergy . OBJECTIVE We sought to investigate the safety , clinical effectiveness , and immunologic changes with SLIT in children with peanut allergy . METHODS In this double-blind , placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind , placebo-controlled food challenge . RESULTS Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge . Dosing side effects were primarily oropharyngeal and uncommonly required treatment . During the double-blind , placebo-controlled food challenge , the treatment group safely ingested 20 times more peanut protein than the placebo group ( median , 1,710 vs 85 mg ; P = .011 ) . Mechanistic studies demonstrated a decrease in skin prick test wheal size ( P = .020 ) and decreased basophil responsiveness after stimulation with 10(-2 ) μg/mL ( P = .009 ) and 10(-3 ) μg/mL ( P = .009 ) of peanut . Peanut-specific IgE levels increased over the initial 4 months ( P = .002 ) and then steadily decreased over the remaining 8 months ( P = .003 ) , whereas peanut-specific IgG4 levels increased during the 12 months ( P = .014 ) . Lastly , IL-5 levels decreased after 12 months ( P = .015 ) . No statistically significant changes were found in IL-13 levels , the percentage of regulatory T cells , or IL-10 and IFN-γ production . CONCLUSION Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy , with evidence of immunologic changes suggesting a significant change in the allergic response . Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance\n\n\nTitle 4:\nTreatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract.\nAbstract 4:\nBACKGROUND Immediate hypersensitivity to peanuts is a frequent cause of anaphylactic reactions and deaths in children and adults . Currently , preventive treatment consists of avoidance , which is difficult because of the widespread and often disguised use of peanuts in the food industry . METHODS Twelve patients with immediate hypersensitivity to ingestion of peanuts were recruited . Half were treated with injections of peanut extract : a maintenance level of tolerance was first achieved by a rush protocol , then maintained with weekly injections for at least 1 year . The other six were untreated control subjects . All patients underwent double-blind , placebo-controlled , oral peanut challenges initially , after approximately 6 weeks , and after 1 year . RESULTS All treated patients achieved the maintenance dose of 0.5 ml of 1:100 wt/vol peanut extract by the rush injection protocol . All experienced increased tolerance to double-blind , placebo-controlled peanut challenge and decreased sensitivity on titrated skin prick testing with peanut extract , whereas the threshold to oral peanut challenge and cutaneous reactivity to peanut extract were unchanged in the untreated control subjects . Systemic reactions were common in the treated group both during rush immunotherapy and with maintenance injections . Only three patients remained tolerant of the full maintenance dose . The increased tolerance to oral peanut challenge was maintained in the three subjects who received full maintenance doses , but there was partial ( n = 2 ) or complete ( n = 1 ) loss of protection in the patients who required dose reduction because of systemic reactions . CONCLUSIONS Injections of peanut extract increase the tolerance of patients with peanut allergy to oral ingestion of peanuts . Injections result in repeated systemic reactions in most patients , even during maintenance injections . For clinical application of this method of treatment , a modified peanut extract is needed\n\n\nTitle 5:\nTreatment of peanut allergy with rush immunotherapy.\nAbstract 5:\nPeanut and peanut products are a common food in the diet . Peanuts are also one of the most common foods responsible for food-induced anaphylaxis . Patients rarely lose sensitivity to peanuts . Although the ideal treatment is avoidance , this is often not possible because of hidden exposures ; therefore , a more effective treatment is needed . Subjects with confirmed peanut allergy were treated in a double-blind , placebo-controlled study with peanut immunotherapy or placebo . Objective measures of efficacy included changes in symptom score during double-blind placebo-controlled peanut challenge ( DBPCPC ) and titrated end point prick skin tests ( PST ) . Three subjects treated with peanut immunotherapy completed the study . These subjects displayed a 67 % to 100 % decrease in symptoms induced by DBPCPC . Subjects also had a 2- to 5-log reduction in end point PST reactivity to peanut extract . One placebo-treated subject completed the study . This subject had essentially no change in DBPCPC symptom scores or PST sensitivity to peanut . Two other placebo-treated subjects underwent a second PST session . These subjects had a 1- to 2-log increase in skin test sensitivity to peanut . All peanut-treated subjects were able to reach maintenance dose , and in no case did an anaphylactic reaction occur secondary to the peanut immunotherapy . The current study provides preliminary data demonstrating the efficacy of injection therapy with peanut extract and provides a future line of clinical investigation for the treatment of this potentially lethal disease . It should be noted , however , that the rate of systemic reactions with rush immunotherapy was 13.3 % . ( ABSTRACT TRUNCATED AT 250 WORDS\n\n\nTitle 6:\nOral and sublingual peanut immunotherapy is not ready for general use.\nAbstract 6:\nFood oral immunotherapy ( OIT ) is an investigational peanut allergy treatment aim ed to achieve specific oral tolerance induction . Allergic children are given titrated oral ( or sublingual ) doses of their allergen on a daily basis , unlike in subcutaneous immunotherapy ( SCIT ) . OIT is theorized to cause a shift from a Th2 to a Th1 regulatory environment , reflected by increases in food-specific IgG4/IgE , and the production of FoxP3 . Peanut OIT holds special promise because peanut allergy has an unfavorable natural history and is rarely outgrown . A high percentage of the participants experience symptoms during peanut OIT , including anaphylaxis , warranting epinephrine and /or discontinuation of therapy . This is a concerning fact given that the studies have mostly targeted only older children , with less historical reactivity for enrollment . The h and ful of peanut OIT studies have shown that some participants can be desensitized to peanut , but none have shown that long-term tolerance can be reestablished . Factors predictive of which patients are most likely to succeed and become desensitized through OIT are unknown . Some private practice s have begun offering peanut OIT as a therapy . Such practice is potentially dangerous given the safety and efficacy of OIT in r and omized controlled clinical trials is still not well established . Therefore , until further investigation emerges that conclusively demonstrates OIT is safe , intermediate and long-term outcomes are better established , the number of participants that experience symptoms is reduced , and proof of concept established in patients of all ages , ( irrespective of past reaction severity ) , OIT is not ready for use in the general allergy practice\n\n\nTitle 7:\nEmergency treatment of anaphylactic reactions--guidelines for healthcare providers.\nAbstract 7:\n* The UK incidence of anaphylactic reactions is increasing . * Patients who have an anaphylactic reaction have life-threatening airway and , or breathing and , or circulation problems usually associated with skin or mucosal changes . * Patients having an anaphylactic reaction should be treated using the Airway , Breathing , Circulation , Disability , Exposure ( ABCDE ) approach . * Anaphylactic reactions are not easy to study with r and omised controlled trials . There are , however , systematic review s of the available evidence and a wealth of clinical experience to help formulate guidelines . * The exact treatment will depend on the patient 's location , the equipment and drugs available , and the skills of those treating the anaphylactic reaction . * Early treatment with intramuscular adrenaline is the treatment of choice for patients having an anaphylactic reaction . * Despite previous guidelines , there is still confusion about the indications , dose and route of adrenaline . * Intravenous adrenaline must only be used in certain specialist setting s and only by those skilled and experienced in its use . * All those who are suspected of having had an anaphylactic reaction should be referred to a specialist in allergy . * Individuals who are at high risk of an anaphylactic reaction should carry an adrenaline auto-injector and receive training and support in its use . * There is a need for further research about the diagnosis , treatment and prevention of anaphylactic reactions", "role": "user" }, { "content": "This study showed a statistically significant benefit of peanut immunotherapy in patients with peanut allergy .", "role": "assistant" } ]

[ { "content": "Given a short query with keyphrases about a research idea in 2017 in the domain of artificial intelligence, recommend the relevant datasets to validate the research idea from the options provided. A short description of the datasets is also provided to help you.\n\nQuery: We propose a self-supervised monocular depth estimation method that exploits the inherent epipolar geometry of the input images\n\nKeyphrases: depth estimation images\n\nDataset description:\nKITTI: KITTI (Karlsruhe Institute of Technology and Toyota Technological Institute) is one of the most popular datasets for use in mobile robotics and autonomous driving. It consists of hours of traffic scenarios recorded with a variety of sensor modalities, including high-resolution RGB, grayscale stereo cameras, and a 3D laser scanner.\nDIODE: Diode Dense Indoor/Outdoor DEpth (DIODE) is the first standard dataset for monocular depth estimation comprising diverse indoor and outdoor scenes acquired with the same hardware setup. The training set consists of 8574 indoor and 16884 outdoor samples from 20 scans each.\nMake3D: The Make3D dataset is a monocular Depth Estimation dataset that contains 400 single training RGB and depth map pairs, and 134 test samples. The RGB images have high resolution, while the depth maps are provided at low resolution.\nDDAD: DDAD is a new autonomous driving benchmark from TRI (Toyota Research Institute) for long range (up to 250m) and dense depth estimation in challenging and diverse urban conditions. It contains monocular videos and accurate ground-truth depth (across a full 360 degree field of view) generated from high-density LiDARs mounted on a fleet of self-driving cars operating in a cross-continental setting.\n\nOptions: A: KITTI B: DIODE C: Make3D D: DDAD", "role": "user" }, { "content": "KITTI", "role": "assistant" } ]

[ { "content": "You will be presented with a citation segment from the section of an NLP research paper, as well as the context surrounding that citation. Classify the intent behind this citation by choosing from one of the following categories:\n- Background: provides context or foundational information related to the topic.\n- Extends: builds upon the cited work.\n- Uses: applies the methods or findings of the cited work.\n- Motivation: cites the work as inspiration or rationale for the research.\n- CompareOrContrast: compares or contrasts the cited work with others.\n- FutureWork: cites the work as a direction for future research.\n\nYour answer should be a single word from the following list of options: [\"Background\", \"Extends\", \"Uses\", \"Motivation\", \"CompareOrContrast\", \"FutureWork\"]. Do not include any other text in your response.\n\nSection Title:\nexperiments\n\nContext before the citation:\nTF is given by TFD,t, and it denotes frequency of term t in document D. IDF is given by IDFt = log(N/dft), where N is the number of documents in the collection, and dft is the number of documents containing the term t. (Salton and Yang, 1973) proposed the combination of TF and IDF as weighting schemes, and it has been shown that their product gave better performance. The importance of each term is assumed to be inversely proportional to the number of documents that contain that term. While the TF measurement concerns the importance of a term in a given document, IDF seeks to measure the relative importance of a term in a collection of documents.\n\nCitation Sentence:\nTF is given by TFD , t , and it denotes frequency of term t in document D. IDF is given by IDFt = log ( N/dft ) , where N is the number of documents in the collection , and dft is the number of documents containing the term t. ( Salton and Yang , 1973 ) proposed the combination of TF and IDF as weighting schemes , and it has been shown that their product gave better performance .\n\nContext after the citation:\nThus, the weight of each term/root in a document is given by wD,t = TFD,t * IDFt. We have conducted five cross validation experiments based on TF-IDF. Experiments are based on selecting, in turn, 50, 100, 500, 1000, and 2000 terms that best represent the predefined 5 categories. We have repeated the experiments in Figure 3 for each number of terms.", "role": "user" }, { "content": "Motivation", "role": "assistant" } ]

[ { "content": "You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.\n\nTitle: Dynamic Conformational Changes in MUNC18 Prevent Syntaxin Binding\nArticle:\nAbstract:\nThe Sec1/munc18 protein family is essential for vesicle fusion in eukaryotic cells via binding to SNARE proteins. Protein kinase C modulates these interactions by phosphorylating munc18a thereby reducing its affinity to one of the central SNARE members, syntaxin-1a. The established hypothesis is that the reduced affinity of the phosphorylated munc18a to syntaxin-1a is a result of local electrostatic repulsion between the two proteins, which interferes with their compatibility. The current study challenges this paradigm and offers a novel mechanistic explanation by revealing a syntaxin-non-binding conformation of munc18a that is induced by the phosphomimetic mutations. In the present study, using molecular dynamics simulations, we explored the dynamics of the wild-type munc18a versus phosphomimetic mutant munc18a. We focused on the structural changes that occur in the cavity between domains 3a and 1, which serves as the main syntaxin-binding site. The results of the simulations suggest that the free wild-type munc18a exhibits a dynamic equilibrium between several conformations differing in the size of its cavity( the main syntaxin-binding site). The flexibility of the cavity's size might facilitate the binding or unbinding of syntaxin. In silico insertion of phosphomimetic mutations into the munc18a structure induces the formation of a conformation where the syntaxin-binding area is rigid and blocked as a result of interactions between residues located on both sides of the cavity. Therefore, we suggest that the reduced affinity of the phosphomimetic mutant/phosphorylated munc18a is a result of the closed-cavity conformation, which makes syntaxin binding energetically and sterically unfavorable. The current study demonstrates the potential of phosphoryalation, an essential biological process, to serve as a driving force for dramatic conformational changes of proteins modulating their affinity to target proteins.\nIntroduction:\nIntracellular membrane fusion in eukaryotes is mediated by a well-conserved fusion machinery composed of SNARE( soluble N-ethylmaleimide-sensitive factor attachment protein receptor) and SM( Sec1/munc18-like) proteins[1]. In the early studies, munc18a was shown to bind syntaxin, one of the central SNARE members and block ternary SNARE complex formation, suggesting that it plays a negative regulatory role[2],[3]. However, genetic and biochemical studies indicated that SM proteins play a positive essential role as demonstrated by their null mutants; studies with mutated worms, flies and mice lacking munc18a, revealed a dramatic decrease in secretory granule fusion, docking and priming[4],[5],[6]. Therefore, the central hypothesis, to date, is that SM proteins play several roles depending on their mode of binding to the SNARE members[7],[8]. The first mode of interaction that was discovered[9] relates to the binding of munc18a to a stable closed-conformation of syntaxin. This mode of interaction allows the specific transfer of syntaxin through the endoplasmic reticulum and the Golgi apparatus to the plasma membrane, keeping syntaxin from engaging to ectopic intracellular SNARE complexes[10],[11]. Recent studies demonstrate that SM proteins bind only or additionally to a short peptide present at the N-terminus of syntaxin, designated as the N-peptide[1],[10],[12]. This mode of interaction was intensively investigated in the last few years and its importance is under a strong debate. One of the main hypotheses for the role of the interaction of munc18a with the N-terminal of syntaxin is that this interaction allows munc18a to bind the SNARE ternary complex suggesting a stimulatory role for munc18a in the last stages of SNARE-mediated fusion[13]. The rat munc18a, which was structurally resolved as part of the complex with syntaxin-1a[9],[12], is an arched-shaped three-domain protein( Figure 1A) that embraces syntaxin in a cavity located between domains 3a and 1( Figure 1, A and B). Phosphorylation by protein kinase C( PKC) or phosphomimetic mutations in residues 306 and 313( S306D, S313D) of munc18a modulate this interaction by reducing the affinity to form a complex[14],[15]. Previous studies have suggested that replacement of the polar serine moieties in domain 3a of munc18a by phosphate groups or negatively charged glutamates disrupts the complex due to electrostatic repulsion between munc18a and the adjacent area of syntaxin( Figure 1B), which contains acidic residues[14]. In the present study, munc18a dynamics was studied, for the first time, using molecular dynamics( MD) simulations under different conditions for several hundred nanoseconds. We show that in the absence of syntaxin, wild-type munc18a exhibits a dynamic equilibrium between several states, differing in the size of the syntaxin-binding site( the cavity between domains 3a and 1). In the next step, we examined the dynamic behavior of the phosphomimetic munc18aS306D, S313D and we show that following in-silico insertion of the mutations into the wild-type structure, munc18a adopted a rigid closed-cavity conformation which makes syntaxin binding less probable. The closed-cavity conformation is induced specifically by the PKC phosphomimetic mutations and reversible upon dephosphorylation of the protein back to the wild-type form.\nDiscussion:\nThe current study reveals, for the first time, new conformations that munc18a can adopt when it is unbounded to syntaxin. Based on a rigorous analysis of a comprehensive set of molecular dynamics simulations we were able to monitor the dynamics of the wild-type free munc18a in comparison to its mutant forms( phosphomimetic, back-mutated and non-phosphorylated mutants), focusing on the structural changes that occur during the trajectories in the main syntaxin-binding site, the cavity between domains 3a and 1. We show that munc18a, in its syntaxin-unbounded form, is in a dynamic equilibrium between conformations varying in the size of its syntaxin-binding cavity located between domains 3a and 1. Specifically, we found that munc18a can adopt a stable conformation where its cavity, serving as the main syntaxin-binding site, is mostly blocked by inter-domain interactions. This conformation is induced following in silico insertion of phosphomimetic mutations in positions 306 and 313( S306D, S313D). We propose that the observed reduction in affinity of munc18a to syntaxin following phosphorylation or insertion of phosphomiemtic mutations as shown experimentally is a result of preferential stabilization of a conformation of munc18a where the syntaxin-binding site is less accessible for syntaxin. This conformation of munc18a makes the binding of syntaxin less probable, and energetically and sterically unfavorable. Our proposed mechanistic explanation is supported by a few studies carried out in the past that already speculated that munc18a might have additional distinct conformations different from the one that was resolved( bound to syntaxin) in the published crystal structure[9],[12]. Previous studies suggested that the munc18a conformations could be induced by interactions with other proteins, such as Rab, Rab effector or munc13[9]. However, to the best of our knowledge, there is no other available resolved conformation( i. e crystal structure) of munc18a. Another indication for the existence of several munc18a conformations is the putative binding site of the protein cyclin-dependent kinase 5( CDK5) in munc18a. CDK5 has been shown to phosphorylate munc18a and to mediate the disassembly of the munc18a-syntaxin-1a complex, with the assistance of other proteins. The site of CDK5-mediated phosphorylation in munc18a is located between domains 2 and 3( residue Thr574). In the crystal structure of the munc18a-syntaxin complex, this region of munc18a is buried in the protein and therefore inaccessible, indicating that CDK5 probably interacts with a different conformation of munc18a that was not determined yet[9],[21]. The closed-cavity conformation of munc18a is specifically induced by the phosphomiemetic mutations; however it is not exclusively present in this mutated form of the protein. Molecular dynamics simulation of another mutated form of munc18a- munc18aF115E[13] showed that the introduction of this mutation induced closure of the cavity as well( Figure 9, A–B). The closure was initiated by a dominant movement of domain 1 towards domain 3a. These results suggest that the closed-cavity conformation can be driven by several types of mutations. The tendency of the protein to form this conformation might be a general mechanism explaining the impaired binding of several mutated forms of munc18a to syntaxin. The established hypothesis attributes the reduced affinity of the phosphorylated munc18a( or the phosphomimetic mutant munc18aS306D, S313D) to syntaxin to the local repulsion of syntaxin by the negative charges of the phosphates( or glutamates) in this region of munc18. This repulsion was suggested to reduce the compatibility and the overall affinity of the complex[14]. The hypothesis presented in the current study, based on extensive molecular dynamics simulation and analyses, challenges this paradigm and suggests that the reduced affinity results from closure of the cavity of munc18a, making it inaccessible for syntaxin binding in this area. Many key biological processes such as the synaptic processes[21],[26] are regulated by protein phosphorylation. In order to understand the effects of this process, it is essential to characterize specifically the structural changes induced by phosphorylation, leading to a change in the affinity of proteins to target proteins. In this study, we followed structural changes that phosphorylation might induce and we were able to provide a novel mechanism for explaining experimental results showing reduced affinity between proteins. As the potential of phosphorylation to induce substantial conformational changes in proteins was already shown in previous studies[27],[28],[29],[30], we suggest that the present conventional paradigm, explaining the reduced affinity of the phosphorylated munc18a to syntaxin as merely a local repulsive phenomenon, is rather simplified. Efforts should be aimed at tracking the global dynamic conformational changes that occur in the phosphorylated munc18a or in other mutated forms of munc18a in attempt to resolve munc18a conformations and in particular the closed-cavity conformation.", "role": "user" }, { "content": "Protein phosphorylation plays a significant regulatory role in multi-component systems engaged in signal transduction or coordination of cellular processes , by activating or deactivating proteins . The potential of phosphorylation to induce substantial conformational changes in proteins , thereby changing their affinity to target proteins , has already been shown but the dynamics of the process is not fully elucidated . In the present study , we investigated , by molecular dynamics simulations , the dynamic conformational changes in munc18a , a protein that is crucial for neurotransmitter release and interacts tightly with the SNARE syntaxin-1 . We further investigated the conformational changes that occur in munc18a when it is phosphorylated , reducing its affinity to syntaxin-1a . The results of the simulations suggest that there is a conformational flexibility of the syntaxin-unbounded munc18a that allows changes in the shape of the syntaxin-1a binding cavity . In silico insertion of phosphomimetic mutations into munc18a led to a reduction in the flexibility and closure of the syntaxin-binding site . We suggest that the reduced affinity of phosphorylated munc18a to syntaxin-1a stems from the difficulty of syntaxin-1a to bind to the munc18a closed-cavity conformation , induced by the PKC phosphorylation of munc18a .", "role": "assistant" } ]

[ { "content": "You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your response other than the answer.\n\nParagraph: Camels are known to produce high levels of MERS-CoV RNA in their URT and lungs [116] . Providing support for a droplet transmission route and perhaps indicating the presence of RNA in smaller, drier droplet nuclei, MERS-CoV RNA was identified in a high volume air sample collected from a barn housing an infected DC [117] . The precise source from which humans acquire MERS-CoV remains poorly studied but it seems likely that animal and human behavioural factors may play roles (Fig. 3) [118] . These factors may prove important for human cases who do not describe any DC contact [119] nor any contact with a confirmed case. Whether the WHO definition of animal contact is sufficient to identify exposure to this respiratory virus remains unclear. Wording focuses on consumption of DC products but does not specifically ascribe risk to a droplet route for acquisition of MERS-CoV from DC [120] . Some MERS patients are listed in WHO disease notices as being in proximity to DCs or farms, but the individuals have not described coming into contact with the animals. No alternative path for acquiring infection is reported in many of these instances. What constitutes a definition of \"contact\" during these interviews has been defined for one study [72] . Despite this lack of clarity, the WHO consider that evidence linking MERS-CoV transmission between DCs to humans is irrefutable (Fig. 4) [120] . The possibility that bats were an animal host of MERS-CoV was initially widely discussed because of the existing diversity of coronaviruses known to reside among them [121] [122] [123] [124] . Conclusive evidence supporting bats as a source for human infections by MERS-CoV has yet to be found, but bats do appear to host ancestral representatives [53, 125] . However, these are not variants of the same virus nor always within the same phylogenetic lineage as MERS-CoV; they are each a genetically distinct virus. Bat-to-human infection by MERS-CoV is a purely speculative event. The only piece of MERS-CoV-specific evidence pointing to bats originates from amplification of a 190 nt fragment of the RNAdependent RNA polymerase gene of the MERS-CoV genome, identified in a faecal pellet from an insectivorous Emballonuridae bat, Taphozous perforatus found in Bisha, the KSA [121] . While very short, the sequence of the fragment defined it as a diagnostic discovery. Subsequently a link to DCs was reported [85] and that link has matured into a verified association [38, 126] (Fig. 4) . (See figure on previous page.) Fig. 3 Monthly detections of MERS-CoV (blue bars) and of cases who died (red bars) with some dates of interest marked for 2012 to 4 th September 2015. An approximation of when DC calving season [128] and when recently born DCs are weaned is indicated. Spring (green) and summer (orange) in the Arabian Peninsula are also shaded. Note the left-hand y-axis scale for 2014 and 2015 which is greater than for 2012/13. Sources of these public data include the WHO, Ministries of Health and FluTrackers [207] [208] [209] . Earlier and subsequent versions of this chart are maintained on a personal blog [210] . Modified and reprinted from Mackay IM, Arden KE. Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd. Virus Res 2015 Vol 202:60-88 with permission from Elsevier [5] DCs, which make up 95 % of all camels, have a central presence in the Arabian Peninsula where human-DC contact ranges from little to close [119] . Contact may be commonplace and could occur in variety of ways (Fig. 4a) . There are several large well-attended festivals, races, sales and parades which feature DCs and DCs are also kept and bred close to populated areas in the KSA [127, 128] . DC milk and meat are widely consumed and the older DC is an animal of ritual significance after the Hajj pilgrimage [129] . However, MERS-CoV infection frequency is reportedly much lower than is the widespread and frequent habit of eating, drinking and preparing DC products. Daily ingestion of fresh unpasteurized DC milk is common among the desert Bedouin and many others in the KSA. DC urine is also consumed or used for supposed health benefits. Despite camel butchery being a local occupation, neither butchers nor other at-risk groups are identifiable among MERS cases; this may simply be a reporting issue rather than an unexplainable absence of MERS. A small case-control study published in 2015 identified direct DC contact, and not ingestion of products, to be associated with onset of MERS [38] . The first sero-survey of livestock living in the Middle East region was conducted during 2012-2013 [85] . DCs were sampled from a mostly Canary Island-born herd and from Omani DCs (originally imported from the Horn of Africa) [85] . A neutralising antibody assay found only 10 % of strongly seropositive Canary Island [5] . b Camel-to-human infections appear to be infrequent, while human-to-human spread of infection is regularly facilitated by poor IPC in healthcare settings where transmission is amplified, accounting for the bulk of cases. There are human MERS cases that do not fall into either category of source and it is unclear if these acquired infection through some entirely separate route, or from cases that escaped diagnosis. c Hypothetical ways in which subclinical (when infection may not meet a previously defined clinical threshold of signs and/or symptoms) or asymptomatic (no obvious signs or measured, noticed or recalled symptoms of illness) MERS-CoV infection may be implicated in transmission DC sera could neutralise MERS-CoV while all Omani DC sera had high levels of specific MERS-CoV neutralizing antibody [85] . This indicated that DCs had in the past been infected by MERS-CoV, or a very similar virus. Since this study, a host of peer-reviewed reports have looked at both DCs and other animals, and the possibility that they may host MERS-CoV infection. Seropositive DCs have been found throughout the Arabian Peninsula including Oman, the KSA, Qatar, Jordan, the United Arab Emirates (UAE), Kuwait as well as Sudan, Somalia, Egypt, Tunisia, Nigeria, Kenya and Ethiopia in Africa and the Canary Islands [85, [130] [131] [132] [133] [134] . Other animals tested include sheep, cows, pigs, horses, donkeys, mules, birds, water buffalo, goats, Bactrian camels, llamas and guanaco (south American camelids) but none had detectable neutralising antibody against MERS-CoV [4, 74, 78, 85, 86, 135, 136] . No virology or serology studies of human samples from areas in Africa where there are camels with a history of MERS-CoV have been reported to date. However,an absence of unexplained pneumonia that may be attributable to MERS-CoV infection may not signal the absence of virus among humans in each country but simply reflect a lack of expensive epidemiology studies conducted by resource-poor countries. It is thus unclear whether MERS-CoV, or an antigenically related CoV, is an unrecognized pathogen in these regions, perhaps circulating for even longer than it has been known in the Arabian Peninsula [133] . MERS-CoV RNA has also been detected in DC samples, and recovery of infectious virus has also been achieved from DC samples [4, 77, 117, 132, [137] [138] [139] [140] [141] . From some of these, full or majority length genomes of MERS-CoV have been sequenced [77, 137, 138] . DC versions of MERS-CoV were found to be as similar to each other, as were variants detected from different humans over time and across distance. Antibody screening assays have also detected crossreactive antibodies in sera. These were identified as such by screening sera against similar viruses, for example BCoV or HCoV-OC43 (as an antigenic facsimile for BCoV). It is possible that other MERS-CoV-like viruses also reside within DCs, but this does not detract from the definitive finding of MERS-CoV genetic sequences in both DCs and humans [117, 142, 143] . Screening studies have shown that juvenile DCs are more often positive for virus or viral RNA while older DCs are more likely to be seropositive and RNA or virus negative [76, 77, 144] . In adult DCs, MERS-CoV RNA has been detected among animals with pre-existing antibody, suggesting re-infection is possible [77, 144] . Viral loads among positive DCs can be very high [4, 76, 77, 139, 144] and DCs have been found positive both when ill with URT respiratory signs [77, 117, 142, 145] or when apparently healthy [137] . These findings indicate DCs host natural MERS-CoV infections. Furthermore, stored DC sera have revealed signs of MERS-CoV in DCs which date back over three decades (the earliest collected in 1983) [4, 133, 135] . Older sera have not been tested and so precisely how long DCs have been afflicted by MERS-CoV, whether the virus is enzootic among them, introduced to them decades or centuries ago from bats in Africa or the Arabian Peninsula, or they are the subject of regular but short-lived viral incursions from an as yet unknown host, cannot be answered. Researchers sought to determine a direction for infection; were DCs transmitting virus to humans or were humans infecting DCs? At a Qatari site, a farm owner and his employee became ill in mid-October 2013 and tested positive for MERS-CoV RNA in a sputum and throat swab sample, respectively. RT-rtPCRs found MERS-CoV RNA in 11 of 14 positive DC nasal swabs at the farm; six (43 %) positive by two or more assays [138] . The results indicated a recent outbreak had occurred in this herd; the first indication of MERS-CoV RNA found within DCs with a temporal association to human infections. Three positive DC samples were confirmed by sequencing a 358 nt portion of the spike gene; these sequences were identical to each other, again with close homology to other human and DC MERS-CoV sequences [138] . The DCs and human contacts yielded ORF1a and ORF4b sequences differing by only a single nucleotide each, clustering closely with the Hafr-Al-Batin_1_2013 variant [138] . Subsequent case studies found evidence of a concurrent human and DC infection and the direction of that infection was inferred to be from the ill DCs and to their human owners [117, 142, 146] . Partial genome sequences indicated that a human and a MERS-CoV RT-rtPCR positive DC had been infected by a variant of the same virus, harbouring the same distinct pattern of nucleotide polymorphisms. [142] All nine DC in the owner's herd, serially sampled, reacted in a recombinant S1 antigen ELISA, with the two animals that had been RT-rtPCR positive showing a small, verifiable rise in antibody titre [142] . A rise in titre theoretically begins 10 to 21 days after DC infection [142] . The authors suggested that the rise in titre in DC sera which occurred alongside a declining RNA load, while the patient was actively ill and hospitalized, indicated that the DCs were infected first followed by the owner [117, 142] . BCoV antibodies were also present, and rising in one of the two RT-rtPCR positive animals but no animal's antibodies could neutralise BCoV infection [142] . Camel calving season occurs in the winter months (between late October and late February; Fig. 3 ) and this may be a time when there is increased risk to humans of spill-over due to new infections among naïve DC populations [128] . What role maternal camel antibody might play in delaying infection of calves remains unknown [128, 142] . Juvenile DCs appear to host active infection more often than adult DCs and thus the sacrificial slaughter of DCs, which must be five years of age or older (termed a thane), may not be accompanied by significant risk of exposure to infection. In contrast to earlier results, slaughterhouse workers who kill both younger and older DCs, may be an occupational group with significantly higher incidence of seropositivity to MERS-CoV when animals have active MERS-CoV infections [129, 139, [147] [148] [149] . Expanded virological investigations of African DCs may lead to more seropositive animals and geographic areas in which humans may be at risk. It is possible that there are areas where humans already harbour MERS-CoV infections that have not been identified because of an absence of laboratory surveillance. Virological investigations of bats may lead to findings of ancestral viruses and viral 'missing links' and identifying any other animal sources of zoonotic spread is important to inform options for reducing human exposures [56, 76] . Infectious MERS-CoV added to DC, goat or cow milk and stored at 4°C could be recovered at least 72 h later and, if stored at 22°C, recovery was possible for up to 48 h [150] . MERS-CoV titre decreased somewhat when recovered from milk at 22°C but pasteurization completely ablated MERS-CoV infectivity [150] . In a subsequent study, MERS-CoV RNA was identified in the milk, nasal secretion and faeces of DCs from Qatar [151] . A single study has examined the ability of MERS-CoV to survive in the environment [150] . Plastic or steel surfaces were inoculated with 10 6 TCID 50 of MERS-CoV at different temperature and relative humidity (RH) and virus recovery was attempted in cell culture. At high ambient temperature (30°C) and low RH (30 %) MERS-CoV remained viable for 24 h [150] . By comparison, a well known and efficently transmitted respiratory virus, influenza A virus, could not be recovered in culture beyond four hours under any conditions [150] . Aerosol experiments found MERS-CoV viability only decreased 7 % at low RH at 20°C. In comparison, influenza A virus decreased by 95 % [150] . MERS-CoV survival is inferior to that previously demonstrated for SARS-CoV [152] . For context, pathogenic bacteria can remain viable and airborne for 45 min\n\nQuestion: How long can pathogenic bacteria remain viable and airborne in a coughed aerosol?", "role": "user" }, { "content": "for 45 min", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nExecutive dysfunction and long-term outcomes of geriatric depression.\nAbstract 1:\nThis study investigated the relationship of executive and memory impairment to relapse, recurrence, and course of residual depressive symptoms and signs after remission of geriatric major depression.\n Fifty-eight elderly subjects remitted from major depression received continuation nortriptyline treatment (plasma levels 60-150 ng/mL) for 16 weeks and then were randomly assigned to either nortriptyline maintenance therapy or placebo for up to 2 years. Diagnosis was made using the Research Diagnostic Criteria and the DSM-IV criteria after an interview using the Schedule for Affective Disorders and Schizophrenia. Executive dysfunction and memory were assessed with the Dementia Rating Scale, disability and social support were rated with the Philadelphia Multiphasic Instrument, and medical burden was assessed with the Cumulative Illness Rating Scale.\n Abnormal initiation and perseveration scores, but not memory impairment, were associated with relapse and recurrence of geriatric depression and with fluctuations of depressive symptoms in the whole group and in subjects who never met criteria for relapse or recurrence during the follow-up period. Memory impairment, disability, medical burden, social support, and history of previous episodes did not significantly influence the outcome of depression in this sample.\n Executive dysfunction was found to be associated with relapse and recurrence of geriatric major depression and with residual depressive symptoms. These observations, if confirmed, will aid clinicians in identifying patients in need of vigilant follow-up. The findings of this study provide the rationale for investigation of the role of specific prefrontal pathways in predisposing or perpetuating depressive syndromes or symptoms in elderly patients.\n\n\nTitle 2:\nEscitalopram prevents relapse in older patients with major depressive disorder.\nAbstract 2:\nThe present study investigated the efficacy and tolerability of escitalopram in the prevention of relapse of major depressive disorder (MDD) in older patients who had responded to acute treatment with escitalopram.\n A total of 405 patients who were aged 65 years or older with a primary diagnosis of MDD (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 22 or more received 12-week, open-label escitalopram 10 or 20 mg per day treatment. Remitters (MADRS </=12) were randomized to 24-week double-blind treatment with escitalopram or placebo. The primary efficacy parameter was the time to relapse, defined as either an increase in MADRS total score to 22 or more or lack of efficacy as judged by the investigator.\n Three hundred five patients achieved remission and were randomly assigned to treatment with escitalopram (N = 152) or placebo (N = 153). The primary analysis showed a clear beneficial effect of escitalopram relative to placebo on the time to relapse (log-rank test, chi(2) = 27.6, df = 1, p <0.001). The risk of relapse was 4.4 times higher for placebo- than for escitalopram-treated patients (chi(2) test, chi(2) = 22.9, df = 1, p <0.001). Significantly fewer escitalopram-treated patients relapsed (9%) compared with placebo (33%) (chi(2) test, chi(2) = 27.1, df = 1, p <0.001). Escitalopram was well tolerated with 53 patients (13%) withdrawn as a result of adverse events during the open-label period and three (2%) escitalopram-treated patients and six (4%) placebo-treated patients during double-blind treatment (not significant). The overall withdrawal rate, excluding relapses, was 7.2% for escitalopram and 8.5% for placebo during the double-blind period (not significant).\n Escitalopram was effective in preventing relapse of MDD in older patients and was well tolerated as continuation treatment.\n\n\nTitle 3:\nOlder community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebo-controlled study.\nAbstract 3:\nDespite a growing use of selective serotonin reuptake inhibitors in older people, only one trial has examined their prophylactic efficacy in people aged 65 years and over.\n To examine the efficacy of sertraline in preventing the recurrence of depression in older people living in the community.\n Participants were openly treated with sertraline and then randomised into a double-blind, placebo-controlled continuation/maintenance study of about 2 years duration. Drug dosage was maintained at levels that achieved remission.\n No significant difference between the sertraline and placebo groups was found in the proportion of recurrences (-7.9%; 95% CI -28.06 to 12.23). Increased age and minor residual symptoms during the continuation phase were associated with recurrence.\n Sertraline at therapeutic dosage does not provide significant protection against recurrence.\n\n\nTitle 4:\nEfficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.\nAbstract 4:\nThe highly recurrent nature of major depression in the young and the elderly warrants long-term antidepressant treatment.\n To compare the prophylactic efficacy of citalopram and placebo in elderly patients; to evaluate long-term tolerability of citalopram.\n Out-patients, > or =65 years, with unipolar major depression (DSM-IV: 296.2 x or 296.3 x) and Montgomery-Asberg Depression Rating Scale score > or =22 were treated with citalopram 20-40 mg for 8 weeks. Responders continued on their final fixed dose of citalopram for 16 weeks before randomisation to double-blind treatment with citalopram or placebo for at least 48 weeks.\n Nineteen of the 60 patients using citalopram v. 41 of the 61 patients using placebo had recurrence. Time to recurrence was significantly different between citalopram- and placebo-patients, in favour of citalopram (log-rank test, P<0.0001). Long-term treatment was well tolerated.\n Long-term treatment with citalopram is effective in preventing recurrence of depression in the elderly and is well tolerated.\n\n\nTitle 5:\nNortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years.\nAbstract 5:\nElderly patients with major depression are at high risk for recurrence, increased mortality, and chronic disability.\n To determine the efficacy of maintenance nortriptyline hydrochloride and interpersonal psychotherapy (IPT) in preventing recurrence of major depressive episodes in patients older than 59 years.\n A 2 x 2 randomized, double-blind, placebo-controlled clinical trial, stratified by therapist.\n University-based psychiatric research clinic.\n Of a total of 187 patients with recurrent nonpsychotic unipolar major depression (average age, 67 years; one third aged > or =70 years) recruited through clinical referral and media announcements, 107 were fully recovered after open acute and treatment continuation with nortriptyline and IPT. These patients were randomly assigned to 1 of 4 maintenance therapy conditions.\n Monthly medication clinic with nortriptyline hydrochloride (80-120 ng/mL steady-state levels) (n = 24); medication clinic with placebo (n = 29); monthly maintenance IPT with placebo (n = 21); and monthly maintenance IPT with nortriptyline (n = 22).\n Recurrence of major depressive episode.\n The time to recurrence of a major depressive episode for all 3 active treatments was significantly better than for placebo. Recurrence rates over 3 years were as follows: nortriptyline and IPT, 20% (95% confidence interval [CI], 4%-36%); nortriptyline and medication clinic visits, 43 % (95% CI, 25%-61%); IPT and placebo, 64% (95% CI, 45%-83%); and placebo and medication clinic visits, 90% (95% CI, 79%-100%). Combined treatment with nortriptyline and IPT was superior to IPT and placebo and showed a trend to superior efficacy over nortriptyline monotherapy (Wald chi2 = 3.56; P = .06). Subjects aged 70 years and older had a higher and more rapid rate of recurrence than those aged 60 to 69 years.\n In geriatric patients with recurrent major depression, maintenance treatment with nortriptyline or IPT is superior to placebo in preventing or delaying recurrence. Combined treatment using both appears to be the optimal clinical strategy in preserving recovery.\n\n\nTitle 6:\nA pilot randomised controlled trial of a brief cognitive behavioural group intervention to reduce recurrence rates in late life depression.\nAbstract 6:\nTo standardise the delivery of a brief group cognitive behaviour therapy intervention (CBT-G). To apply the intervention in a research setting and to estimate its effect on recurrence rates in recently depressed older adults, in preparation for a definitive study.\n A CBT-G therapy manual was produced and the Cognitive Therapy Rating Scale (CTS-R) modified to assess therapy delivery. Forty-five adults aged 60 and over who had met ICD-10 criteria for major depression in the previous year and were still taking antidepressant medication were randomly allocated to CBT-G/antidepressant combination or antidepressant alone. Depression severity was measured at baseline, randomisation and 6 and 12 months after start of CBT-G using the Montgomery Asberg Rating Scale for Depression (MADRS).\n One-year recurrence rates on the MADRS were encouragingly lower in participants receiving CBT-G [5/18 (27.8%)] compared with controls [8/18 (44.4%)] although this did not achieve statistical significance (adjusted RR 0.70 [95% CI 0.26-1.94]). In contrast, overall scores on the secondary outcome measure, the Beck Depression Inventory, increased in participants receiving CBT-G. The CBT-G manual was successfully implemented and therapy delivery achieved an overall satisfactory level of competence. We believe that evaluation of this promising intervention in a full-scale trial is warranted.\n (c) 2008 John Wiley & Sons, Ltd.\n\n\nTitle 7:\nHow long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. Old Age Depression Interest Group.\nAbstract 7:\nOf 219 elderly patients with a major depressive disorder (meeting RDC), 69 recovered sufficiently and consented to enter a two-year double-blind placebo-controlled trial of dothiepin. Survival analysis revealed that dothiepin reduced the relative risk of relapse by two and a half times. Past but not current serious physical illness was also associated with a favourable outcome, whereas a prolonged index depressive illness trebled the relative risk of relapse. In the light of previous research on prognosis it is suggested that elderly persons who recover from a major depressive illness should continue with antidepressant medication for at least two years, if not indefinitely.", "role": "user" }, { "content": "The long-term benefits of continuing antidepressant medication in the prevention of recurrence of depression in older people are not clear and no firm treatment recommendations can be made on the basis of this review. Continuing antidepressant medication for 12 months appears to be helpful but this is based on only three small studies with relatively few participants using differing classes of antidepressants in clinically heterogeneous populations. Comparisons at other time points did not reach statistical significance. Data on psychological therapies and combined treatments are too limited to draw any conclusions.", "role": "assistant" } ]

[ { "content": "You will be shown a question, followed by excerpts from biomedical research papers. Please answer the question based on the provided context. Do not include any text in your response other than the answer.\n\nQuestion: what is the role of GATA-4 in regeneration of the heart after myocardial infarction?\n\nContext: TGF-beta conducted the myogenic differentiation of CD117+ stem cells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the intramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively assisted the myocardial regeneration and induced therapeutic angiogenesis, contributing to functional cardiac regeneration.\nG-CSF treatment also led to activation of signal transducer and activator of transcription-3 and induction of GATA-4 and various sarcomeric proteins such as myosin heavy chain, troponin I and desmin.\nWe describe here the identification of a subpopulation of primitive cells from rat heart, processing stem cell marker, c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, and cardiac specific proteins, troponin-I, alpha-sarcomeric actinin and connexin-43. They exhibited a high in vitro proliferative potential. These findings strongly suggest that these cells are putative cardiomyocyte precursors. After transplantation, they were able to be retained and proliferate (13.63 +/- 5.97% after 2 weeks) within the ischemic heart. Progeny of implanted cells migrated along the infarcted scar, reconstituted regenerated cardiomyocytes with incorporation into host myocardium, and inhibited cardiac remodeling with decreased scar formation.\nHistological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of human specific alpha-cardiac actin. Human alpha cardiac actin-positive cells also expressed cardiac nuclear factors; nkx2.5 and GATA-4. Our results suggest that intracoronary artery transplantation of hCLCs is a potentially effective therapeutic strategy for future cardiac tissue regeneration.\nThis pattern of colocalization was also found in developing embryonic myocardium. Cardiac transcription factors Nkx-2.5 and GATA-4 were strongly expressed in the muscle bundles.\nAfter hypergravity and 5-Aza treatment, BMSCs showed positive for the early muscle and cardiac markers GATA-4, MEF-2, and Nkx2-5 with RT-PCR\nExperiments in murine models of myocardial infarction (MI) demonstrated population of VSELs expressed also early markers of cardiac and endothelial lineages (GATA-4, Nkx2.5/Csx, VE-cadherin, von Willebrand factor) which migrated to stromal-derived factor-1 (SDF-1) and other chemoattractant gradient and underwent rapid mobilization into peripheral blood in experimental MI mice models.\nWe conclude that GATA-4 overexpression in MSCs increased both MSC survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct remodeling.\nThese cardiac c-kit+AT2+ cells, represented approximately 0.19% of total cardiac cells in infarcted heart, were characterized by upregulated transcription factors implicated in cardiogenic differentiation (Gata-4, Notch-2, Nkx-2.5) and genes required for self-renewal (Tbx-3, c-Myc, Akt).\nthese findings suggest G-CSF administration could be an effective approach to treating chronic heart failure following a large MI.", "role": "user" }, { "content": "GATA-4 is implicated in cardiogenic differentiation of cardiac c-kit+AT2+ cells that represent approximately 0.19% of total cardiac cells in infarcted heart. GATA-4 overexpression in mesenchymal stem cells increases both survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct regenaration. In addition, interventions, such as hypergravity and 5-Aza treatment, induce expression of early muscle and cardiac markers like GATA-4 in BMSCs. A subpopulation of primitive cells from rat heart, expressing c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, exhibit a high in vitro proliferative potential. Progeny of these implanted cells have been shown to migrate along the infarcted scar, reconstitute regenerated cardiomyocytes with incorporation into host myocardium, and inhibit cardiac remodeling with decreased scar formation. In another study, TGF-beta has been shown to conduct the myogenic differentiation of stem cells by upregulating GATA-4 and NKx-2.5 expression and the intramyocardial implantation of TGF-beta-preprogrammed stem cells effectively assisted the myocardial regeneration. Furthermore, G-CSF treatment in postinfarcted murine hearts appears to be an effective approach for treating heart failure and also leads to induction of GATA-4 resulting in expression of various sarcomeric proteins.", "role": "assistant" } ]

[ { "content": "You are provided with a research question, keyphrases about the question, a description of candidate datasets and dataset options. Read the description of popular datasets provided below and select the ones that can be used to validate the following research question. Use your knowledge of machine learning datasets to make the best judgement.\nYour response should be formatted as a `json` array. For instance, for the query \"Semi supervised image classification\", a sample response might be: [\"CIFAR-10\", \"CIFAR-100\"]. Do not include any extra text in the response other than the answer array.\n\nQuery: The proposed approach outperforms state-of-the-art baselines on [DATASET] with small batch sizes.\n\nKeyphrases: image classification images\n\nDataset description:\nApolloCar3D: ApolloCar3DT is a dataset that contains 5,277 driving images and over 60K car instances, where each car is fitted with an industry-grade 3D CAD model with absolute model size and semantically labelled keypoints. This dataset is above 20 times larger than PASCAL3D+ and KITTI, the current state-of-the-art.\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.\nAQUA: The question-answer (QA) pairs are automatically generated using state-of-the-art question generation methods based on paintings and comments provided in an existing art understanding dataset. The QA pairs are cleansed by crowdsourcing workers with respect to their grammatical correctness, answerability, and answers' correctness.\nDeepScores: DeepScores contains high quality images of musical scores, partitioned into 300,000 sheets of written music that contain symbols of different shapes and sizes. For advancing the state-of-the-art in small objects recognition, and by placing the question of object recognition in the context of scene understanding.\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.\n\nOptions:- A: ApolloCar3D B: ImageNet C: AQUA D: DeepScores E: COCO", "role": "user" }, { "content": "[\"ImageNet\", \"COCO\"]", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"RNA\", \"CellType\", \"CellLine\", \"Protein\", \"DNA\"].\n\nPlease return the output as a JSON object of the format: {\"DNA\" : [\"TAL1\", ...], \"RNA\": [\"mRNAs\", ...], \"CellLine\": [\"T cells\", ...], \"CellType\": [\"monocytes\", ...], \"Protein\": [\"IL-2\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nalpha-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-kappa B mobilization. The adherence of monocytes to activated endothelium is an early event in atherogenesis. Because antioxidants have been considered to be of antiatherosclerotic potential, we investigated the effects of alpha-tocopherol (TCP) and its acetate and succinate esters on monocyte adhesion to cytokine-stimulated human umbilical vein endothelial cells (HUVEC). Endothelial cells were treated with TCP, alpha-tocopherol acetate (TCP acetate), or alpha-tocopheryl succinate (TCP succinate) before stimulation with tumor necrosis factor-alpha (TNF-alpha; 10 U / ml, 6 h) or interleukin-1 beta (IL-1 beta; 10 U / ml, 6 h). Cytokine-stimulated cell surface expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (ELAM-1, CD62E), but not of intercellular adhesion molecule-1 (ICAM-1, CD54), was time-and dose-dependently inhibited by TCP succinate but not by TCP or TCP acetate. TCP succinate (200 microM, 24 h) reduced TNF-induced VCAM-1 and E-selectin expression from a specific mean fluorescence intensity of 151 + /-28 to 12 + /-4 channels and from 225 + /-38 to 79 + /-21 channels, respectively. Succinate alone had no effect. Decreased adhesion molecule expression was associated with a reduction of monocytic cell adhesion. TCP succinate (20 microM, 72 h), but not TCP (200 microM, 72 h), reduced U-937 cell adhesion to TNF-alpha-stimulated (10 U / ml, 6 h) HUVEC by 30% (P < 0. 025) and to IL-1 beta-stimulated HUVEC by 56% (P < 0. 010). Electrophoretic mobility-shift assays of HUVEC nuclear proteins revealed a decrease in TNF-alpha-stimulated nuclear factor-kappa B (NF-kappa B) activation after pretreatment of HUVEC with TCP succinate but not with TCP, TCP acetate, or succinate alone. In conclusion, we demonstrate that the vitamin E derivative TCP succinate prevents monocytic cell adhesion to cytokine-stimulated endothelial cells by inhibiting the activation of NF-kappa B, further emphasizing the antiatherosclerotic potential of lipid soluble antioxidants.", "role": "user" }, { "content": "{\"CellLine\": [\"U - 937 cell\", \"TNF - alpha - stimulated (10 U / ml , 6 h) HUVEC\", \"cytokine - stimulated human umbilical vein endothelial cells\", \"HUVEC\", \"Endothelial cells\", \"cytokine - stimulated human umbilical vein endothelial cells (HUVEC)\", \"cytokine - stimulated endothelial cells\", \"IL - 1 beta - stimulated HUVEC\"], \"CellType\": [\"monocytes\", \"Endothelial cells\", \"endothelial cells\"], \"DNA\": [], \"Protein\": [\"vascular cell adhesion molecule - 1\", \"CD62E\", \"VCAM - 1\", \"ICAM - 1\", \"TNF - alpha\", \"tumor necrosis factor - alpha\", \"intercellular adhesion molecule - 1\", \"CD54\", \"E - selectin\", \"IL - 1 beta\", \"TNF - alpha - stimulated nuclear factor - kappa B\", \"ELAM - 1\", \"NF - kappa B\", \"nuclear proteins\", \"interleukin - 1 beta\", \"TNF - induced VCAM - 1\", \"CD106\", \"adhesion molecule\"], \"RNA\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with a citation segment from the section of an NLP research paper, as well as the context surrounding that citation. Classify the intent behind this citation by choosing from one of the following categories:\n- Background: provides context or foundational information related to the topic.\n- Extends: builds upon the cited work.\n- Uses: applies the methods or findings of the cited work.\n- Motivation: cites the work as inspiration or rationale for the research.\n- CompareOrContrast: compares or contrasts the cited work with others.\n- FutureWork: cites the work as a direction for future research.\n\nYour answer should be a single word from the following list of options: [\"Background\", \"Extends\", \"Uses\", \"Motivation\", \"CompareOrContrast\", \"FutureWork\"]. Do not include any other text in your response.\n\nSection Title:\nNone\n\nContext before the citation:\nWe further add rules for combining with punctuation to the left and right and allow for the merge rule X → X X of Clark and Curran (2007). \u0000\u0000 We follow Lewis and Steedman (2014) in allowing a small set of generic, linguistically-plausible unary and binary grammar rules. A category (s\\np)/pp might describe an intransitive verb with a prepositional phrase complement; it combines on the right (/) with a constituent with category pp, and then on the left (\\) with a noun phrase (np) that serves as its subject.\n\nCitation Sentence:\nWe further add rules for combining with punctuation to the left and right and allow for the merge rule X → X X of Clark and Curran ( 2007 ) .\n\nContext after the citation:", "role": "user" }, { "content": "Uses", "role": "assistant" } ]

[ { "content": "You are provided with the abstract of a scientific paper and the abstracts of the papers it references. Your task is to write a Related Work section for the main paper. This section should concisely summarize and integrate the key points from the cited abstracts, reflecting how they relate to the main paper's contributions and context. In your summary, use numerical citation markers like [1], [2], etc., to refer to the corresponding papers.\n\nMain Abstract:\nMatrix multiplication @math appears as intermediate operation during the solution of a wide set of problems. In this paper, we propose a new cache-oblivious algorithm for the @math multiplication. Our algorithm, A @math A, calls classical Strassen's algorithm as sub-routine, decreasing the computational cost (expressed in number of performed products) of the conventional @math multiplication to @math . It works for generic rectangular matrices and exploits the peculiar symmetry of the resulting product matrix for sparing memory. We used the MPI paradigm to implement A @math A in parallel, and we tested its performances on a small subset of nodes of the Galileo cluster. Experiments highlight good scalability and speed-up, also thanks to minimal number of exchanged messages in the designed communication system. Parallel overhead and inherently sequential time fraction are negligible in the tested configurations.\n\nCited Abstract(s):\n[1]: Strassen's matrix multiplication (MM) has benefits with respect to any (highly tuned) implementations of MM because Strassen's reduces the total number of operations. Strassen achieved this operation reduction by replacing computationally expensive MMs with matrix additions (MAs). For architectures with simple memory hierarchies, having fewer operations directly translates into an efficient utilization of the CPU and, thus, faster execution. However, for modern architectures with complex memory hierarchies, the operations introduced by the MAs have a limited in-cache data reuse and thus poor memory-hierarchy utilization, thereby overshadowing the (improved) CPU utilization, and making Strassen's algorithm (largely) useless on its own. In this paper, we investigate the interaction between Strassen's effective performance and the memory-hierarchy organization. We show how to exploit Strassen's full potential across different architectures. We present an easy-to-use adaptive algorithm that combines a novel implementation of Strassen's idea with the MM from automatically tuned linear algebra software (ATLAS) or GotoBLAS. An additional advantage of our algorithm is that it applies to any size and shape matrices and works equally well with row or column major layout. Our implementation consists of introducing a final step in the ATLAS GotoBLAS-installation process that estimates whether or not we can achieve any additional speedup using our Strassen's adaptation algorithm. Then we install our codes, validate our estimates, and determine the specific performance. We show that, by the right combination of Strassen's with ATLAS GotoBLAS, our approach achieves up to 30 22 speed-up versus ATLAS GotoBLAS alone on modern high-performance single processors. We consider and present the complexity and the numerical analysis of our algorithm, and, finally, we show performance for 17 (uniprocessor) systems.", "role": "user" }, { "content": "In this work, we consider a particular matrix multiplication, that is the multiplication between @math and @math , where @math may have any size and shape. We exploit the recursive Strassen's algorithm, that is recursively applied to conceivably rectangular matrices, exploiting the idea described in [1] .", "role": "assistant" } ]

[ { "content": "You will be presented with a sentence from biomedical research text. Extract all terms that correspond to chemical entities of biological interest (ChEBI).\nReturn your identified terms in a JSON array, formatted like this: [\"Entity1\", \"Entity2\", ...].\nIf no such entities are detected, respond by providing an empty JSON array [].\n\nBiomedical context:\nTheaccessionnumberforthisgeneisCG40084inBDGP(BerkeleyDrosophilaGenomeProject).", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"UnapprovedDrug\", \"Brand\", \"DrugGroup\", \"Drug\"].\n\nPlease return the output as a JSON object of the format: {\"Brand\": [\"Aspirin\", ...], \"DrugGroup\": [\"Salicylate\", ...], \"Drug\": [\"Phenobarbital\", ...], \"UnapprovedDrug\": [\"Heroin\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nActivity of buforin II alone and in combination with azithromycin and minocycline against Cryptosporidium parvum in cell culture. The in vitro anti-cryptosporidial activity of buforin II alone and in combination with azithromycin and minocycline was investigated. Buforin II showed moderate activity, which increased with increasing concentration to 55.7% suppression of growth at 20 microM. Moreover, its activity was enhanced when it was combined with either azithromycin or minocycline with 90% parasite reduction at the highest concentration tested. Buforin II may be active in inhibiting Cryptosporidium parvum growth in vitro upon combination with either azithromycin or minocycline.", "role": "user" }, { "content": "{\"Brand\": [], \"Drug\": [\"azithromycin\", \"minocycline\"], \"DrugGroup\": [], \"UnapprovedDrug\": [\"buforin II\", \"Buforin II\"]}", "role": "assistant" } ]

[ { "content": "You will be shown a claim about public health and the abstract of a biomedical research paper. Each sentence from the abstract will be on a separate line. Your task is to return a JSON object with two fields:\n\n- \"verdict\": The fact-checking verdict. If the information in the abstract supports the claim, write \"SUPPORT\". If the abstract contradicts the claim, write \"CONTRADICT\". If the abstract does not provide enough information to arrive at a verdict, write \"NEI\" (for \"not enough information\").\n- \"evidence\": An array of sentences providing evidence for the verdict. Please copy all relevant sentences verbatim from the abstract. If the verdict was \"NEI\", then return an empty array.\n\nFor instance, if the model were given the claim \"wearing masks can prevent the spread of COVID\", the output might be:\n{\n \"verdict\": \"SUPPORT\",\n \"evidence\": [\"Our findings indicate that mass mask-wearing reduces the transmission rate for COVID-19.\"]\n}\n\nClaim: Surgical masks don't offer any protection for the wearer against the new coronavirus\n\nAbstract:\nBACKGROUND: Recommendations on masks for preventing coronavirus disease 2019 (COVID-19) vary.\nPURPOSE: To examine the effectiveness of N95, surgical, and cloth masks in community and health care settings for preventing respiratory virus infections, and effects of reuse or extended use of N95 masks.\nDATA SOURCES: Multiple electronic databases, including the World Health Organization COVID-19 database and medRxiv preprint server (2003 through 14 April 2020; surveillance through 2 June 2020), and reference lists.\nSTUDY SELECTION: Randomized trials of masks and risk for respiratory virus infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and observational studies of mask use and coronavirus infection risk were included.\nNew evidence will be incorporated by using living review methods.\nDATA EXTRACTION: One reviewer abstracted data and assessed methodological limitations; a second reviewer provided verification.\nDATA SYNTHESIS: 39 studies (18 randomized controlled trials and 21 observational studies; 33 867 participants) were included.\nNo study evaluated reuse or extended use of N95 masks.\nEvidence on SARS-CoV-2 was limited to 2 observational studies with serious limitations.\nCommunity mask use was possibly associated with decreased risk for SARS-CoV-1 infection in observational studies.\nIn high- or moderate-risk health care settings, observational studies found that risk for infection with SARS-CoV-1 and Middle East respiratory syndrome coronavirus probably decreased with mask use versus nonuse and possibly decreased with N95 versus surgical mask use.\nRandomized trials in community settings found possibly no difference between N95 versus surgical masks and probably no difference between surgical versus no mask in risk for influenza or influenza-like illness, but compliance was low.\nIn health care settings, N95 and surgical masks were probably associated with similar risks for influenza-like illness and laboratory-confirmed viral infection; clinical respiratory illness had inconsistency.\nBothersome symptoms were common.\nLIMITATIONS: There were few SARS-CoV-2 studies, observational studies have methodological limitations, and the review was done by using streamlined methods.\nCONCLUSION: Evidence on mask effectiveness for respiratory infection prevention is stronger in health care than community settings.\nN95 respirators might reduce SARS-CoV-1 risk versus surgical masks in health care settings, but applicability to SARS-CoV-2 is uncertain.\nPRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.", "role": "user" }, { "content": "{\"verdict\": \"CONTRADICT\", \"evidence\": [\"Community mask use was possibly associated with decreased risk for SARS-CoV-1 infection in observational studies.\", \"In high- or moderate-risk health care settings, observational studies found that risk for infection with SARS-CoV-1 and Middle East respiratory syndrome coronavirus probably decreased with mask use versus nonuse and possibly decreased with N95 versus surgical mask use.\", \"CONCLUSION: Evidence on mask effectiveness for respiratory infection prevention is stronger in health care than community settings.\"]}", "role": "assistant" } ]

[ { "content": "You will be shown sections from a scientific research paper, together with a question about the paper. This is an extractive question-answering task, where you must find and extract relevant text spans directly from the paper to answer the question. Your response should strictly be a `json` object with two fields:\n\n\"answer\": An array of strings extracted directly from the paper which, collectively, answer the question.\n\"evidence\": An array of strings. Each should be an excerpt from the paper, in which one or more of the extracted answers can be found.\n\nFor example, for the question \"What baselines did the authors compare against?\", a sample response might be:\n{\n \"answer\": [\"BERT\", \"RoBERTa\"],\n \"evidence\": [\"In our experiments, we compare the performance of our model against BERT and RoBERTa.\"]\n}\n\nDo not include any text in your response other than the json.\n\nIf the question is unanswerable given the provided excerpts, respond with the single word \"null\".\n\nPaper: Attentional Encoder Network for Targeted Sentiment Classification\n\nTargeted sentiment classification aims at determining the sentimental tendency towards specific targets. Most of the previous approaches model context and target words with RNN and attention. However, RNNs are difficult to parallelize and truncated backpropagation through time brings difficulty in remembering long-term patterns. To address this issue, this paper proposes an Attentional Encoder Network (AEN) which eschews recurrence and employs attention based encoders for the modeling between context and target. We raise the label unreliability issue and introduce label smoothing regularization. We also apply pre-trained BERT to this task and obtain new state-of-the-art results. Experiments and analysis demonstrate the effectiveness and lightweight of our model.\n\nRelated Work\nThe research approach of the targeted sentiment classification task including traditional machine learning methods and neural networks methods.\nTraditional machine learning methods, including rule-based methods BIBREF9 and statistic-based methods BIBREF10 , mainly focus on extracting a set of features like sentiment lexicons features and bag-of-words features to train a sentiment classifier BIBREF11 . The performance of these methods highly depends on the effectiveness of the feature engineering works, which are labor intensive.\nIn recent years, neural network methods are getting more and more attention as they do not need handcrafted features and can encode sentences with low-dimensional word vectors where rich semantic information stained. In order to incorporate target words into a model, Tang et al. tang2016effective propose TD-LSTM to extend LSTM by using two single-directional LSTM to model the left context and right context of the target word respectively. Tang et al. tang2016aspect design MemNet which consists of a multi-hop attention mechanism with an external memory to capture the importance of each context word concerning the given target. Multiple attention is paid to the memory represented by word embeddings to build higher semantic information. Wang et al. wang2016attention propose ATAE-LSTM which concatenates target embeddings with word representations and let targets participate in computing attention weights. Chen et al. chen2017recurrent propose RAM which adopts multiple-attention mechanism on the memory built with bidirectional LSTM and nonlinearly combines the attention results with gated recurrent units (GRUs). Ma et al. ma2017interactive propose IAN which learns the representations of the target and context with two attention networks interactively.\n\nProposed Methodology\nGiven a context sequence INLINEFORM0 and a target sequence INLINEFORM1 , where INLINEFORM2 is a sub-sequence of INLINEFORM3 . The goal of this model is to predict the sentiment polarity of the sentence INLINEFORM4 over the target INLINEFORM5 .\nFigure FIGREF9 illustrates the overall architecture of the proposed Attentional Encoder Network (AEN), which mainly consists of an embedding layer, an attentional encoder layer, a target-specific attention layer, and an output layer. Embedding layer has two types: GloVe embedding and BERT embedding. Accordingly, the models are named AEN-GloVe and AEN-BERT.\n\nEmbedding Layer\nLet INLINEFORM0 to be the pre-trained GloVe BIBREF12 embedding matrix, where INLINEFORM1 is the dimension of word vectors and INLINEFORM2 is the vocabulary size. Then we map each word INLINEFORM3 to its corresponding embedding vector INLINEFORM4 , which is a column in the embedding matrix INLINEFORM5 .\nBERT embedding uses the pre-trained BERT to generate word vectors of sequence. In order to facilitate the training and fine-tuning of BERT model, we transform the given context and target to “[CLS] + context + [SEP]” and “[CLS] + target + [SEP]” respectively.\n\nTarget-specific Attention Layer\nAfter we obtain the introspective context representation INLINEFORM0 and the context-perceptive target representation INLINEFORM1 , we employ another MHA to obtain the target-specific context representation INLINEFORM2 by: DISPLAYFORM0 \n The multi-head attention function here also has its independent parameters.\n\nOutput Layer\nWe get the final representations of the previous outputs by average pooling, concatenate them as the final comprehensive representation INLINEFORM0 , and use a full connected layer to project the concatenated vector into the space of the targeted INLINEFORM1 classes. DISPLAYFORM0 \n where INLINEFORM0 is the predicted sentiment polarity distribution, INLINEFORM1 and INLINEFORM2 are learnable parameters.\n\nRegularization and Model Training\nSince neutral sentiment is a very fuzzy sentimental state, training samples which labeled neutral are unreliable. We employ a Label Smoothing Regularization (LSR) term in the loss function. which penalizes low entropy output distributions BIBREF14 . LSR can reduce overfitting by preventing a network from assigning the full probability to each training example during training, replaces the 0 and 1 targets for a classifier with smoothed values like 0.1 or 0.9.\nFor a training sample INLINEFORM0 with the original ground-truth label distribution INLINEFORM1 , we replace INLINEFORM2 with DISPLAYFORM0 \n where INLINEFORM0 is the prior distribution over labels , and INLINEFORM1 is the smoothing parameter. In this paper, we set the prior label distribution to be uniform INLINEFORM2 .\nLSR is equivalent to the KL divergence between the prior label distribution INLINEFORM0 and the network's predicted distribution INLINEFORM1 . Formally, LSR term is defined as: DISPLAYFORM0 \nThe objective function (loss function) to be optimized is the cross-entropy loss with INLINEFORM0 and INLINEFORM1 regularization, which is defined as: DISPLAYFORM0 \n where INLINEFORM0 is the ground truth represented as a one-hot vector, INLINEFORM1 is the predicted sentiment distribution vector given by the output layer, INLINEFORM2 is the coefficient for INLINEFORM3 regularization term, and INLINEFORM4 is the parameter set.\n\nDatasets and Experimental Settings\nWe conduct experiments on three datasets: SemEval 2014 Task 4 BIBREF15 dataset composed of Restaurant reviews and Laptop reviews, and ACL 14 Twitter dataset gathered by Dong et al. dong2014adaptive. These datasets are labeled with three sentiment polarities: positive, neutral and negative. Table TABREF31 shows the number of training and test instances in each category.\nWord embeddings in AEN-GloVe do not get updated in the learning process, but we fine-tune pre-trained BERT in AEN-BERT. Embedding dimension INLINEFORM0 is 300 for GloVe and is 768 for pre-trained BERT. Dimension of hidden states INLINEFORM1 is set to 300. The weights of our model are initialized with Glorot initialization BIBREF16 . During training, we set label smoothing parameter INLINEFORM2 to 0.2 BIBREF14 , the coefficient INLINEFORM3 of INLINEFORM4 regularization item is INLINEFORM5 and dropout rate is 0.1. Adam optimizer BIBREF17 is applied to update all the parameters. We adopt the Accuracy and Macro-F1 metrics to evaluate the performance of the model.\n\nModel Comparisons\nIn order to comprehensively evaluate and analysis the performance of AEN-GloVe, we list 7 baseline models and design 4 ablations of AEN-GloVe. We also design a basic BERT-based model to evaluate the performance of AEN-BERT.\n \nNon-RNN based baselines:\n INLINEFORM0 Feature-based SVM BIBREF18 is a traditional support vector machine based model with extensive feature engineering.\n INLINEFORM0 Rec-NN BIBREF0 firstly uses rules to transform the dependency tree and put the opinion target at the root, and then learns the sentence representation toward target via semantic composition using Recursive NNs.\n INLINEFORM0 MemNet BIBREF19 uses multi-hops of attention layers on the context word embeddings for sentence representation to explicitly captures the importance of each context word.\n \nRNN based baselines:\n INLINEFORM0 TD-LSTM BIBREF1 extends LSTM by using two LSTM networks to model the left context with target and the right context with target respectively. The left and right target-dependent representations are concatenated for predicting the sentiment polarity of the target.\n INLINEFORM0 ATAE-LSTM BIBREF3 strengthens the effect of target embeddings, which appends the target embeddings with each word embeddings and use LSTM with attention to get the final representation for classification.\n INLINEFORM0 IAN BIBREF4 learns the representations of the target and context with two LSTMs and attentions interactively, which generates the representations for targets and contexts with respect to each other.\n INLINEFORM0 RAM BIBREF5 strengthens MemNet by representing memory with bidirectional LSTM and using a gated recurrent unit network to combine the multiple attention outputs for sentence representation.\n \nAEN-GloVe ablations:\n INLINEFORM0 AEN-GloVe w/o PCT ablates PCT module.\n INLINEFORM0 AEN-GloVe w/o MHA ablates MHA module.\n INLINEFORM0 AEN-GloVe w/o LSR ablates label smoothing regularization.\n INLINEFORM0 AEN-GloVe-BiLSTM replaces the attentional encoder layer with two bidirectional LSTM.\n \nBasic BERT-based model:\n INLINEFORM0 BERT-SPC feeds sequence “[CLS] + context + [SEP] + target + [SEP]” into the basic BERT model for sentence pair classification task.\n\nMain Results\nTable TABREF34 shows the performance comparison of AEN with other models. BERT-SPC and AEN-BERT obtain substantial accuracy improvements, which shows the power of pre-trained BERT on small-data task. The overall performance of AEN-BERT is better than BERT-SPC, which suggests that it is important to design a downstream network customized to a specific task. As the prior knowledge in the pre-trained BERT is not specific to any particular domain, further fine-tuning on the specific task is necessary for releasing the true power of BERT.\nThe overall performance of TD-LSTM is not good since it only makes a rough treatment of the target words. ATAE-LSTM, IAN and RAM are attention based models, they stably exceed the TD-LSTM method on Restaurant and Laptop datasets. RAM is better than other RNN based models, but it does not perform well on Twitter dataset, which might because bidirectional LSTM is not good at modeling small and ungrammatical text.\nFeature-based SVM is still a competitive baseline, but relying on manually-designed features. Rec-NN gets the worst performances among all neural network baselines as dependency parsing is not guaranteed to work well on ungrammatical short texts such as tweets and comments. Like AEN, MemNet also eschews recurrence, but its overall performance is not good since it does not model the hidden semantic of embeddings, and the result of the last attention is essentially a linear combination of word embeddings.\n\nModel Analysis\nAs shown in Table TABREF34 , the performances of AEN-GloVe ablations are incomparable with AEN-GloVe in both accuracy and macro-F1 measure. This result shows that all of these discarded components are crucial for a good performance. Comparing the results of AEN-GloVe and AEN-GloVe w/o LSR, we observe that the accuracy of AEN-GloVe w/o LSR drops significantly on all three datasets. We could attribute this phenomenon to the unreliability of the training samples with neutral sentiment. The overall performance of AEN-GloVe and AEN-GloVe-BiLSTM is relatively close, AEN-GloVe performs better on the Restaurant dataset. More importantly, AEN-GloVe has fewer parameters and is easier to parallelize.\nTo figure out whether the proposed AEN-GloVe is a lightweight alternative of recurrent models, we study the model size of each model on the Restaurant dataset. Statistical results are reported in Table TABREF37 . We implement all the compared models base on the same source code infrastructure, use the same hyperparameters, and run them on the same GPU .\nRNN-based and BERT-based models indeed have larger model size. ATAE-LSTM, IAN, RAM, and AEN-GloVe-BiLSTM are all attention based RNN models, memory optimization for these models will be more difficult as the encoded hidden states must be kept simultaneously in memory in order to perform attention mechanisms. MemNet has the lowest model size as it only has one shared attention layer and two linear layers, it does not calculate hidden states of word embeddings. AEN-GloVe's lightweight level ranks second, since it takes some more parameters than MemNet in modeling hidden states of sequences. As a comparison, the model size of AEN-GloVe-BiLSTM is more than twice that of AEN-GloVe, but does not bring any performance improvements.\n\nConclusion\nIn this work, we propose an attentional encoder network for the targeted sentiment classification task. which employs attention based encoders for the modeling between context and target. We raise the the label unreliability issue add a label smoothing regularization to encourage the model to be less confident with fuzzy labels. We also apply pre-trained BERT to this task and obtain new state-of-the-art results. Experiments and analysis demonstrate the effectiveness and lightweight of the proposed model.\n\nFigure 1: Overall architecture of the proposed AEN.\n\nTable 1: Statistics of the datasets.\n\nTable 2: Main results. The results of baseline models are retrieved from published papers. Top 2 scores are in bold.\n\nTable 3: Model sizes. Memory footprints are evaluated on the Restaurant dataset. Lowest 2 are in bold.\n\nQuestion: How is their model different from BERT?", "role": "user" }, { "content": "{\"answer\": [\"overall architecture of the proposed Attentional Encoder Network (AEN), which mainly consists of an embedding layer, an attentional encoder layer, a target-specific attention layer, and an output layer.\"], \"evidence\": [\"Figure FIGREF9 illustrates the overall architecture of the proposed Attentional Encoder Network (AEN), which mainly consists of an embedding layer, an attentional encoder layer, a target-specific attention layer, and an output layer. Embedding layer has two types: GloVe embedding and BERT embedding. Accordingly, the models are named AEN-GloVe and AEN-BERT.\"]}", "role": "assistant" } ]

[ { "content": "You will be presented with a paragraph from a COVID-19 literature. Your task is to classify the topics of this piece of text by choosing from the following categories:\n\n- Epidemic Forecasting: The content relates to predictions about the spread of COVID-19.\n- Treatment: The paragraph discusses therapeutic methods or medication for COVID-19.\n- Prevention: The content covers measures to prevent the spread of COVID-19.\n- Mechanism: The paragraph explains the biological mechanisms of the virus.\n- Case Report: The content is a report of a COVID-19 case.\n- Transmission: The paragraph discusses how COVID-19 is transmitted.\n- Diagnosis: The content is about diagnosing COVID-19 in individuals.\n\nYour classification should be provided as an element within a JSON array. The array should be formatted with topics enclosed in double quotes and separated by commas, following the JSON format, for example: [\"Topic1\", \"Topic2\", ...]. Include all applicable categories within the array. \nYour output should be a valid JSON array, and no additional text should be included in your response.\n\nArticle:\n\nFor various infectious diseases, vaccination has become a major intervention strategy. However, the importance of social distancing has recently been highlighted during the ongoing COVID-19 pandemic. In the absence of vaccination, or when vaccine efficacy is poor, social distancing may help to curb the spread of new virus strains. However, both vaccination and social distancing are associated with various costs. It is critical to consider these costs in addition to the benefits of these strategies when determining the optimal rates of application of control strategies. We developed a game-theoretic epidemiological model that considers vaccination and social distancing under the assumption that individuals pursue the maximization of payoffs. By using this model, we identified the individually optimal strategy based on the Nash strategy when both strategies are available and when only one strategy is available. Furthermore, we determined the relative costs of control strategies at which individuals preferentially adopt vaccination over social distancing (or vice versa).", "role": "user" }, { "content": "[\"Prevention\", \"Treatment\"]", "role": "assistant" } ]

[ { "content": "You will be shown a claim about public health and the abstract of a biomedical research paper. Each sentence from the abstract will be on a separate line. Your task is to return a JSON object with two fields:\n\n- \"verdict\": The fact-checking verdict. If the information in the abstract supports the claim, write \"SUPPORT\". If the abstract contradicts the claim, write \"CONTRADICT\". If the abstract does not provide enough information to arrive at a verdict, write \"NEI\" (for \"not enough information\").\n- \"evidence\": An array of sentences providing evidence for the verdict. Please copy all relevant sentences verbatim from the abstract. If the verdict was \"NEI\", then return an empty array.\n\nFor instance, if the model were given the claim \"wearing masks can prevent the spread of COVID\", the output might be:\n{\n \"verdict\": \"SUPPORT\",\n \"evidence\": [\"Our findings indicate that mass mask-wearing reduces the transmission rate for COVID-19.\"]\n}\n\nClaim: the risk of death from COVID-19 is up to 50 percent higher in people with diabetes than in those without it.\n\nAbstract:\nSome comorbidities are associated with severe coronavirus disease (Covid-19) but it is unclear whether some increase susceptibility to Covid-19.\nIn this case-control Mexican study we found that obesity represents the strongest predictor for Covid-19 followed by diabetes and hypertension in both sexes and chronic renal failure in females only.\nActive smoking was associated with decreased odds of Covid-19.\nThese findings indicate that these comorbidities are not only associated with severity of disease but also predispose for getting Covid-19.\nFuture research is needed to establish the mechanisms involved in each comorbidity and the apparent \"protective\" effect of cigarette smoking.", "role": "user" }, { "content": "{\"verdict\": \"NEI\", \"evidence\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should only include the abstract and no additional text.\n\nPaper text:\na 54-year - old insulin dependent diabetic female presented to a district hospital , where she was found to be in diabetic ketoacidotic coma ( dka ) , with peri - orbital cellulitis and neurological impairment .\non arrival at the referral hospital , the ent surgeons elicited a two - day history of right sided facial and eye swelling , associated with progressively decreasing vision of the right eye .\nthe patient was hiv negative and had no other medical or surgical history of note besides diabetes mellitus . on physical examination\n, she was found to be well orientated with a glascow coma scale of 15/15 , blood pressure of 102/52 mm / hg , a pulse rate of 112 and a respiratory rate of 15 .\nshe was noted to have an extensive right sided periorbital cellulitis with marked proptosis of the right eye .\nopthalmological examination of the right eye , revealed opthalmoplegia ( frozen eye ) with mild chemosis , a clear cornea and lens , with the presence of a pale optic disc .\nthe patient was assessed as having irreversible blindness of the right eye secondary to optic atrophy . on neurological examination , she was found to have multiple cranial nerve palsies , involving cranial nerves 4 , 5 , 6 , 7 , 8 and 9 .\nroutine laboratory investigations revealed a glucose level of 12.5 mmol / l with 1 + ketones present on urine dipstick testing .\nthe c reactive protein was raised to 38 , whilst the full blood count , urea and electrolytes , and liver function tests were all within normal ranges .\nan urgent computerized tomography ( ct ) scan of the paranasal sinuses showed partial opacification of the right maxillary , bilateral ethmoid and right sphenoid sinuses , with a possible filling defect of the right cavernous sinus . in view of these findings\nthe patient was booked for an emergency endoscopic antrostomy for debridement of the necrotic tissue , as well as an external fronto - ethmoidectomy ( efe ) .\nintra - operative findings revealed extensive right sided intra - nasal necrotic tissue requiring autoethmoidectomy .\nalthough the mucosa of the superior turbinate had a dusky appearance , it remained intact .\nthe normal anatomy of the sphenoid sinus was distorted and there was difficulty accessing the ostium .\nantrostomy of the right maxillary sinus revealed a large defect in the wall caused by the disease process .\nefe revealed that the frontal sinus was clear with no evidence of pus or mucosal damage . in light of these intra operative findings\n, the patient was commenced empirically on intravenous amphotericin b. the patient was clinically stable post operatively . however , on consultation with the neurologist , a ct scan of the brain was ordered to exclude a possible infarct in the temporal lobe .\nct scan findings showed a right medial hypodensity with possible early cerebritis . a magnetic resonance imaging ( mri ) of the brain\nwas therefore requested and showed extensive sinus disease involving the orbit with spread to the extra ocular muscles . a non enhancing hypo - density of the right temporal lobe , representing ischaemia was seen .\nintra - operative specimens from the right nasal cavity , middle turbinate and maxillary sinus were submitted to the laboratory for histology and microbiological investigation .\nmicroscopy of these specimens revealed broad , aseptate hyphae suggestive of zygomycetes sp . and thin , septate hyphae with dichotomous branching suggestive of aspergillus sp\nhistology confirmed invasive co - infection with rhizopus sp . and aspergillus sp . while in hospital\nintra - operative findings revealed extensive bony and tissue necrosis of the septum , lamina papyracae and maxillary sinus .\nall necrotic and non - viable tissue was debrided and biopsies were taken from the septum and inferior turbinate .\nmicrobiology and histology of intra operative specimens were negative for both rhizopus sp . and aspergillus sp .\nintra operative findings included crusts involving the right nasal cavity and maxillary sinus with an anterior septal perforation .\nonce again , specimens received at the laboratory did not reveal any fungi on microscopy and culture .\nthe patient remained clinically stable and the ct prior to discharge revealed residual disease in right nasal cavity and sphenoid .\na naso - endoscopy was performed which revealed right sided crusting due to possible inadequate douching .\nthe patient completed 4 weeks of amphotericin b and was thereafter discharged on oral posaconazole 200 mg three times daily . on\nfollow up 6 weeks later , the irreversible blindness in the right eye as well as cranial nerve palsies were still present .\nacute invasive fungal sinusitis is an aggressive disease seen particularly in immunocompromised individuals with neutropenia , hiv and diabetes mellitus .\nmortality rates remains very high , especially if the diagnosis and appropriate management is not timely instituted .\netiological agents responsible for invasive fungal sinusitis include aspergillus spp . ; that are more commonly seen in patients with neutropenia ; and zygomycetes ( rhizopus spp . , mucor spp . , absidia spp . ) that are more commonly seen in diabetic patients , particularly in the setting of dka as was seen in this patient .\ninvasive fungal infections of the oro - rhinocerebral area , due to mixed mucormycosis and aspergillosis infections have rarely been reported , , , , .\nthe disease is acquired by inhalation of fungal spores into the nasal cavity with subsequent invasion of the sinus mucosa .\nfever , headache and nasal congestion , accompanied by facial pain and swelling are the earliest symptoms reported .\ndisease thereafter rapidly progresses with extensive involvement of the cavernous sinus , orbit or intracranial compartment .\nsubsequently , peri - orbital cellulitis , restriction of ocular movements , ptosis , proptosis and visual deterioration due to occlusion of the central retinal artery may follow , which is highlighted in this case report , .\ndiagnosis is currently dependent on microscopy and culture as well as histological examination of specimens , .\nhowever , microscopic identification of fungal species is highly dependent on the quantity and quality of hyphae present .\nidentification of mixed fungal infections is even more challenging , as illustrated in this case , wherein , the mixed infection resulted in only the rhizopus sp .\nthis was attributed to the rapid growth of rhizopus , which hindered the growth of aspergillus sp .\nthis illustrates the important role that initial direct microscopy plays in making the diagnosis of mixed fungal infections .\nthe introduction of molecular techniques that use broad - range pcr amplification and reverse line blot hybridization ( pcr / rlb ) also allow for the detection and differentiation of mixed fungal infections .\nalthough these molecular methods have the advantage of providing a rapid diagnosis ; they are not freely available in low resource countries . in the diagnosis of invasive sinusitis ,\nct is sensitive for the detection of changes in the ostium ; however mri remains superior for the evaluation of intracranial and intraorbital extension .\nthese investigations were an integral part of the management in this patient . a combination of early surgical intervention , appropriate antifungal therapy and the correction of underlying causes such as metabolic acidosis improves prognosis . in addition\n, serial endoscopic debridements have been shown to improve cure rates , as was illustrated in this patient .\na disadvantage is that it can only be administered parenterally and is also potentially nephrotoxic .\nposaconozole is the only triazole with activity against both rhizopus sp . and aspergillus sp . .\nits availability in oral formulations has facilitated the outpatient management of patients with severe fungal disease .\nthis case highlights the importance of close liaison between clinicians and the laboratory in the management of rare and complicated infections .", "role": "user" }, { "content": "we report on an unusual case of oro - rhinocerebral disease caused by mucormycosis and aspergillus co - infection in a 54-year - old insulin dependent diabetic patient . \n although she was successfully treated with parenteral amphotericin b followed by oral posaconazole , she was left with irreversible blindness of the right eye and multiple cranial nerve palsies .", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Finding\", \"Bacterium\", \"ProfessionalOrOccupationalGroup\", \"InjuryOrPoisoning\", \"Eukaryote\", \"BodySystem\", \"Virus\", \"ResearchActivity\", \"BodySubstance\", \"PopulationGroup\", \"Chemical\", \"AnatomicalStructure\", \"SpatialConcept\", \"HealthCareActivity\", \"Organization\", \"BiomedicalOccupationOrDiscipline\", \"Food\", \"ClinicalAttribute\", \"MedicalDevice\", \"BiologicFunction\", \"IntellectualProduct\"].\n\nPlease return the output as a JSON object of the format: {\"Virus\": [\"HIV\", ...], \"Bacterium\": [\"MRSA\", ...], \"AnatomicalStructure\": [\"Lung\", ...], \"BodySystem\": [\"CNS\", ...], \"BodySubstance\": [\"Serum\", ...], \"Finding\": [\"Headache\", ...], \"InjuryOrPoisoning\": [\"Fracture\", ...], \"BiologicFunction\": [\"Death\", ...], \"HealthCareActivity\": [\"Biopsy\", ...], \"ResearchActivity\": [\"Clinical trial\", ...], \"MedicalDevice\": [\"Lenses\", ...], \"SpatialConcept\": [\"Camps\", ...], \"BiomedicalOccupationOrDiscipline\": [\"Forensic medicine\", ...], \"Organization\": [\"WHO\", ...], \"ProfessionalOrOccupationalGroup\": [\"Provider\", ...], \"PopulationGroup\": [\"Swimmers\", ...], \"Chemical\": [\"Gold\", ...], \"Food\": [\"Rice\", ...], \"IntellectualProduct\": [\"RPAM\", ...], \"ClinicalAttribute\": [\"Biomarker\", ...], \"Eukaryote\": [\"Dogs\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nPrescribing Patterns in Outpatient Clinics of Township Hospitals in China: A Comparative Study before and after the 2009 Health System Reform Objective: China introduced a series of health reforms in 2009, including a national essential medicines policy and a medical insurance system for primary care institutions. This study aimed to determine the changing prescribing patterns associated with those reforms in township hospitals. Methods: A multi-stage stratified random cluster sampling method was adopted to identify 29 township hospitals from six counties in three provinces. A total of 2899 prescriptions were collected from the participating township hospitals using a systematic random sampling strategy. Seven prescribing indicators were calculated and compared between 2008 and 2013, assessing use of medicines (antibiotics and adrenal corticosteroids) and polypharmacy, administration route of medicines (injections), and affordability of medicines. Results: Significant changes in prescribing patterns were found. The average number of medicines and costs per- prescription dropped by about 50%. The percentage of prescriptions requiring antibiotics declined from 54% to 38%. The percentage of prescriptions requiring adrenal corticosteroid declined from 14% to 4%. The percentage of prescriptions requiring injections declined from 54% to 25%. Despite similar changing patterns, significant regional differences were observed. Conclusions: Significant changes in prescribing patterns are evident in township hospitals in China. Overprescription of antibiotics, injections and adrenal corticosteroids has been reduced. However, salient regional disparities still exist. Further studies are needed to determine potential shifts in the risk of the inappropriate use of medicines from primary care settings to metropolitan hospitals.", "role": "user" }, { "content": "{\"AnatomicalStructure\": [], \"Bacterium\": [], \"BiologicFunction\": [], \"BiomedicalOccupationOrDiscipline\": [], \"BodySubstance\": [], \"BodySystem\": [], \"Chemical\": [\"adrenal corticosteroid\", \"antibiotics\", \"medicines\", \"adrenal corticosteroids\"], \"ClinicalAttribute\": [], \"Eukaryote\": [], \"Finding\": [\"medical insurance\", \"prescribing indicators\", \"polypharmacy\"], \"Food\": [], \"HealthCareActivity\": [\"Overprescription\"], \"InjuryOrPoisoning\": [], \"IntellectualProduct\": [\"prescriptions\", \"prescription\"], \"MedicalDevice\": [], \"Organization\": [\"Outpatient Clinics\", \"primary care institutions\", \"hospitals\", \"metropolitan hospitals\", \"Hospitals\", \"primary care settings\"], \"PopulationGroup\": [], \"ProfessionalOrOccupationalGroup\": [], \"ResearchActivity\": [\"systematic random sampling strategy\", \"study\", \"stratified random cluster sampling method\", \"Comparative Study\"], \"SpatialConcept\": [\"regional\", \"China\", \"counties\", \"provinces\"], \"Virus\": []}", "role": "assistant" } ]

[ { "content": "You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should only include the abstract and no additional text.\n\nPaper text:\nbowen 's disease is synonymous with squamous cell carcinoma in situ and was originally described by james t. bowen in 1912 .\nit is a disease of old age ( median age of presentation is 6/7 decade of life ) with slight female predilection [ 2 , 3 ] .\nthe most common sites of affliction are head and neck ( 29 - 54% ) and scalp ( with a predilection towards male ) is involved in around 20% of the cases .\ndiagnosis is made clinically based on typical findings of an erythematous , ill - defined , hyperkeratotic plaque like lesion , and additional help of dermoscopy is often sought .\na punch biopsy is done , if a confirmation is required in doubtful or recurrent / refractory cases .\nthe risk of progression to invasive squamous cell carcinoma has been reported to be 3 - 5% based on retrospective reviews , but it has been reported to be as high as 20% in some studies [ 5 , 6 ] .\nno standard treatment exists and the treatment of bowen 's disease is widely variable . the usual treatment approach is to use non - invasive topical therapies and reserve other treatments for recurrent / refractory cases . however , treatment options for recurrent / refractory lesion particularly large sized lesions and lesions at difficult sites like lower extremity or scalp are very limited . surgical excision in these cases not only has poor wound healing rates , but also is cosmetically unacceptable .\nradiation therapy has been used in these cases with excellent local control and cosmetic outcome [ 810 ] .\nvarying radiation treatment techniques has been used , but the reports of computed tomography ( ct ) based high dose rate ( hdr ) brachytherapy for the treatment of bowen 's disease of scalp is limited . we report treatment of a large recurrent bowen 's disease of scalp refractory to topical therapy and not amenable to surgical excision with ct based customized hdr ( remote after - loaded iridium-192 ) surface mold brachytherapy .\na 46-year - old female presented with a non - healing , erythematous ulcer on the left side of her scalp for one year to the department of dermatology in our institute .\nshe complained of purulent discharge from the lesion off and on , but there was no history of pain , itching or photosensitivity .\nno history of trauma to the local site , chronic sun exposure or any chemical exposure could be elicited .\nthere was no history of any co - morbidities or immunosupression ( history of recurrent infections , organ transplant etc . ) . at the time of presentation to dermatology department in 2008 ,\na 1 cm 1 cm erythematous lesion with erosion and purulent crust was noted on the antero - lateral aspect of the left scalp .\nno similar lesion or other lesion was noted in any other muco - cutaneous sites and systemic examination did not reveal any abnormality .\npatient was started on fluticasone ( steroid ) and mupirocin ( antibiotic ) and the lesion resolved , but re - appeared after 3 months . at this time\n, she complained of itching , purulent discharge from the lesion and also burning sensation on sun exposure .\nlesion size was 2.5 cm 2.5 cm ( erythematous with purulent crusting ) and a skin biopsy was ordered at this point ( june 2009 ) .\nshe received topical 5% 5-florouracil ( in august 2009 ) and had non - complete resolution of the lesion .\nsubsequently , the lesion progressed to a size of 5 cm 5 cm and 0.1% topical tacrolimus was tried with minimal response . in view of recurrent nature , a repeat biopsy was done in january 2012 , which again revealed same histology .\nshe was started on 5% imiquimod , to which she developed dermatitis and could not tolerate it well .\nshe also intermittently received steroids , antibiotics , sun protectants etc . throughout this course of treatment\nin view of intolerance to therapy / non - responsiveness and progression of the lesion , she was referred to our department in july 2013 .\na ) the epidermis show irregular acanthosis with loss of normal maturation pattern ( h&e 4 ) .\nb ) focally the epidermal abnormality also extending into the follicular infandibulam ( h&e 10 ) .\nc ) marked cellular disarray in the epidermis with no evidence of invasion ( h&e 20 ) .\nd ) the neoplastic cells showing moderate degree of pleomorphism and high nucleo - cytoplasmic ratio .\nfrequent mitotic figures are seen ( arrow ) ( h&e 40 ) she was evaluated jointly by a radiation oncologist and surgical oncologist . at presentation to us , she had complains of pain , itching , and purulent discharge from the lesion , with exacerbation of symptoms since the last 6 months . on examination , she had a 15 cm 10 cm erythematous , hyperpigmented , crusted plaque in the superior and antero - lateral aspect of the left side of scalp with well defined irregular border and extension to forehead ( fig .\nhematological parameters were normal and hiv ( human immunodeficiency virus ) was non - reactive .\nsurgery was deferred in view of large lesion size , cosmetic and reconstructive issues , and patient 's un - willingness .\na decision was taken to treat the patient with radiotherapy after discussion with the patient and after an informed consent .\nd ) eight weeks after completion of treatment a customized thermoplastic immobilization cast of the head was made .\nflexible plastic brachytherapy catheters ( 12 catheters at a distance of 1 cm from each other ) inserted between layers of wax was pasted in close contact with the thermoplastic cast ( fig .\ncomputed tomography scan ( 3 mm thickness ) was acquired and a lead wire was also placed around the circumference of the lesion ( before the assembled cast was applied ) for proper delineation of the treatment area .\nthe planning ct scan was transferred to oncentra treatment planning system ( nucletron , an elekta company , elekta ab , stockholm , sweden ) .\nclinical target volume ( ctv ) was delineated based on the markers and clinical findings .\norgans at risk including brain parenchyma , bones of skull , eyes , lens , optic nerves , optic chiasm , and brainstem was also delineated on serial ct slices ( fig .\ndwell positions were created with spacing of 5 mm and normalization was done using catheter points .\na dose of 35 gy was prescribed in 10 fractions ( 2 fractions per day , 6 hours apart )\n. lesion coverage factor was 0.951 ( tvri [ volume of target covered by the reference isodose line]/tv [ target volume ] ) .\nbrain parenchyma received a mean dose of 0.39 gy / fraction and dose to whole brain was 0.07 gy / fraction of treatment .\ntreatment was administered using an iridium-192 source ( microselectron hdr , nucletron , an elekta company , elekta ab , stockholm , sweden ) ( fig .\nfigure 2b shows the clinical picture at completion of the treatment . at 2 weeks after completion of the treatment ( fig .\n2c ) , healthy granulation tissue with partial resolution of the lesion was appreciable along with alopecia in the adjacent area .\nalopecia was resolved in the adjacent area and there is no evidence of radiation dermatitis or ulceration .\norange arrow shows the brachytherapy catheters with lead wire and green arrows show the lead wire around the lesion placed to delineate the treatment area .\nc ) isodose lines ( green color shows 80% and red color shows 100% isodose lines ) for the treatment .\nd ) shows patient being treated on remote after loading hdr brachytherapy unit doses values to the oars oars organ at risk , dmax maximum point dose received by organ patient is asymptomatic 14 months post treatment and reports cosmesis as excellent . however , in view of chances of late recurrences and secondary malignancy , she needs to be on long term follow up .\nthe treatment of bowen 's disease ranges from observation , topical therapies , surgery to radiotherapy based on a number of factors including lesion site , lesion size , thickness of lesion , patient 's age , and preference , availability of therapeutic modalities , and physician 's choice of treatment . of the local therapies , 5% fluorouracil cream [ 12 , 13 ] and 5% imiquimod [ 14 ,\nthirty - eight percent of patients in a study by mackenzie - wood et al . discontinued 5% imiquimod because of side effects of treatment .\ntreatment of bowen 's disease of scalp , which is refractory to topical therapies is challenging .\nsurgical resections , particularly of large lesions are not only cosmetically unacceptable , but are also associated with increased wound complication rates .\nchemotherapy or other systemic therapies are usually not indicated for localized premalignant or malignant lesions of scalp .\nradiation therapy remains an underutilized treatment option for this disease and is often called in to action when all other treatment options have failed or is not possible .\nradiation therapy for bowen 's disease is not new and is particularly suited for the patients with large , recurrent or multiple tumors at cosmetically sensitive body sites , and more so in patients who refuse surgery or are predisposed to keloids .\nradiation therapy for lower extremity has been associated with poor wound healing . in a study by dupree et al . [ 10 , 17 ] , 25% of the patients had unhealed lesions after radiotherapy and all of them belonged to lower extremity .\nscalp is a difficult site to be treated with radiation therapy owing to its irregular convex contour and its predisposition towards poor wound healing .\nlimited studies have explored the role of external beam radiotherapy for bowen 's disease of scalp .\ntwenty percent patients ( 9 patients ) in the study by lukas vanderspek et al . had lesions of scalp .\nthe median biologically effective dose used in this study was 49.3 gy ( range : 26.4 - 65.3 gy ) .\nradiation therapy has been used in doses ranging from 25 - 70 gy with dose per fraction ranging from 2 - 5 gy .\ndose per fraction more than 4 gy has been associated with impaired healing and a dose per fraction less than this should always be encouraged .\nwe , in our study , used a dose of 35 gy at 3.5 gy per fraction and achieved an excellent outcome .\ntreatment of superficial skin tumors with mold brachytherapy technique dates back to 1989 by ashby et al . .\nthese authors treated 642 patients of non - melanoma skin malignancies using wax molds loaded with radon sources .\nmold brachytherapy has been tried for sites like oral cavity and mold based surface brachytherapy has been used for scalp irradiation for leukemic infiltrates of the scalp by liebmann et al . .\nreported their experience of 200 patients of non - melanoma skin cancers treated with hdr brachytherapy using a special applicator ( leipzig surface applicator ) , and reported an excellent local control rate ( 98% ) and good to excellent cosmesis ( 88% ) at a median follow up of 66 months ( range 25 - 121 months ) .\ndescribed results of 32 patients ( with 45 non - melanoma skin cancers ) treated with valencia applicator with hdr brachytherapy and reported a 98% local control rate at a median follow up of 47 months .\ndescribed ct based hdr surface mold brachytherapy technique for three unfavorably localized malignant lesion and have described in detail the process of manufacturing individual applicator .\nbased plan helps to more clearly visualize the coverage of intended treatment area and also evaluate irradiation of underlying critical structure .\nthe time points of evaluation of toxicities and cosmesis in hdr surface mold brachytherapy is also important .\nstudy by guix et al . illustrates the temporal patterns of treatment complication and cosmesis .\nskin toxicities should be evaluated at longer time points of 6 - 12 weeks , as most of the reactions settle and cosmesis is best evaluated . in this study by guix et al .\n, cosmesis was good or excellent in only 38% of patients at 2 weeks and was 98% at 3 months post completion of treatment . also , no definite guidelines exist to grade reactions in surface mold brachytherapy .\nhowever , the definition used by lukas vanderspek et al . seems to be reasonable to use . grade 4 toxicity in this study\nwas defined as necrosis ( cartilage / bone damage ) and/or ulceration for a duration of > 3 months . in our patient\nalso , the reaction subsided only by 4 weeks of treatment and complete resolution was seen roughly 6 weeks after the completion of treatment . yet another innovative approach to treat areas of face ( eyelids , nose , lips etc . )\nis the application of a specially designed radioactive skin patch coated with high energy beta - emitter holmium-166 .\nused this approach to treat bowen 's disease of face in eight patients ( 29 sites ) with complete resolution in all patients at 1 - 5 months .\nthe patches were topically applied for 30 - 60 minutes for a total radiation dose of 35 gy .\nall patients developed desquamation , erythema or erosion after 1 - 2 weeks of treatment , but all at good functional and cosmetic outcomes later on .\nin conclusion , based on the available evidence , radiation therapy is a highly effective therapy for bowen 's disease of the scalp .\ncustomized ct based hdr surface mold brachytherapy with iridium-192 is well tolerated , highly reproducible , suited for accurate dose calculation and optimization , is associated with acceptable short term radiation morbidity , and an excellent outcome in terms of local control and cosmesis .\nit 's non - hesitant use should be considered in all patients responding poorly to topical therapies , particularly for cosmetically sensitive areas of body like scalp .", "role": "user" }, { "content": "our case is a 46-year - old female presenting to us with bowen 's disease of scalp since 5 years . \n patient had failed topical therapy with 5% 5-florouracil , 0.1% tacrolimus and was intolerant to topical imiquimod . at presentation \n , she had 15 cm 10 cm erythematous , hyperpigmented , crusted plaque with irregular border in the superior and lateral aspect of left side of scalp with extension in to forehead . \n patient was treated with computed tomography based customized surface mold high dose rate brachytherapy with iridium-192 to a dose of 35 gy in 10 fractions ( twice daily , 6 hours apart ) over 5 days . \n patient tolerated the treatment well and showed regression of the lesion with mild dermatitis at the end of treatment . \n though dermatitis increased at 2 weeks , at 4 weeks post treatment there was near complete resolution of the lesion with adjacent alopecia . at 8 weeks after completion of the treatment , there was complete resolution of the lesion and patient was asymptomatic . \n alopecia in the adjacent area has resolved and the skin pigmentation has begun . \n patient is satisfied with both the disease control and the cosmetic outcome of the procedure . \n our case report demonstrates successful application of surface mold high dose rate brachytherapy in the treatment of recurrent bowen 's disease of the scalp . \n brachytherapy can play an important role in the management of recurrent malignant and premalignant diseases of the complex treatment sites like scalp and it 's non - hesitant use should be encouraged in appropriately selected patients at the earliest .", "role": "assistant" } ]

[ { "content": "You will be shown a claim about public health and the abstract of a biomedical research paper. Each sentence from the abstract will be on a separate line. Your task is to return a JSON object with two fields:\n\n- \"verdict\": The fact-checking verdict. If the information in the abstract supports the claim, write \"SUPPORT\". If the abstract contradicts the claim, write \"CONTRADICT\". If the abstract does not provide enough information to arrive at a verdict, write \"NEI\" (for \"not enough information\").\n- \"evidence\": An array of sentences providing evidence for the verdict. Please copy all relevant sentences verbatim from the abstract. If the verdict was \"NEI\", then return an empty array.\n\nFor instance, if the model were given the claim \"wearing masks can prevent the spread of COVID\", the output might be:\n{\n \"verdict\": \"SUPPORT\",\n \"evidence\": [\"Our findings indicate that mass mask-wearing reduces the transmission rate for COVID-19.\"]\n}\n\nClaim: public should wear face masks to combat COVID-19\n\nAbstract:\nWe present two models for the COVID-19 pandemic predicting the impact of universal face mask wearing upon the spread of the SARS-CoV-2 virus--one employing a stochastic dynamic network based compartmental SEIR (susceptible-exposed-infectious-recovered) approach, and the other employing individual ABM (agent-based modelling) Monte Carlo simulation--indicating (1) significant impact under (near) universal masking when at least 80% of a population is wearing masks, versus minimal impact when only 50% or less of the population is wearing masks, and (2) significant impact when universal masking is adopted early, by Day 50 of a regional outbreak, versus minimal impact when universal masking is adopted late.\nThese effects hold even at the lower filtering rates of homemade masks.\nTo validate these theoretical models, we compare their predictions against a new empirical data set we have collected that includes whether regions have universal masking cultures or policies, their daily case growth rates, and their percentage reduction from peak daily case growth rates.\nResults show a near perfect correlation between early universal masking and successful suppression of daily case growth rates and/or reduction from peak daily case growth rates, as predicted by our theoretical simulations.\nOur theoretical and empirical results argue for urgent implementation of universal masking.\nAs governments plan how to exit societal lockdowns, it is emerging as a key NPI; a\"mouth-and-nose lockdown\"is far more sustainable than a\"full body lockdown\", on economic, social, and mental health axes.\nAn interactive visualization of the ABM simulation is at http://dek.ai/masks4all.\nWe recommend immediate mask wearing recommendations, official guidelines for correct use, and awareness campaigns to shift masking mindsets away from pure self-protection, towards aspirational goals of responsibly protecting one's community.", "role": "user" }, { "content": "{\"verdict\": \"SUPPORT\", \"evidence\": [\"We present two models for the COVID-19 pandemic predicting the impact of universal face mask wearing upon the spread of the SARS-CoV-2 virus--one employing a stochastic dynamic network based compartmental SEIR (susceptible-exposed-infectious-recovered) approach, and the other employing individual ABM (agent-based modelling) Monte Carlo simulation--indicating (1) significant impact under (near) universal masking when at least 80% of a population is wearing masks, versus minimal impact when only 50% or less of the population is wearing masks, and (2) significant impact when universal masking is adopted early, by Day 50 of a regional outbreak, versus minimal impact when universal masking is adopted late.\", \"We recommend immediate mask wearing recommendations, official guidelines for correct use, and awareness campaigns to shift masking mindsets away from pure self-protection, towards aspirational goals of responsibly protecting one's community.\"]}", "role": "assistant" } ]

[ { "content": "You will be presented with a citation segment from the section of an NLP research paper, as well as the context surrounding that citation. Classify the intent behind this citation by choosing from one of the following categories:\n- Background: provides context or foundational information related to the topic.\n- Extends: builds upon the cited work.\n- Uses: applies the methods or findings of the cited work.\n- Motivation: cites the work as inspiration or rationale for the research.\n- CompareOrContrast: compares or contrasts the cited work with others.\n- FutureWork: cites the work as a direction for future research.\n\nYour answer should be a single word from the following list of options: [\"Background\", \"Extends\", \"Uses\", \"Motivation\", \"CompareOrContrast\", \"FutureWork\"]. Do not include any other text in your response.\n\nSection Title:\nNone\n\nContext before the citation:\nIn practice, perceptron-type algorithms are often applied in a batch learning scenario, i.e., the algorithm is applied for K epochs to a training sample of size T and then used for prediction on an unseen test set (Freund and Schapire, 1999; Collins, 2002). Generalization for Online-to-Batch Conversion. The generalization bound tells us how far the expected average regret E[REGT] (or average risk, in terms of Cesa-Bianchi et al. (2004)) is from the average regret that we actually observe in a specific instantiation of the algorithm.\n\nCitation Sentence:\nIn practice , perceptron-type algorithms are often applied in a batch learning scenario , i.e. , the algorithm is applied for K epochs to a training sample of size T and then used for prediction on an unseen test set ( Freund and Schapire , 1999 ; Collins , 2002 ) .\n\nContext after the citation:\nThe difference to the online learning scenario is that we treat the multi-epoch algorithm as an empirical risk minimizer that selects a final weight vector wT,K whose expected loss on unseen data we would like to bound. We assume that the algorithm is fed with a sequence of examples x1, ... , xT, and at each epoch k = 1, ... , K it makes a prediction yt,k. The correct label is y∗t . For k = 1, ... , K and t = 1, ... , T, let `t,k = U(xt, y∗t ) − U(xt, yt,k), and denote by Δt,k and ξt,k the distance at epoch k for example t, and the slack at epoch k for example t, respectively.", "role": "user" }, { "content": "CompareOrContrast", "role": "assistant" } ]

[ { "content": "Given an abstract from a research paper, your task is to identify and label relationships between chemical compounds and genes mentioned in the abstract.\n\nThe relationship type must be one of ['DOWNREGULATOR', 'SUBSTRATE', 'INDIRECT-REGULATOR', 'PART-OF', 'MODULATOR-ACTIVATOR', 'REGULATOR', 'INHIBITOR', 'COFACTOR', 'UPREGULATOR', 'ACTIVATOR', 'ANTAGONIST', 'NOT', 'INDIRECT-DOWNREGULATOR', 'SUBSTRATE_PRODUCT-OF', 'INDIRECT-UPREGULATOR', 'AGONIST', 'PRODUCT-OF', 'MODULATOR', 'DIRECT-REGULATOR', 'UNDEFINED', 'AGONIST-INHIBITOR', 'AGONIST-ACTIVATOR', 'MODULATOR-INHIBITOR'].\n\nPlease format your output as a JSON array. Each entry in the array should express a single relation, formatted as [\"<Entity_A>\", \"<RELATION_A_B>\", \"<Entity_B>\"]. If no relations can be found, please output an empty JSON array [].\n\nAbstract:\n\nAlbiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D). DATA SOURCES: A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide. References were reviewed to identify additional sources. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included. DATA SYNTHESIS: Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety. Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing. Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents. Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from -0.55% to -0.9%. Noninferiority was not achieved when compared to liraglutide and pioglitazone. Weight changes ranged from + 0.28 to -1.21 kg. The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions. CONCLUSION: Albiglutide is the fourth GLP-1 RA approved in the United States. Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide. It has not been compared head to head with other GLP-1 RAs.", "role": "user" }, { "content": "[]", "role": "assistant" } ]

[ { "content": "You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.\n\n\n\nTitle 1:\nBetter correction of metabolic acidosis, blood pressure control, and phagocytosis with bicarbonate compared to lactate solution in acute peritoneal dialysis.\nAbstract 1:\nLactate solution has been the standard dialysate fluid for a long time. However, it tends to convert back into lactic acid in poor tissue-perfusion states. The aim of this study was to evaluate the efficacy of magnesium (Mg)- and calcium (Ca)-free bicarbonate solution compared with lactate solution in acute peritoneal dialysis (PD). Renal failure patients who were indicated for dialysis and needed acute PD were classified as shock and nonshock groups, and then were randomized to receive either bicarbonate or lactate solution. Twenty patients were enrolled in this study (5 in each subgroup). In the shock group, there were more rapid improvements and significantly higher levels of blood pH (7.40 +/- 0.04 versus 7.28 +/- 0.05, p < 0.05), serum bicarbonate (23.30 +/- 1.46 versus 18.37 +/- 1.25 mmol/L, p < 0.05), systolic pressure (106.80 +/- 3.68 versus 97.44 +/- 3.94 mm Hg, p < 0.05), mean arterial pressure (80.72 +/- 2.01 versus 73.28 +/- 2.41 mm Hg, p < 0.05), percentages of phagocytosis of circulating leukocytes (65.85% +/- 2.22 versus 52.12% +/- 2.71, p < 0.05), and percentages of positive nitroblue tetrazolium (NBT) reduction test without and with stimulation (14.43 +/- 1.93 versus 9.43 +/- 2.12, p < 0.05 and 65.08 +/- 6.80 versus 50.23 +/- 4.21, p < 0.05, respectively) in the bicarbonate subgroup compared with the lactate subgroup. In the nonshock group, blood pH, serum bicarbonate, and phagocytosis assays in both subgroups were comparable. Lactic acidosis was more rapidly recovered and was significantly lower with bicarbonate solution for both shock and nonshock groups (3.63 +/- 0.37 versus 5.21 +/- 0.30 mmol/L, p < 0.05 and 2.92 +/- 0.40 versus 3.44 +/- 0.34 mmol/L, p < 0.05, respectively). Peritoneal urea and creatinine clearances in both subgroups were comparable for both shock and nonshock groups. There was no peritonitis observed during the study. Serum Mg and Ca levels in the bicarbonate subgroup were significantly lower, but no clinical and electrocardiographic abnormality were observed. We concluded that Mg- and Ca-free bicarbonate solution could be safely used and had better outcomes in correction of metabolic acidosis, blood pressure control, and nonspecific systemic host defense with comparable efficacy when compared to lactate solution. It should be the dialysate of choice for acute PD especially in the poor tissue-perfusion states such as shock, lactic acidosis, and multiple organ failure.", "role": "user" }, { "content": "There is no strong evidence that any clinical advantage for patients requiring acute PD for AKI when comparing conventional (lactate) with low GDP dialysis solutions (bicarbonate).", "role": "assistant" } ]

[ { "content": "You will be shown an abstract from a biomedical research paper. Given this abstract, your task is to extract all unique entities of the following types: [\"Disease\"].\n\nPlease return the output as a JSON object of the format: {\"Disease\": [\"COVID-19\", ...]}. The keys should be entity types and values should be lists of extracted entities belonging to the corresponding type. If you cannot find entities belonging to a specific type, the value should be [].\n\nOnly output the JSON object and do not include any additional text.\n\nAbstract:\n\nHypopigmentation in the Prader-Willi syndrome. Cutaneous and ocular pigmentation were evaluated in 29 individuals with the Prader-Willi syndrome (PWS). Criteria for hypopigmentation included the presence of type I or II skin, the lightest skin type in the family by history, and iris translucency on globe transillumination. On the basis of these criteria, 48% of the PWS individuals were hypopigmented. The presence of hypopigmentation correlated with a small interstitial deletion on the proximal long arm of chromosome 15; however, this deletion was also found in individuals who did not meet the full criteria for hypopigmentation. Hairbulb tyrosinase activity and glutathione content, as well as urine cysteinyldopa excretion, were low in PWS individuals with and without hypopigmentation and did not separate these two groups. We conclude that hypopigmentation is found in a significant proportion of individuals with PWS and that the hypopigmentation may be associated with a deletion of the long arm of chromosome 15. The mechanism for the hypopigmentation is unknown..", "role": "user" }, { "content": "{\"Disease\": [\"Prader-Willi syndrome\", \"hypopigmented\", \"Hypopigmentation\", \"PWS\", \"Cutaneous and ocular pigmentation\", \"hypopigmentation\"]}", "role": "assistant" } ]