dataesr/scientific-paragraphs-categorization huggingface dataset:
Whole genome sequencing analysis Whole genome sequencing was performed on Huh7 T2 31. 3 and Huh7 wildtype (WT) cells to validate the specificity of shmiRHCV318 integration and to identify possible offtarget integration sites. After library preparation, sequencing was performed using the Illumina HiSeq platform. Sequencing reads were aligned against the human reference genome hs37d5 (http://www. 1000genomes. org/home) and the shmiRHCV318 as separate contig using the BWA-MEM (v0. 7. 8) software  (39). Resulting BAM files were coordinate-sorted, merged and PCR duplicates marked by biobambam (v0. 0. 148) software  (40). The resulting BAM files have an average coverage of 19. 82x and 21. 69x for WT and T2 31. 3 cells, respectively (0x and 12. 69x on the shmiRHCV318 contig). The integration site at chr18 and the shmiRHCV318 contig were visualized by using IGV  (41).
05 were assigned to be differentially expressed with high significance. MiRNA expression profiling was performed using the Agilent-046064 Unrestricted Human miRNA V19. 0 Mic roarray. Raw miRNA microarray data were pre-processed with background subtraction using the 'normexp' convolution standard method with subsequent quantile normalization as implemented in the Bioconductor limma package (v3. 22. 1) (42) for R statistical software (v3. 1. 2). Expression values were log2-transformed, and probe duplicates were averaged and quantile normalized to ensure comparability between samples. Potential batch effects between Agilent chips conducted at different dates were reduced by the ComBat-function in the Bioconductor sva-package (v3. 12. 0) on the basis of an empirical Bayesian framework  (43). We calculated differential gene expression on quantilenormalized Affymetrix mRNA expression profiles with the R statistical software (44) (v3.
1. 0). Data were filtered for low expression and variance with standard parameters, retaining 12 680 (of 54 675) probe IDs. Significance Analysis of Microarrays ((45), R-package 'siggenes' v1. 40. 0 (46)) was performed and differentially expressed probe IDs were called at a false discovery rate threshold of <0. 05. The same procedure was applied to the Agilent microarray data to identify differentially expressed miRNAs.
Data access All microarray data are available in the NCBI Gene Expression Omnibus database (GEO; http://www. ncbi. nlm. nih. gov/geo/) under accession number GSE68638. The whole genome sequencing data have been deposited in the European Genome-phenome Archive (EGA, https://www. ebi. ac. uk/ega/home) under accession number EGAS00001001252.
ACKNOWLEDGEMENTS The authors thank the microarray and sequencing units of the  DKFZ Genomics and Proteomics Core Facility  for providing gene expression, miRNA expression as well as whole genome sequencing analysis. The authors are grateful to  Sarah Klinnert  for help with cloning, as well as to members of the  Grimm lab  for critical reading. FUNDING  German Research Foundation [DFG ,  EXC81  ( Cluster of Excellence CellNetworks ) to E. S. , S. G. , S. M. and D. G. , SFB1129 (Collaborative Research Center  1129 ) to D. G. ( TP2 ),  TRR179  ( Transregional Collaborative Research Center 179 ) to R. B. ( TP9 ) and  D. G. SPP1395  ( InKoMBio ,  TH 900/6-1 ) to B. K. ];  Helmholtz Initiative  for Synthetic Biology [E. S and D. G. ];  Heidelberg University Graduate Academy  [PhD completion grant to E.
Data Analysis Results are expressed as mean AE SEM, with n values indicating the number of animals used for a particular set of experiments. Statistical analysis was carried out using SigmaStat 3. 5 software. After checking the normality, paired Student's t-test and Mann Whitney Rank Sum test were used for statistical analysis. For multiple comparisons, one-way ANOVA followed by Kruskall Wallis on Ranks was used. P < 0. 05 ( Ã ) values were considered to show significant differences between means.
Study Design Telemetric devices. Transmitter used for these experiments were PhysioTel PA-C40 (Data Science International), allowing pressure (accuracy AE 3 mmHg) and activity measurement in small animals (7. 8 g and 4. 5 cc). Pressure of each transmitter was calibrated in three points by the manufacturer. Calibration values were checked in three points (0, 30, and 100 mmHg) by a sphygmomanometer just before implantation and after animal euthanasia to ensure validity of data obtained. Surgical procedure. Pre-operative analgesic (buprenorphine and ketofen) and antibiotic (enrofloxacin) treatments were given to all animals before anaesthesia (isoflurane 2-4%). In aseptic conditions, a small laparotomy was performed. The transmitter was placed on the right side of the abdominal cavity and sutured on the abdominal wall (silk 4/0) in order to avoid contact with the bladder.
Results obtained were comparable to those with conventional cystometry (data not shown). Using such records the ''classical'' cystometry parameters, Basal Pressure (BP), Micturition Pressure (MP), Inter Contraction Interval (ICI), and voided volume (V), were determined. Cystometry parameters were evaluated for 13 out of 14 telemetered rats included in the study after a single oral administration of CMC at 0. 5% in water (vehicle). One animal did not respond to the furosemide pulse in the vehicle group and was excluded. One hour later, furosemide injection induced a mean of 7 AE 1 voids in 60 min for a total voided volume of 9. 0 AE 0. 6 ml and 1. 4 AE 0. 1 ml per void; the mean amplitude of micturition was 38. 0 AE 3. 5 mmHg (Fig. 3 ).
In this series of experiments, furosemide induced no modification of the voiding pattern even after many pulses in contrast to previous reports in dogs  10  and in rats. 21 hese contradictory results regarding voided volumes per void may be explain by the difference of species, dose, and route of administration of furosemide (2 mg. kg À1 in dogs, i. m. ) and duration of the recording. Regarding bladder pressure levels in rats recorded by telemetry, they were comparable to conventional cystometry obtained in our laboratory (data not shown) and results reported previously. 22, 23 The differences of bladder pressure levels between conventional cystometry and telemetry reported by Moody et al. 21 could be explain by the implantation techniques in the bladder dome. The latter described significant reductions in simultaneously measured basal and micturition pressures by telemetry when compared to conventional technique in rats.
Event reconstruction and selections The analysis is based on data from pp interactions observed with the CMS detector at √ s = 8 TeV. The data correspond to an integrated luminosity of 19. 7 fb -1. Events are collected using at least one of the two specific trigger conditions based on jets reconstructed online: the first trigger requires a large m jj calculated for the two jets of highest transverse momentum (referred to as leading jets); the second trigger requires a large value of H T = ∑ i p i T , where the sum runs over the reconstructed jets in the event with transverse momenta p T > 40 GeV. The lower thresholds applied to m jj and the H T triggers were changed during the data-taking period to maintain a constant trigger rate while the LHC peak luminosity steadily increased. More than half of the data were collected with m jj > 750 GeV and H T > 650 GeV.
The remaining data were collected with the requirement H T > 750 GeV. Events are required to have at least one reconstructed pp collision vertex within |z| < 24 cm of the center of the detector along the longitudinal beam directions. Many additional vertices, corresponding to pileup interactions, are usually reconstructed in an event using charged particle tracks. We assume that the primary interaction vertex corresponds to the one that maximizes the sum in p 2 T of these associated tracks. Individual particles are reconstructed using a particle-flow (PF) algorithm  [40, 41]  that combines the information from all the CMS detector components. Each such reconstructed particle is referred to as a PF candidate. The five classes of PF candidates correspond to muons, elec-trons, photons, and charged and neutral hadrons.
Acknowledgments We congratulate our colleagues in the CERN accelerator departments for the excellent performance of the LHC and thank the technical and administrative staffs at  CERN  and at other  CMS institutes  for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centers and personnel of the Worldwide LHC Computing Grid for delivering so effectively the computing infrastructure essential to our analyses. Finally, we the  Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA-Belgium) ; the  Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium) ; the  Ministry of Education, Youth and Sports (MEYS)  of the Czech Republic; the  Council of Science and Industrial Research, India ; the  HOMING PLUS program  of the  Foundation for Polish Science , cofinanced from  European Union, Regional Development Fund ; the  OPUS program  of the National Science Center (Poland); the  Compagnia di San Paolo (Torino) ;  MIUR  project  20108T4XTM  (Italy); the Thalis and Aristeia programs cofinanced by  EU-ESF  and the  Greek NSRF ; the  National Priorities Research Program  by  Qatar National Research Fund ; the  Rachadapisek Sompot Fund for Postdoctoral Fellowship, Chulalongkorn University (Thailand) ; the  Chulalongkorn Academic into Its 2nd Century Project Advancement Project (Thailand ); and the  Welch Foundation , contract  C-1845.
β3 agonist CL-316243 failed to activate thermogenesis in Bscl2 -/-mice. To ascertain Bscl2 -/- BAT thermogenesis dysfunction, we then assessed the response of Bscl2 -/-BAT to a pharmacological stimulus. Bscl2 -/-and Bscl2 +/+ mice were treated during 4 weeks with a β 3 adrenergic agonist (CL-316243). No difference in body weight was noticed in any of the four experimental groups (data not shown). BAT mass was increased by the treatment in both genotypes (Fig. 3A ). CL-316243 induced significantly the mRNA expression of the Figure  3. Chronic β3 agonist CL-316243 treatment in Bscl2 -/-and Bscl2 +/+ mice. Bscl2 -/-and Bscl2 +/+ mice were treated with CL-316243 during 4 weeks. (A) BAT mass in treated (KO CL, stripped white bar) or control (KO control, white bar) Bscl2 -/-mice, and in treated (WT CL, stripped black bar) or control (WT control, black bar) Bscl2 +/+ mice.
Micro-PET/CT (positron emission tomography computed tomography). Two-hour-fasted animals were anesthetized with isoflurane (1. 5-3%) in an oxygen/nitrous oxide mix (0. 6 L/min) via spontaneous breathing, and were placed on a warming pad (37 °C). No exogenous insulin was injected during PET exams. A microcatheter was surgically inserted in the tail vein prior to animal installation in a dedicated preclinical micro-PET/ CT scanner (Inveon ® , Siemens Medical Solutions, Knoxville, TN, USA). When blood glucose ranged between 5. 5 and 9. 9 mmol/L, a 60 min PET acquisition was started along with a 10 s tail vein injection of  18  F-FDG (15-20 MBq in 50-100 μ l). For BAT assessment, data were summed on a static frame and analyzed using the open source software OsiriX (http://www. osirix-viewer. com/) with the Standardized Uptake Value (SUV) plugin.
Acknowledgements We thank  Mark Lathrop  ( McGill University and Génome Québec Innovation Centre, Canada ),  Jean-François Deleuze ,  Masazumi Takahashi  ( CNG-CEA, Evry, France ) for donating the Bscl2 -/-mouse model,  C. Dumet ,  S. Suzanne , and  S. Lemarchand-Minde  ( Animal facility, l'Institut du Thorax, Nantes, France ) for animals care and  F. Moreau ,  Q. Venara  ( INSERM UMR_S1087, L'Institut du Thorax, Nantes, France ),  K. Pavageau ,  S. Saleun  and  F. Broucque  ( UMR_S1089, Nantes, France ) for technical assistance. We also thank the microPIcell core.
, 2007). These studies paved the way for all subsequent trials. Three meta-analyses, including controlled randomized studies and excluding studies where evaluation was only assessed by neurophysiological measurement, were controversial  (Klomjai et al. , 2015). • A Cochrane database analysis of the ability of rTMS to improve motor function after stroke selected 19 randomized controlled trials and 588 patients between 2002 and 2012, regardless of the delay after stroke (4 h to 6 years), the ischemic or hemorrhagic type, the cortical or subcortical location, the initial severity, the type of evaluation, but they excluded studies where only electrophysiological parameters were assessed. The study failed to support the use of rTMS for stroke rehabilitation  (Hao et al. , 2013). • Hsu et al. (2012) , selected 18 studies and 392 patients between 1990 and 2011.
8, 100 mM ammonium acetate and 2 mM MgCl 2. The specimen was adsorbed for 60 min. on a small piece of carbon partially floated off a mica sheet at the surface of a Teflon well containing 37 ml of sample. The carbon film was the transferred on an EM copper grid covered by a perforated carbon film (Quantifoil R2/2). The grid is flash frozen in liquid ethane using an automated plunger (Vitrobot, FEI) with controlled blotting time (4 s. ), blotting force (5), humidity (95%) and temperature (20 °C). The particles were imaged using a cryo-transmission electron microscope (Titan Krios, FEI) equipped with a field emission gun operating at 300 kV and a Cs corrector. Images were recorded under low-dose condition (total dose of 22 e À Å À 2 ) using the automated data collection software EPU (FEI) on a 4,096 Â 4,096 direct detector camera (Falcon II, FEI) at a magnification of Â 59,000 resulting in a pixel size on the specimen of 0.
108 nm. A total of 17 frames with an electron dose of 3. 2 e À Å À 2 /frame were collected and the frames 2-8 were aligned using the optical flow protocol  53  and averaged for further analysis. A high dose image (55 e À Å À 2 ), generated by summing all frames, was used as reference for frame alignment and for particle picking. Image processing. Particles were selected manually from a subset of images using the boxer application in the EMAN2 software package (http://blake. bcm. tmc. edu/ EMAN2/)  54. The contrast transfer function of the microscope was determined for each micrograph using the CTFFIND3 programme  55  within the frame of the RELION software package  56  , and the image phases were flipped accordingly. The molecular images were subjected to reference-free classification in RELION to produce representative two-dimensional (2D) class averages that were used as cross-correlation references for automated particle picking in all frames with the gEMpicker software  57.
60). Illustrations were prepared using the Chimera visualization software  61. Molecular images of the Pol I-Rrn3 complex were extracted from 4,121 frames, while the WT Pol I molecule were selected from 2,934 frames. Local resolution estimation. Local resolution estimation was performed using the 'ResMap' programme  62. The data set was split randomly into two halves to obtain two reconstructions that were used to estimate the local resolution. The maps were coloured based on the local resolution estimation using the 'Surface color' tool implemented in Chimera.
Acknowledgements We are grateful to  Drs Cramer ,  Hahn and Knutson  for providing us with plasmids. We thank  Dr Perez-Fernandez  for constructing and providing us with strain y2670 and  Dr Van Thai Huang  for help with flexible fitting programs. This work was supported through grants of the  Deutsche Forschungsgemeinschaft  ( SFB 960 ), the  Fondation pour la Recherche Medicale , the  Institut National de la Santeet de la Recherche Medicale , the  Centre National pour la Recherche Scientifique , the  Strasbourg University , the  Association pour la Recherche sur le Cancer , the  Agence Nationale pour la Recherche , the  Labex INRT , the  French Infrastructure for Integrated Structural Biology (FRISBI)  [ ANR-10-INSB-05-01 ] and INSTRUCT as part of the  European Strategy Forum on Research Infrastructures (ESFRI).
Epitope mapping. Peptides were spotted on an Amino-PEG500-UC540 membrane using a MultiPep peptide synthesizer (Intavis AG, Cologne, Germany) at a loading capacity of 400 nmol/cm 2. After synthesis the membrane was dried then the capped side-chains were deprotected by cleavage for 1h with a cocktail containing 95% trifluoroacetic acid, 3% tri-isopropyl, 2% H2O. The trifluoroacetic acid was removed and the membrane rinsed with dichloromethane, followed by dimethylformaldehyde and then ethanol. The membrane was saturated before incubation with the considered recombinant protein for 2h at room temperature. After which, it was washed three times, positive peptides were revealed using antibodies coupled to a fluorochrome. Typhoon (GE Healthcare, France) was used to determine fluorescence. The binding intensities of the considered recombinant protein for the spotted peptides were determined by quantification using ImageJ software and converted to sequence-specific normalized units.
Acknowledgements This work was supported by a grant from  "Ligue Contre le Cancer, committees of Loire-Atlantique, Maine et Loire and Vendée  ( AO2012-Subvention2013 )". MC was supported by a fellowship from  Cancéropole Grand Ouest/Région Pays de la Loire. We also thank " En Avant la Vie " (an association supporting the patients suffering from gliomas and their family, and the research on glioma field) for the funding of the Bioruptor plus sonicator (Diagenode).
Study designs and population Data from 3 randomized double-blind, placebo-controlled clinical trials of the qHPV vaccine were used in this analysis. Protocols 013 and 015 included 17,622 women (8798 in placebo group) 15-26 years old from 23 countries enrolled between December 2001 and May 2003, while Protocol 019 included 3819 women (1908 in placebo group) 24-45 years old from 7 countries enrolled between June 2004 and April 2005. Participants in the trials were followed for approximately 4 years. As Protocols 013 and 015 enrolled only a small percentage of women above the age of 23, the age range for Protocol 019 was chosen to overlap with these studies. The proportions of subjects enrolled from the following regions for the younger and older age groups, respectively, are: North America (13%, 14%), Latin America (32%, 42%), Europe (51%; 13%), Asia (2%; 31%) and Oceania (2%, only included for women aged 15-26 years).
Acknowledgments We thank  Scott Vuocolo, Ph. D. and  Karyn Davis  ( Merck & Co. , Inc. ) for assistance in the preparation of this manuscript and  Kathy Harkins ,  Jane Liao ,  Mary Anne Rutkowski ,  Weifeng Xu ,  Se Li , and  Xingshu Zhu  ( Merck & Co. , Inc. ) for statistical programming support.
Major advances in functional annotations are found in novel transcripts, promoters, enhancers, insulators, chromatin modification sites, transcription factor binding sites, as well as inter-species and intra-species conserved DNA elements. Given the flood of new genomic projects and annotations, researchers looking for the best candidate causal genetic variants are faced with a challenging task of how to efficiently integrate all current genomic information. Although some genomic databases such as Ensembl  [14]  combine information from several different genome annotation projects, they still lack some information and tools to explore in detail a particular segment of the genome. Our unique polygenic Lean (L) and Fat (F) mouse models have been described in detail in previous studies  [15] [16] [17].
Ensembl genome database and tools A 7400 bp-long segment of interest was analysed in the Ensembl database (Mouse genome coordinates:15:78399000 -78406400) (release 79)  [14]. Evolutionary constrained elements were extracted based on the nucleotide conservation between the 39 eutherian mammals in the "Location" tab under "Comparative Genomics -Alignments (text)" tree item. SNPs were categorized into variation consequence typesupstream gene variant, synonymous variant, intron variant, missense variant, nonsense variant, 5′ or 3′ untranslated region (UTR) variant and downstream gene variant. In the "Region in detail" tree item constrained elements for 39 eutherian mammals were obtained. DNA methylation state was indicated from dark blue (highly methylated), through green and then towards yellow (low methylation) and was based on the analysis in the mouse embryonic stem (ES) line.
Samples were verified on 1. 5 % agarose gel and purified with GenElute™ PCR Clean-Up Kit (Sigma). Each amplified segment was then analysed in 10 μl sequencing reactions, containing 20-80 ng/μl of PCR product and 5 μM primers for detailed Sanger-sequencing (GATC Biotech). The MEGA 6 software  [35]  was used to assemble obtained sequences and to examine possible variations between the two mouse lines. Positions and direction of forward and reverse sequencing primers are displayed schematically in Figure  S2 -B (Additional file 11: Figure  S2 ) whereas, nucleotide sequences of these primers are collated in Table  S10  (Additional file 10: Table  S10 ). Ethics statement: DNA was isolated from mouse spleen and liver of two mice per parental F and L line at 14 weeks of age. Mice were humanely euthanised using CO 2 followed by cervical dislocation.
Locus-wide analysis of the Tst regulatory elements To construct an integrative map of important regulatory elements of the Tst locus, we employed various bioinformatics tools and databases as shown in the schematic overview in Additional file 12: Figure  S1. Specifically, we searched for chromatin structure-related features such as histone modifications, open chromatin regions, potential DNA methylation sites, transcription factor, RNA polymerase and miRNA binding sites, as well as for genetic variants in all known sequenced mouse strains. As we used multiple available bioinformatics tools that often report or identify different elements or different size ranges for the same element, we decided to include all available information in a comprehensive map of Tst regulatory elements (Fig. 1 ).
The top panel of Fig. 1  shows the gene structure of the Tst gene. Ensembl database-derived reference sequence of the mouse Tst gene is 7400 bp-long and consists of 2 exons and one intron. The Ensembl or the UCSC Genome Browser do not provide annotations of any other overlapping protein or non-coding RNA gene in this segment, which was confirmed by our comprehensive bioinformatics analyses using other tools and prediction programs (see below). We next searched for evolutionary conservation of the ~7. 4kb segment across a set of 39 eutherian mammals to identify constrained elements (Fig. 1a ). Other regulatory features (Fig. 1b-h ) overlapping with sequences of constrained elements are emphasized with a grey area in Fig. 1a. These constrained elements can serve as a guide to pinpoint regions of noncoding or coding DNA with conserved biological functions, and thus may be more likely to harbour SNP variants with functional consequences  [37].
The ENCODE project uncovered two open chromatin sites for the mouse Tst gene (Fig. 1b ). The proximal DNase I hypersensitive site was found within the intron. A larger DNAse I hypersensitive site was located distally and overlapped the Tst promoter. The existence of functional open chromatin sites is corroborated by mapping TF binding sites within these regions using two different transcription factor binding sites (TFBS) analyses algorithms (Alibaba2. 1 and Motifmap) and Ensembl database annotations (Fig. 1c ; Additional file 7: Table  S7 ). Additionally, Ensembl database annotated various histone modification regions (Fig. 1d ) to the two aforementioned open chromatin regions. RNA polymerase II binding sites have been experimentally demonstrated in two different cell lines examined by ENCODE within the promoter open chromatin region (Fig.