dataesr/scientific-paragraphs-categorization huggingface dataset:
The  Rotterdam Study  is funded by  Erasmus MC and Erasmus University, Rotterdam ,  Netherlands ; Organization for the  Health Research and Development (ZonMw) , the  Research Institute for Diseases in the Elderly (RIDE) , the  Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports , the  European Commission (DG XII) , and the  Municipality of Rotterdam. SENSE-COG  consortium has received funding from the  European Union 's  Horizon 2020 research and innovation program  under grant agreement No  668648. Stichting Lijf en Leven ,  Krimpen aan de Lek; MD Fonds , Utrecht;  Rotterdamse Vereniging Blindenbelangen ,  Rotterdam ;  Stichting Oogfonds Nederland, Utrecht; Blindenpenning, Amsterdam; Blindenhulp, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht; Swart van Essen, Rotterdam; Stichting Winckel-Sweep, Utrecht; Henkes Stichting, Rotterdam; Laméris Ootech BV, Nieuwegein; Medical Workshop, de Meern ;  Topcon Europe BV, Capelle aan de IJssel , all in the Netherlands, and  Heidelberg Engineering, Dossenheim, Germany.
Also supported by the  NWO   Graduate Programme 2010 BOO  ( 022. 002. 023 ;HS), the  National Institute of Health (Bethesda, MD)  Grants  R01 EY019112  and  R01 EY018853 ,  Veterans Administration Grant   I01 CX000119 , and the  Arnold and Mabel Beckman Initiative for Macular Research. TwinsUK phenotyping was funded by the  International Glaucoma Association  (2013 research award) and the  Wellcome Trust. Supported by the  National Institute for Health Researchefunded Bio-Resource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust  in partnership with King's  College London. R. P. F. 's research group receives funding from the  Else Kröner-Fresenius-Stiftung  ( GSO/EKFS 16 ) and the  Jackstädt Stiftung. HUMAN SUBJECTS: Human subjects, human-derived materials, or human medical records were part of this study protocol.
25 to 1. 50 mA. All patients signed an informed consent. The study was approved by the institutional ethics committee (11-CHUG-28) and registered in ClinicalTrials. gov (Identifier: NCT01569503; First received: March 30, 2012). The primary endpoint was to induce clinical remission (CDAI< 150) and the secondary endpoints to induce biological and endoscopic remission and restore vagal tone. The first patient was implanted on April 2012 and the last one on March 2016. All the patients entered in a one year follow-up study. Only two patients were under azathioprine (2. 5 mg/kg) on inclusion. VNS induced a deep (clinical-biological-endoscopical) remission in 5 of the nine patients with restored vagal tone. The patient on remission on inclusion was still in deep remission under VNS alone at 1 year.
VNS was well tolerated with the classical minor side effect represented essentially by hoarseness. We did not observe any problem of infection either local or systemic and no VNS device was removed. The data on the first seven implanted patients after a 6-month follow-up were recently reported for the first time  (Bonaz et al. , 2016). In a second pilot study (SetPoint Medical Corporation, ClinicalTrials. gov Identifier: NCT02311660; First received: December 3, 2014), D  'Haens et al. (D'Haens et al. , 2016)  have reported in an abstract form the effect of VNS for 16 weeks in 8 patients with biologicrefractory small bowel and/or colonic CD. Patients had a moderate to severe CD (220 < CDAI< 450) on inclusion, a CRP ≥ 5 mg/L, a fecal calprotectin ≥200 μg/g, an endoscopic score of activity (SES-CD: Simple Endoscopic Scale for Crohn's Disease, an endoscopic score correlated with the CDEIS) with the presence of a minimal ulcer score of 2 or 3 in at least 1 segment, with a history of inadequate response and/or intolerance or adverse events to one or more TNF-alpha inhibitors (e.
Results: A database of 230 cox1 sequences belonging to 42 Afrotropical Culicoides species was found to be reliable for species-level assignments, which enabled us to identify cox1 sequences of Culicoides larvae from the Niayes area of Senegal. Of the 933 cox1 sequences of Culicoides larvae analyzed, 906 were correctly identified by their barcode sequences corresponding to eight species of Culicoides. A total of 1131 cox1 sequences of adult and larval Culicoides were analyzed, and a hierarchical increase in mean divergence was observed according to two taxonomic levels: within species (mean = 1. 92%, SE = 0. 00), and within genus (mean = 17. 82%, SE = 0. 00). Conclusions: Our study proves the efficiency of DNA barcoding for studying Culicoides larval diversity in field samples. Such a diagnostic tool offers great opportunities for investigating Culicoides immature stages ecology and biology, a prerequisite for the implementation of eco-epidemiological studies to better control AHSV in the Niayes region of Senegal, and more generally in sub-Saharan Africa.
The performance of DNA barcoding can vary within the same group of specimens among geographical regions and ecosystems  [15]. Species with large effective population sizes can have high intraspecific genetic diversity, which could overlap with interspecific divergence  [16]. Furthermore, imperfect taxonomy also could lead to erroneous identifications  [17]. Therefore, morphological and molecular identification have both limitations and advantages, but in the absence of a large body of work on morphological identification of the Culicoides immature diversity in the Afrotropical region, advances in molecular identification would be a crucial stepping stone. In the present study, our objectives were: (i) to establish DNA barcode libraries for adult Culicoides species collected in different sites in the Afrotropical region  [18] ; (ii) to assess the accuracy of the cox1 gene in identifying of these Culicoides species; and (iii) to test the usefulness of DNA barcoding for species identification on a large dataset of Culicoides larvae from the Niayes area of Senegal, West Africa.
Barcode gap analysis In our reference DNA sequences, we counted how often the maximum intraspecific distance exceeded the minimum interspecific distance. Using length and which functions in SPIDER to query how many times this occurred in our reference DNA sequences, we found that this was the case on 14 occasions (Additional file 2: Figure  S2 ). Molecular identification for Culicoides larvae DNA sequences of Culicoides larvae collected in the Niayes area of Senegal were successfully obtained for 958 out of 1632 larvae (58. 6%). PCR amplifications failed for 99 out of 773 samples of stages L1-L2, while all selected samples of stage L3-L4 were successfully amplified (859/859 samples). This might be explained by the physical size of the different larval stages (L1 and L2 stages are < 2 mm). The sequences were edited in Geneious R11  [19]  and 933 cox1 sequences of better quality were used in this study.
The overall rate of cox1 sequences successfully matched within our reference DNA sequences used as Search Set in BLAST search was 97. 1%. Thus, 906 out of 933 cox1 sequences of larvae were successful identified to Culicoides species. However, 27 cox1 sequences were unmatched within our DNA barcode reference libraries. In order to find a match, these cox1 sequences were used as a query in NCBI (https://blast. ncbi. nlm. nih. gov/Blast. cgi). However, no matches were found for these sequences. The sequences matched corresponded to eight Culicoides species (Table  2 ). Of these species, Culicoides oxystoma Kieffer had the highest percentage (66. 8%), followed by Culicoides nivosus de Meillon (21. 5%), Culicoides distinctipennis Austen and Culicoides similis Carter, Ingram & Macfie (both slightly above 3%) (Table  2 ).
DNA barcoding database analyses A total of 1131 cox1 sequences were submitted to the BOLD database under the project code "AFCUL" (details see Additional file 3: Table  S1 ). A hierarchical increase in mean divergence was observed according to two taxonomic levels: within species (mean = 1. 92%, SE = 0. 00) and within genus (mean = 17. 82%, SE = 0. 00). In the barcode gap analysis using the BOLD Management and Analysis System, situations where the distance to the nearest neighbour was less than the max intra-specific distance were encountered in seven species (Additional file 4: Table  S2 ). Haplotype data analysis detected 360 haplotypes in 1131 cox1 sequences for 40 Afrotropical Culicoides species.
DNA barcodes can also be used to link different life stages of insects, e. g. larvae, pupae and adults. This is particularly useful in situations where sympatry exists, or larvae are difficult to rear, as frequently occurs for Culicoides. A first attempt to identify Culicoides larvae using molecular techniques was conducted by Yanase et al. [36]  in a very restricted area in Japan and on a limited number of species. The provision of DNA barcode data for Culicoides species, particularly species of medical and veterinary importance in the Afrotropical region, fills an important gap in our knowledge of the phylogeny of these species and identification of immature Culicoides. The analysis of the quality of our DNA reference database through distance-and tree-based measures of the identification success rates showed satisfactory results (Fig.
1 ) and allowed its application to DNA sequences from Culicoides larvae collected in various habitats in the Niayes area of Senegal, West Africa, in order to identify species at the larval stage. The abundance of the larval stages for each species needs to be investigated in relation to the type of larval habitat sampled. Although this study highlights that the barcode database developed here can be reliable for species-level assignments at the larval stage, the possible presence of cryptic diversity within these species is to be taken into account. Our study showed that the most abundant species in the larval sampling was C. oxystoma. Considering the vector role of C. oxystoma  [37] [38] [39] [40]  its wide distribution (from Africa to South East Asia), previously described ecological heterogeneity and morphological plasticity  [8, 41, 42] , studies are needed to validate its taxonomic status.
Reference DNA sequences Reference DNA sequences constituted 230 cox1 sequences representing 42 Culicoides species (Table  1 ). These species were collected in different sites in the Afrotropical region  [18, 41, 54, 55]. We described summary statistics and analyzed the quality of our reference DNA sequences (230 cox1 sequences representing 42 Culicoides) by distance-and tree-based measures of identification success rates using R software v. 3. 3. 2  [56]  with APE and SPIDER libraries  [57, 58]. Every sequence in our reference DNA sequences was considered as unknown and used as a query against the entire data set of identified sequences species name was assigned based on criteria  [57] : nearest neighbour (NN), threshold analyses (TA), best close match (BCM), and monophyly of each species (Mono).
These criteria are not identification tools, but permit investigation whether sequences can be used for species identification  [57, 59]. The barcode gap was calculated and plotted using the maximum intraspecific distance and the minimum interspecific distance. The barcoding gap  [17]  is an important concept in DNA barcoding. It is assumed that the amount of genetic variation within species is smaller than the extent of variation between species. Genetic distances were calculated using SPIDER employing the Kimura-2-parameter (K2P) distance metric. Haplotype and nucleotide diversity were calculated using DnaSP v. 5  [60].
Molecular identification for Culicoides larvae Reference DNA sequences were transformed as a BLAST database using makeblastdb of the BLAST software v. 2. 2. 31  [62]. To discriminate Culicoides species within the larvae generated sequences, cox1 sequences of Culicoides larvae were edited in Geneious R11  [19]  and used as a query in BLAST search in the BLAST database, considering the different thresholds of divergence generated and used in the identification success rates previously described. ) were submitted to the BOLD database under the project code "AFCUL" for acquiring accession numbers and BOLD-IDs. Sequence alignment was performed using the BOLD Management and Analysis System  [63]. Overall data sequences were compared using the Distance Summary and Barcode Gap Analysis tools on BOLD.
DNA sequences in this study (except the sequences of C. candolfii Delécolle, Paupy, Rahola & Mathieu [54] (GenBank: KC986403. 1 and KC986404. 1) and C. dubitatus Kremer, Rebholtz-Hirtzel & Delécolle [55] (GenBank: KY707796. 1, KY707797. 1 and KY707798. 1.
All DNA sequences in this study (except the sequences of C. candolfii Delécolle, Paupy, Rahola & Mathieu [54] (GenBank: KC986403. 1 and KC986404. 1) and C. dubitatus Kremer, Rebholtz-Hirtzel & Delécolle [55] (GenBank: KY707796. 1, KY707797. 1 and KY707798. 1.
Acknowledgments The authors are grateful to  Nestle Foundation  for financing this research project. The authors likewise thank the  French Embassy in Chad  and the  Centre National d'Appui à la Recherche (CNAR/CNRD) of Chad  for their financial support in the organization and writing of this project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank  Scribendi  for the English proofreading of the manuscript.
Second, the ryanodine receptor antagonist Dantrolene (ClinicalTrials. gov Identifier: NCT02829268; F. Urano, personal communication) is expected to counteract calcium leakage from the endoplasmic reticulum (ER). WS is an autosomal-recessive genetic disease and the causative gene is WFS1, encoding for the Wolframin (WFS1) protein  7, 8. WFS1 is involved in the regulation of ER calcium homeostasis  9. ER serves as a cellular calcium store and quality control system for identifying abnormally conformed proteins and targeting them to degradation. In case of pathological accumulation of aberrant proteins, the ER initiates a stress response, termed unfolded protein response (UPR)  10. Pancreatic β-cell death and neuronal cell dysfunction in WS are indeed considered to be due to high levels of ER stress in affected cells  [11] [12] [13].
Acknowledgements This work was supported by external ressources from " Institut National de la Santé et de la Recherche Médicale" (INSERM) ,  Université de Montpellier , and  Association Syndrome de Wolfram (Grand-Champ, France)  and grants from the  Agence Nationale pour la Recherche  ( ANR-12-JSV1-0008-01 ),  Fondation pour la Recherche Médicale , and  Fondation de France.
related frontotemporal lobar degeneration have received grants from the French Ministry of Health (PHRC) as the principal investigator of A 3 ICH trial. I have been an investigator for clinical trials funded by AstraZeneca, Boehringer-Ingelheim, Daichii-Sankyo, and Servier, and have participated on an advisory board for Bristol-Myers Squibb-Pfizer. 2 Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/ Alcohol Concomitantly) score. J Am Coll Cardiol 2011; 57: 173-80. 3 Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation.
Study design and patients SERAPHIN was a multicenter, randomized controlled, event-driven study designed to assess the long-term efficacy and safety of macitentan in patients with PAH (NCT00660179). The study design has been described in detail elsewhere  [17]. Briefly, patients were included if they were 12 years of age or older and diagnosed by right heart catheterization with idiopathic PAH, heritable PAH or PAH related to connective tissue disease, repaired congenital systemic to pulmonary shunts, HIV infection, drug use or toxin exposure  [16]. Patients had to be in World Health Organization functional class (WHO FC) II-IV, achieve a baseline 6MWD of 50 m or more, and could be either treatment-naïve or receiving a stable dose of phosphodiesterase type 5 inhibitors, oral or inhaled prostanoids, calcium channel blockers, or L-arginine for at least 3 months prior to randomization.
Statistical analysis To evaluate the association between 6MWD and long-term outcome, the risk for PAH-related death or hospitalization up to EOT and for all-cause death up to EOS was calculated among: 1) patients with available 6MWD data at Month 6, dichotomized as above or below the median 6MWD value at Month 6 (400 m), or categorized by quartiles; 2) all randomized patients, categorized according to quartiles of 6MWD values at baseline; and 3) patients with available 6MWD data at baseline and Month 6, categorized according to quartiles of changes in 6MWD at Month 6. Event-free Kaplan-Meier (K-M) estimates of PAH-related death or hospitalization or all-cause death were determined for each categorization of 6MWD values and compared by the log-rank test. Associations were analyzed using univariate Cox regression models and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs).
term outcome in PAH (age, sex, PAH etiology, and WHO FC)  [2]. Interaction tests were employed to evaluate potential heterogeneity across the treatment groups (placebo, macitentan 3 mg and macitentan 10 mg) with respect to the associations between 6MWD and long-term outcome. As the p-values for interaction indicated no heterogeneity (S2 Table ), the associations between 6MWD and long-term outcomes were therefore performed combining all study treatment groups. As the objective was to determine the importance of a second measure of 6MWD on long-term outcome beyond Month 6, only patients with both baseline and Month 6 data were included in the analyses at Month 6. Patients who experienced an event under investigation (PAH-related death or hospitalization, or all-cause death) prior to Month 6 were excluded from these analyses.
Study population The study cohort included all MSM patients who were diagnosed with acute HCV infection at the Infectious Disease Department of the Hospices Civils de Lyon, France, and for whom NS5B sequencing was performed between January 2014 and December 2016. Data on drug use patterns and risk behaviours were collected. HCV isolated from 42 non-MSM, HIV-negative, male patients of similar age (genotype 1a: 30; genotype 4d: 12) were analysed by NS5B sequencing at the same time for phylogenetic analysis. This study was conducted in accordance with French ethics regulations. All patients gave their written inform consent to allow the use of their personal clinical data. The study was approved by the Ethics Committee of Hospices Civils de Lyon.
HCV testing and sequencing HCV RNA was detected and quantified using the Abbott RealTime HCV assay (Abbott Molecular, Rungis, France). The NS5B fragment of HCV was amplified between nucleotides 8256 and 8644 by RT-PCR as previously described  [22]  and sequenced using the Sanger method. Electrophoresis and data collection were performed on a GenomeLab™ GeXP Genetic Analyzer (Beckman Coulter). Consensus sequences were assembled and analysed using the GenomeLab™ sequence analysis software. The genotype of each sample was determined by comparing its sequence with HCV reference sequences  [23]  obtained from GenBank.
Phylogenetics Phylogenetic trees for genotype 1a and genotype 4d sequences were constructed using Meta-PIGA v. 3. 100 software. The Maximum Likelihood criterion was applied using the Hasegawa-Kishino-Yano (HKY) substitution model  [24]. MetaPIGA calculations were stopped when the mean relative error of 10 consecutive consensus trees stayed below 5% using trees sampled every five generations. Consensus trees were visualized in Figtree v. 1. 4. 3 (http://tree. bio. ed. ac. uk/software/figtree/). Reference strains for genotype 1a (Genbank accession numbers AF009606, EF407457, HQ850279, M62321 and M67463) and for genotype 4d (Genbank accession numbers DQ418786, FJ462437 and EU392172) were chosen for comparison. Identification of transmission clusters was performed using Cluster Picker software with a support threshold of 0.
Primer design and PCR The target region was selected based on the alignment of the full genomes of three SPPVs, Sheeppox virus 10,700-99 (AY077832), Sheeppox virus A (AY077833) and Sheeppox virus NISKHI, (AY077834), retrieved from GenBank, and the unpublished genome of the Romanian vaccine strain used in Morocco. PCR primers, flanking a unique nucleotide deletion in the Romanian vaccine strain, were designed using Primer3Plus online tool. The target was an intergenic region located between the DNA ligase gene and the VARV B22R homologue gene of CaPVs corresponding to position 121,500-122,799 of SPPV A (AY077833). The primers (Table  2 ) were designed to amplify amplicons of 302 bp in SPPV field isolates and 218 bp fragments for SPPV vaccines. The specificity of the primers was checked by using the Basic Local Alignment Search Tool (BLAST).
Sequence analysis For all CaPVs used in this study, the targeted region of the genome was sequenced to confirm the accuracy of the assay. Thus, all amplified PCR products of the above described PCR reactions were purified using Wizard SV Gel and PCR Clean Up System (Promega) and sequenced commercially by LGC Genomics (Germany). The sequence data were edited and the fragments assembled using Vector NTI 11. 5 software (Invitrogen). Multiple sequence alignments were performed using the CLUSTALW algorithm implemented in BioEdit 7. 5 software package to compare SPPV field isolates and vaccine strains. All sequences were deposited in GenBank under accession number MG764242 to MG764286.
Acknowledgements The authors would like to thank  Dr. El Harrak M. (Biopharma , Morocco),  Dr. Velý Gulyaz  ( Pendik-VCRI, Turkey ) and  Dr. Erdenebaataar Janchivdorj  ( IVM, Mongolia ) and  Dr. Adi Steinrigl  ( AGES, Austria ) for providing capripoxvirus and bovine herpes virus samples. We also like to thank,  Dr. Esayas Gelaye  ( NVI, Ethiopia ) and  Dr. Jenna E. Achenbach  ( Battelle, VA, USA ) for critically assessing the manuscript.
Therapies targeting the druggable enzyme PLCG2  [17, 68]  might, thus, provide a novel therapeutic approach with the potential for disease modification in AD might as well buffer the deleterious effect of APOE-ε4. Acknowledgements Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project "Diet-Body-Brain: from epidemiology to evidence-based communication". and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California.
ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND; PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government's LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer's disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo.