dataesr/scientific-paragraphs-categorization huggingface dataset:
ACKNOWLEDGMENTS We thank  Damien Coudreuse  for assistance with bioinformatic analysis and critical reading of the manuscript. We are grateful to members of the laboratory of  Julie Cooper , in particular  Michael Klutstein , for help with pulsed-field gel electrophoresis (PFGE). P. -Y. J. W. was supported by the  Women and Science Foundation  and the  Fondation pour la Recherche Medicale. This study was supported by grants from the  CNRS/INSERM  ( ATIP-Avenir ), The  Breast Cancer Research Foundation ,  The Anderson Center for Cancer Research, The Wellcome Trust  (grant  093917 ), and The  Rockefeller University.
This supported PP1 as a phosphatase removing S28p from the H3K27me3S28p double-marked chromatin in vivo. Next, we analyzed the outcome of the global reduction in H3K27me3S28p on regulatory regions of specific genes. Lesioned DARPP-32 T34A and wt mice were treated with L-DOPA and striatal tissue from the lesioned and unlesioned striatum was analysed by ChIP-qPCR. The induction of H3K27me3S28p at the Atf3, Klf4, Npas4 and Hoxa2 genes was significantly reduced in chromatin from the lesioned striatum of DARPP-32 T34A mice compared to wt mice (Figure  5D ). Notably, this reduction correlated with decreased expression of Atf3, Klf4 and Npas4 mRNA in the lesioned striatum of L-DOPA injected DARPP-32 T34A mice compared to wt mice (Figure  5E ). Overall these data suggested that D1R stimulation induces transcription associated to H3K27me3S28 phosphorylation via two parallel pathways: 1) activation of Erk-Msk kinases and 2) concomitant PKA-mediated DARPP-32-phosphorylation, leading to inhibition of PP1 and suppression of H3K27me3S28p dephosphorylation.
L-DOPA induced H3K27me3S28 phosphorylation and gene activation are dependent on a functional PP1 interaction site on DARPP-32. A) H3K27me3S28p was attenuated in T34A mutant mice following chronic administration of L-DOPA (lesioned x genotype interaction: F (1,28) = 12. 21, p = 0. 002). *** p,0. 001 vs unlesioned wt hemisphere, uuu p,0. 001 vs lesioned wt hemisphere. N = 8 per condition. Data are means 6S. E. M. ). B) PP1 efficiently dephosphorylates H3K27me3S28p in vitro. H3 non-modified, H3S28p or H3K27me3S28p modified peptides were incubated in the presence or absence of PP1. The peptide dot-blots were developed using an anti-H3S28p antibody. C) Striatal tissue slice culture experiment showing that H3K27me3S28p was induced after 50 min incubation with 1 mM, but not 100 nM, okadaic acid (effect of treatment: F (2,8) = 19.
0. 001, ** p,0. 01, * p,0. 05 vs unlesioned hemisphere of the same day. n = 3-6 per condition. Data are means 6S. E. M. B-D) Histograms of differentially expressed transcripts in lesioned striata after chronic L-DOPA compared to acute L-DOPA, from H3K27me3S28p positive and H3K27me3 positive genes (B), from H3K27me3S28p negative but H3K27me3 positive genes (C), and from genes regardless of specific histone marks (D). E) Venndiagram showing number of genes induced exclusively by acute (53; subgroup a) or chronic (71; subgroup b) and genes commonly induced after both acute and chronic L-DOPA administration (43; subgroup c). F-H) mRNA levels of (F) Ppm1n, Galr2, (G) Atf3, Klf4, Npas4, (H) Nurr1, Ngf, Lipg relative to Tbp in unlesioned and lesioned striata of acutely or chronically saline or L-DOPA injected mice determined by RT-qPCR.
ChIP-sequencing analysis All quantitation, scoring, gating, and visualization was done in the program EaSeq (Lerdrup et al, manuscript in preparation). A list of all transcripts including genomic coordinates was derived from Genomatix (see RNA-sequencing for details), and the amounts of ChIP-seq signal at the genomic regions corresponding to 21 kbp to +1 bkp was quantified and normalized to dataset size and a region-size of 1 kbp. Transcripts were scored positive or negative by fitting the abundance to the quantified ChIP-seq signal at all transcripts genome-wide to a normal distribution. A threshold was automatically applied at the level where the only 5% of the regions were expected to score positive by chance (thresholds were 6. 8 for left hemisphere H3K27me3 and 16. 9 for right hemisphere H3K27me3S28P).
RNA-sequencing A TruSeq RNA Sample preparation kit (Illumina) was used for library generation out of 0. 5 mg of total RNA per condition. The generated libraries were sequenced on a Genome Analyzer II (Illumina) at the National High-throughput Sequencing Centre in Copenhagen. Reads were mapped to the mouse genome (mm9) using the Genomatix Mining Station software (Genomatix). Differential expression analysis was done on triplicates using the region miner task ''Expression Analysis for RNASeq Data'' on a Genomatix Genome Analyzer (Genomatix) using the DeSeq algorithm  [58].
Accession number The Geo accession number for the ChIP-seq and RNA-seq data reported in this paper is GSE60703. Table  S1  List of unlesioned striatum H3K27me3 and lesioned striatum H3K27me3S28p positive genes with a significant (p. 0. 05) fold change of more than log2 = 0. 58 in the lesioned hemisphere compared to the unlesioned hemisphere 1 h after a first L-DOPA injection (''acute'') based on RNA-seq data. The corresponding change in expression in chronically L-DOPA treated lesioned to unlesioned hemispheres are listed in the second column if significant. Genes with a normalized expression value of ,0. 004 were considered non-detectable. Genes that significantly changed expression in the unlesioned striata after L-DOPA injection and genes that changed expression in the lesioned hemisphere compared to the unlesioned hemisphere were not listed.
Acknowledgments We would like to thank  Professor Michael E. Greenberg  for providing the Npas4 antibody for our studies,  Professor Paul Greengard  for the DARPP-32 T34A mouse strain,  Liv Widell  for help with illustrations,  Kathryn Wattam  for technical support, colleagues in the Hansen and Fisone research groups for valuable discussions throughout the project. We furthermore would like to thank  Jens Vilstrup Johansen  for alignment of the ChIP-sequencing reads to the mouse genome.
No acanthocytosis was present on any of several blood smears. No mutations were identified in DYT1, PANK2, PLA2G6, SCA17, or APTX, genes known to be involved in neurodegenerative diseases with cerebellar atrophy and/or dystonia. Given consanguinity in the family, we assumed a recessive mode of inheritance and predicted the causative variant would fall in a region of homozygosity. Homozygosity mapping revealed six homozygous regions greater than 2 Mb. Whole exome sequencing produced 142 million reads, 98% of which could be aligned to the targeted sequence. Mean coverage of the targeted sequence was 77 fold. 56 687 SNVs and 7 265 indels were called. Only nine homozygous variants with frequency below 1% in internal (IntegraGen) and public databases (dbSNP 132; HapMap; 1,000 Genomes Project) were filtered out of these.
This variant was not observed in any of 100 ethnically matched controls and was absent from >6500 exomes at the Exome Variant Server. To gain insight into the pathogenicity of the TOR1-AIP1 mutation, we evaluated primary skin fibroblasts from the patient. By western blot, a strong reduction in the expression of LAP1 isoforms was observed relative to control cells (Figure  2A ). Immunolabeling revealed a significant reduction in LAP1 staining in the nuclear envelope of patient cells (Figure  2B ). Although the endoplasmic reticulum was generally faintly stained, some areas showed accumulation of LAP1 (Figure  2B ), indicating mislocalization of the mutated LAP1. No defects in A-type or B-type lamins, SUN1, SUN2, or nesprin-1 or 2 protein localization were observed (data not shown). Similarly, no blebs  [4]  in nuclear envelopes were observed by electron microscopy in patient cells (Figure  2C ).
Acknowledgments The authors thank the patient and his family for their strong support to report this case,  Alexandra Durr  for helpful comments,  William T. Dauer  for the anti-LAP1 antibody, the  DNA and Cell Bank of the Institut du Cerveau et de la Moelle épinière , and the  Fond National de la Recherche Scientifique  for the fellowship attributed to M. C. (aspirant FNRS). This work was financially supported by the  French National Agency for Research (ANR) , the  Institut national de la santé et de la recherche médicale (INSERM) , the  Université Paris Diderot-Sorbonne Paris Cité, DHU PROTECT  and the  ELA Fondation  (post doc fellowship for I. D. ), the  Université Pierre et Marie Curie Paris 06 , the  Centre National de la Recherche Scientifique (CNRS) , the  Association Française contre les Myopathies (AFM) , the  Verum Foundation , the  Fondation Roger de Spoelberch , and the program " Investissements d'avenir "  ANR-10-IAIHU-06.
Using a statistical method, we quantify the propensity of several classical visual features to drive gazes (faces, center bias, static and dynamic low-level saliencies). We find that classical low-level saliency globally fails to predict eye positions, whereas faces (and especially talking faces) are good predictors. Therefore, we suggest the joint use of face detector and speaker diarization algorithms to distin-guish talking from mute faces and label them with appropriate weights. Keywords: faces, speech, gaze, scanpath, saliency, audiovisual integration, expectation-maximization, database.
Despite the low, but detect- In the acromegaly tumors, excess ligand GDNF is preventing RET-induced apoptosis and correlates positively with RET but negatively with p53. A, Quantitative TaqMan RT-PCR detection in whole pituitary adenomas. Four acromegalies (ACRO-2, ACRO-3, ACRO-5, and ACRO-6) were compared with 4 NFPAs. Because we only had frozen tissue from NFPA-1 and NFPA-5, we added 2 other frozen NFPAs obtained during the same period (NFPA-6 and NFPA-7). Data were obtained in relation to gene expression of the control TBP and are expressed in relation to median of the NFPA tumors (taken as value 1). RET is highly expressed in GH-secreting adenomas and is poorly expressed in NFPAs. However, in the ACRO-2 tumors, RET expression is not much bigger than in NFPAs. However, ACRO-2 primary cultures presented a strong RET-dependent apoptosis and expressed RET protein (Figure  2 ).
Acknowledgments We thank  Sihara Perez-Romero  for her expert technical assistance with PCR. This work has been possible thanks to the Spanish registry of pituitary adenomas, REMAH. Address all correspondence and requests for reprints to:  Justo P. Castaño, PhD ,  Department of Cell Biology, Physiology, and Immunology, Maimonides Institute for Research in Biomedicine of Cordoba, Edificio Severo Ochoa, Planta 3, Campus de Rabanales, University of Córdoba , E-14014 Córdoba, Spain. E-mail: justo@uco. es;or  Clara V. Alvarez, MD, PhD. Neoplasia  and Endocrine Differentiation, IDIS-CIMUS, Department of.
Introduction The Global Monitoring for Environment and Security initiative (COPERNICUS) 'Space' was explicitly identified in the Constitutional Treaty, recognizing that it represents a critical issue for the European Union (EU), for its society, its economy and its global role in the world  [Verheugen, 2005]. In 2005, the EU made the strategic choice of developing an independent European Earth Observation capacity called Global Monitoring for Environment and Security (formerly known as GMES and renamed as COPERNICUS) in order to deliver services in the environmental and security fields. COPERNICUS consists of the following three components: (I) Space Component -consists of a space observation infrastructure addressing service data needs with the missions of observing land, atmospheric and oceanographic parameters; (II) In-Situ Component -will rely on a large number of facilities, instruments and services owned and operated at national, regional and intergovernmental levels inside and outside the EU; (III) Service Component -the basis for Europe's autonomy in information provision world-wide.
This is precisely the aim of DORIS_Net where the regional actors themselves have formed a consortium and taken the initiative to coordinate and stimulate COPERNICUS downstream services on a regional level  [SRCTE, 2011]. DORIS_Net (Downstream Observatory organized by Regions active In Space -Network) is a Coordinated Action (CSA) project funded by the European Commission, under the 3rd FP7 Space Call. The project name DORIS_Net signals a fully user led approach for the establishment of a network linking European LRA, service providers and other COPERNICUS stakeholders at regional, national and European level. All partners in the DORIS_Net project have been mandated by their regions who are all members of NEREUS and DORIS_Net is specified, designed and implemented by the Regions themselves.
Concept and functions of COPERNICUS Regional Contact Offices (RCO) A COPERNICUS Regional Contact Office (RCO) acts as a focal point in its region, at the interface of industry (services providers), R&D actors, regional users and policy-makers. Hosted by one or more an independent entities and endorsed by its regional authority, it serves as regional centre of COPERNICUS expertise. The RCO facilitates an access by creating a public interface between the region and the stakeholders located in it, promoting information available under the COPERNICUS banner and making in this way the regional link. The RCO has the following main functions: (I) identifying potential users of COPERNICUS services; (II) raising awareness of the potential offered by COPERNICUS and Earth Observation services; (III) providing a service for regional actors to access data and information on COPERNICUS at global, national and European levels; (IV) knowing the COPERNICUS portfolio and observe new services, particularly at regional scale; (V) assisting users in the expression of their needs or in the search of services answering their needs; (VI) favoring dialogue between users and service providers; (VII) promoting new services developed by regional actors; (VIII) developing opportunities to produce new services in line with identified needs; (IX) supporting training in Earth Observation field  [SRCTE, 2013a].
RCO and COPERNICUS governance at European and National levels The European Commission is the administrative and political body responsible for the COPERNICUS program. Within DG Enterprise, the COPERNICUS Bureau acts with the European Commission on the coordination of this wide flagship program. On the technical side, ESA is responsible for the implementation of data and infrastructure. In parallel, five core services are being developed in different issued domains: land, marine, atmosphere, emergency, security and climate change. In order to make the link with the EU members, a COPERNICUS committee of delegates was created, composed of national COPERNICUS coordinators. COPERNICUS User Forums are also organized in the Member States. No regional entity is part of the COPERNICUS governance. More generally, no political support from the regions is expressed in COPERNICUS policies.
RCO could provide the COPERNICUS Bureau annual reports on events organized, needs collected, feedback and especially needs for new products. This report should be coordinated by the European Network of RCO's coordinator. Regional activities could also be reported to the COPERNICUS Bureau. RCO could also provide articles and communications on regional uses to the COPERNICUS Bureau and to ESA. In parallel, RCO should also work closely with COPERNICUS providers of data in order to be informed of available products and their access. To improve liability of COPERNICUS products, a national referent for each core service could work in close relationship with the RCO so as to address RCO users' questions. This was experienced in Midi-Pyrénées for the "Land domain" issues and was very fruitful. This will improve RCO regional actions and, in parallel, data and service providers can collect feedbacks on their data access.
Acknowledgements This article has been developed in the framework of the  DORIS_Net  project funded by the  European Commission  in the Call "Coordination and support action (Coordinating)  FP7-SPACE-2010-1 ". Authors especially acknowledge all the persons directly involved in the setup, development and management of this project, namely (in alphabetical order):  Alba L'Astorina ,  Anna Rampini ,  Bastian Muller ,  Carmela Cornacchia ,  Daniela Grewe ,  Didier Treinsoutrot ,  Federica Bordelot ,  Florence Ghiron ,  José Azevedo ,  Marlene Assis ,  Paulo Menezes ,  Rhys Cowsill ,  Rosa Petracca ,  Roya Ayazi ,  Sónia Nicolau ,  Virginia Puzzolo  and  Volker Schumacher. Authors also acknowledge all the entities involved in the consortium responsible for this project, which was constituted by the following entities:  Consiglio Nazionale delle Ricerche  ( CNR-IREA -Coordination of DORIS_Net ) and  Tecnologie per le Osservazioni della Terra e i Rischi Naturali (TeRN) -Italy ;  Centre for Communication, Earth Observation and Navigation Services GmbH (CEON)  and  Forum Luft und Raumfahrt Baden-Württemberg e.
Introduction: Teriflunomide, indicated for the treatment of relapsing-remitting multiple sclerosis, is contraindicated in pregnancy based on signs of developmental toxicity in the offspring of rats and rabbits; developmental toxicity has also been observed in preclinical studies of other disease-modifying therapies. Despite the requirement to use reliable contraception in clinical trials evaluating the safety and efficacy of teriflunomide, a number of pregnancies have been reported. This work reports pregnancy outcomes in teriflunomide clinical trials. Methods: Pregnancy outcomes were evaluated in a retrospective analysis of the global pharmacovigilance database. The following information was collected from the pharmacovigilance database or individual patient files: treatment allocation, pregnancy outcome, teriflunomide exposure, and use of the accelerated elimination procedure.
In this regard, global pregnancy registries for teriflunomide will capture prospective data from pregnancies that occur worldwide in the postmarketing setting. In North America, the independent OTIS group has established a pregnancy registry to collect prospective data for women exposed to teriflunomide during pregnancy  [11]. A second registry will collect pregnancy data from patients in Europe and Australia. was administered orally for 11 days following teriflunomide treatment. Adapted with permission from Freedman  [14].
pharmacovigilance database was conducted to evaluate pregnancy outcomes identified in female study participants and female partners of male study participants in teriflunomide clinical trials. The following studies were included: monotherapy studies Phase 2 proof-of-concept (NCT01487096) and extension (NCT00228163), beta; NCT01252355). The following information was collected from the pharmacovigilance database or individual patient files: treatment allocation, pregnancy outcome, teriflunomide exposure, and use of the accelerated elimination procedure.
funded by  Genzyme , a Sanofi company, provided by  Scott Chambers , of  Fishawack Communications Ltd, Abingdon, UK , and was funded by  Genzyme. No other funding or sponsorship was received for this study or publication of this article. this work as a whole, and have given final approval of the version to be published. Conflict of interest. BK has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from  Bayer Schering, Biogen Idec ,  Merck Serono ,  Novartis ,  Sanofi , and  Teva Neuroscience. MB is an employee of Sanofi R&D.
Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3. 99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases.
Ethical review boards of the International Agency for Research on Cancer and local participating centers approved the project. We identified and verified cases of incident T2D by using multiple data sources of evidence, including self-report, linkage to primary care registers, secondary care registers, medication registers, hospital admissions, and mortality data  (13). Follow-up was censored on 31 December 2007 or the date of death or T2D diagnosis, whichever occurred first. In total, we identified 12,403 verified incident cases of T2D. We randomly selected a center-stratified subcohort of 16,835 individuals from the 340,234 eligible participants. After exclusion of participants with prevalent diabetes or unknown diabetes status (n = 681), 16,154 individuals were included in the subcohort.
Because of random selection, this subcohort also included a random set of 778 individuals who developed incident T2D during follow-up. The casecohort design allows for the random occurrence of incident cases in the subcohort and accounts for this in the statistical analysis. Of the 27,779 participants, we excluded 619 participants with a ratio of energy intake to energy expenditure in the top and bottom 1% of the distribution and 1072 participants with missing information on dietary intake or other covariates used in the statistical analysis. The final analysis sample included 26,088 participants (11,559 cases and a subcohort of 15,258 participants, including 729 cases in the subcohort). Data collection. At baseline, usual dietary intake during the year before recruitment was measured by country-specific validated dietary questionnaires designed to reflect local dietary patterns  (14, 15).
We estimated total energy and nutrient intakes by using the standardized EPIC Nutrient Database  (16). We obtained baseline information on other lifestyle variables from face-to-face or self-administered and standardized questionnaires including questions on education, medical history, physical activity, and smoking  (14, 17). We measured anthropometric data by using standardized protocols, except in Oxford (UK) and France, where we collected selfreported measurements  (14). Flavanol and flavonol intake. Estimated flavanol and flavonol intakes were derived from foods included in the dietary questionnaires through a comprehensive food composition database on flavonoids as previously described  (11, 12, 18). Our database on flavanols (flavan-3-ol monomers, proanthocyanidins, and theaflavins) and flavonols was based on USDA databases  (19, 20)  and Phenol-Explorer  (21).
This online database compiles composition data on individual flavan-3-ol monomers (catechin, epigallocatechin, epicatechin, epicatechin 3-gallate, epigallocatechin 3-gallate, gallocatechin, catechin 3-gallate), proanthocyanidin groups (dimers, trimers, 4-6 monomers, 7-10 monomers, polymers), and the individual flavonols (isorhamnetin, kaempferol, myricetin, quercetin). Data on flavonoids were expressed as aglycone equivalents, after conversion of the flavonoid glycosides into aglycone contents using their respective molecular weights. The final database contains 1877 food items, including raw foods, cooked foods, and recipes, and 10% of values for these food items are missing. Statistical analysis. We assessed the distributions of intakes of total and individual flavan-3-ol monomers, proanthocyanidins, theaflavins, and flavonols by using means, SDs, medians, and 5th and 95th percentiles because the data were skewed to the right.