dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgement The authors would like to thank the  National Council for Scientific Research in Lebanon (CNRS-L) , the  Lebanese University and Imaging and Brain Laboratory  and the  National Institute for Health and Medical Research, INSERM U930 in Tours (France)  for financially supporting this work. The authors are also grateful to  Prof. F. Perrotin  and his team in the Obstetric Department at  CHRU-Bretonneau Hospital of Tours  for the FHR database, and are grateful to  Miss Faten Khatib  from the  Sharp Chula Vista Medical Center  in the  U. S. for her valuable feedback.
Memory-Related Neuropsychological Data The semantic dementia patients underwent working, episodic, and semantic memory assessments. Working memory was evaluated by means of a digit span test (forward and backward;  Weschler, 1991). A visuospatial episodic learning task was conducted by using the ''Test de la Ruche''  (Violon and Wijns, 1984). In this test, patients had to learn the position of 10 black boxes in a 41-box matrix. Lastly, semantic memory was assessed by means of two tasks based on words and pictures: the French celebrities questionnaire (described in  Piolino et al. , 2003)  and a semantic sorting test, which is a type of categorization task. In the latter, patients were presented with 64 words and the corresponding colored pictures. The procedure consisted of sorting the words or pictures first into superordinate categories (e.
Statistical Analysis In view of the small sample size of the two groups, nonparametric analyses were used for internal consistency. Intergroup comparisons were examined by using the Mann-Whitney U-test. Individual differences were examined by using Z scores. Intra-group effects were examined with Wilcoxon pairwise comparisons to evaluate the effect of the experimental condition (personally familiar names vs. famous) in each group. We also used Wilcoxon pairwise comparisons to evaluate whether ''low vs. high'' emotional importance and ''low vs. high'' frequency of encounter had an impact on performance, splitting our data set according to this variable. For each task, first, we performed intra-group comparisons, including both famous and familiar names in the same model. Second, we analyzed famous and familiar names separately.
Study design USCOL (Study on the Conditions of Use and Safety of COLokit) is an observational, longitudinal, prospective, national study conducted in 108 centers in France. It was initiated in the context of a risk management plan for NaP tablets (Colokit) after Colokit became available on the French market in 2010. French health authorities approved the protocol and the administration scheme information sheet intended for patients. The primary objective was to describe the conditions of use of NaP tablets in current medical practice based on available information given by physicians to patients in France. The secondary endpoints were assessments of safety, quality of colon cleansing, result of colonoscopy, and patient's acceptability. Hospital-based or private physicians were recruited from a professional French database (Cegedim) including 3720 gastroenterologists.
Questionnaire data Physicians and patients completed dedicated questionnaires. The physicians recorded the following data for each patient at the inclusion visit and on the day of the colonoscopy: demographics, medical and surgical history, concomitant diseases and treatments, clinical examination findings, details of the procedure, laboratory tests when requested, result of gastroscopy if performed, quality of colon cleansing, result of colonoscopy, and adverse effects. In the self-administered questionnaire that each patient was given by the gastroenterologist, the patient assessed the oral and written information received regarding the administration of NaP tablets and indicated the following: number of tablets taken with the time of administration; amounts of clear liquids taken; use of a low-fiber diet and, if applicable, its duration; adverse effects; and preparation acceptability.
To take into account patients who could not be analyzed and inactive centers, 120 physicians had to be selected. The primary endpoint analysis was performed on the population of patients without missing data regarding the conditions of use. The secondary endpoints were quality of colon cleansing, lesions of the colon, safety, and acceptability. A logistic regression model (Cox model) was used for multivariate analyses (backward selection method with P < 0. 20 for the se-Table  1  Assessment of gastric lesions and their imputability to NaP tablets based on total score, according to the safety committee. 1.
Fundic localization 2 0 Multiple lesions 1 0 No gastrotoxic drug intake 1 0 No gastric symptoms 2  1 0 Negative Helicobacter pylori search result 3 0 lection of variables in univariate analysis and P < 0. 15 in multivariate analysis) of independent predictive factors of adequate use of NaP tablets and quality of colon cleansing. The data were analyzed with SAS 9. 1. 3 software (SAS Institute, Cary, North Carolina, USA).
10) from the one from the professional database. This distribution matches the results of an endoscopy survey conducted in France in 2008, which reported that 72 % of colonoscopies were performed by physicians in private practice  [15]. Because the current clinical practice was not modified in this observational study, the study population is likely representative of outpatients undergoing colonoscopy and eligible for preparation with NaP tablets. The conditions of use of NaP tablets, the primary objective of the study, identified "adequate use" when the patient complied with all the criteria for adequate conditions of use. We found that 3 of every 4 patients (75. 1 %) were in compliance with all these criteria, including the absence of contraindications. Of the patients with misuse (n = 105), half (n = 59) ingested less than 250 mL of clear liquids on at least one occasion; however, it must be emphasized that these patients drank a total of more than 2 L of clear liquids over the 2 sequences and as such consumed the total amount of liquid required in the prescribing information.
However, the evidence to support this statement was limited, and the quality of the data included in the paper was questionable  [16]. The data presented related only to the use of oral over-the-counter NaP products or oral NaP solutions and were based mainly on case series and most often collected retrospectively. In contrast, a recently published study by Layton et al. , which analyzed a large U. S. database, found no evidence of an increased risk of acute kidney injury in the general population or in high-risk subgroups of patients undergoing colonoscopy and using NaP or PEG for bowel cleansing  [23]. More controlled and prospective studies are needed to investigate these findings further. Gastric lesions were mainly erythematous gastritis-like lesions, erosive gastritis, or superficial gastric ulcerations with a blackish base, most often asymptomatic and spontaneously regressive, in agreement with post-marketing pharmacovigilance data  [24].
44), ikaros  45  , lck  46  , lysozyme C 47 , nephrosin (GenBank accession number. AY330223), csf1ra  48. The naca wild-type cDNA cloned into pCS2 þ vector was used for naca probe synthesis. Morpholino and mRNA injections. One to two-cell-stage embryos were microinjected with 4 ng of a splice blocking antisense morpholino (MO) synthesized against naca; naca MO1, 5 0 -TTAAAAGCAGTACTAACCCGTCTCA-3 0 , Genetools). Efficacy of MO knockdown was assessed by typical morphological abnormalities of oloca mutant and following SB staining. Parallel studies using another splice blocking MO (naca MO2, 5 0 -AAAAGAAAGGCATCTTACCTGTGCC-3 0 ) produced similar results, so all data presented in this study were derived from using naca MO1. For control embryos, the same amount of a standard control morpholino (5 0 -CCTCT TACCTCAGTTACAATTTATA-3 0 ) was used.
Wild-type and mutant mRNA used in the rescue assays were generated using the SP6 mMessage mMachine kit (Ambion) and co-injected with naca MO1 at a concentration of 125 ng ml À 1. Wide-field microscopy. VE-DIC and fluorescence microscopy were performed as described previously  6, 9  through the 60x/1. 00 NA water-immersion objective of a Nikon 90i microscope. Time-lapse recording of VE-DIC images was performed using BTVpro software (Bensoftware, London). Bodipy ceramide staining. Vital staining using Bodipy ceramide (Molecular probes) was performed as described previously  22. Briefly, embryos at 19. 5 h. p. f. were incubated in the staining solution (100 mM Bodipy ceramide, 2% dimethylsulphoxide (DMSO) in 10 mM HEPES (pH7. 4)/E3 medium) for 30 min. at 28 °C. Embryos were rinsed in Volvic water and subjected to confocal microscopy.
Confocal microscopy, image processing and quantification. Confocal fluorescence microscopy was performed on Leica SPE and SP8 setups as described previously  18. For quantification of the mean nls-mCherry fluorescence intensity per cell type in double Tg [TCF:nls-mCherry; Fli1:gfp] embryos, a volume of interest (VOI) was defined in 10 cells of each population of interest (stromal, somite muscle and fin mesenchymal cells) per embryo, and for each VOI the mean fluorescence/ voxel was calculated using Imaris software (Bitplane). Eight control and eight naca MO-injected embryos were thus processed. The mean of 10 cells from each cell population was subjected to statistical analysis using unpaired two-tailed Student's t-test (GraphPad Prism software). For nuclear tracking of Bodipy ceramide-stained TCF:nls-mCherry embryo, Imaris software was used for semiautomated four-dimensional tracking of nuclei over time; the tracks were manually checked under stereoscopic viewing, using Nvidia 3D-Vision glasses coupled to a double-frequency (120 Hz) video display.
The transplant capillary was cut at 25 mm inner diameter and filled with Ringer solution before use. At 40% epiboly stage (5 h. p. f. ), B50-100 cells from the donor embryos were aspirated, targeting the ventral margin of the blastoderm that will give rise to somitic mesoderm, using the CellTram micromanipulator (Eppendorf). Around 50 cells were transplanted into the exact same location of each recipient embryo. The transplanted embryos were kept in the same solution overnight at 28 °C, then the medium was replaced with Volvic/PTU the next day. The number of GFP and nls-mCherry positive stromal cells in the CHT was counted at 42 and 60 h. p. f. for in each successfully transplanted recipient embryo. Statistical analysis was performed using paired t-test (GraphPad Prism software). 4-PBA treatment.
Gene-specific primers were designed to detect an amplicon of each target gene of B150 bp. Each PCR reaction was performed with 10 ng cDNA using Power SYBR Green Master Mix (Life Technologies) and 250 nM of each primer. Primer sets used in this study are listed in Supplementary Table  2. qPCR was carried out for three biological replicates with measurements taken from three technical replicates using a ABI7300 real-time PCR machine (Life Technologies). The relative expression of each gene was determined after being normalized to zebrafish elongation factor 1a (ef1a). Data in bars represent mean ± s. d. Statistical analyses were performed using unpaired two-tailed Student's t-test (GraphPad Prism software) and P values o0. 001 were considered as significant. For the detection of apoptosis, oloca sibling and mutant embryos in various transgenic backgrounds were fixed at 3 d.
Acknowledgements The oloca mutant was identified through a large-scale genetic screen carried out at  Max-Planck Institute in Tu ¨bingen , within the  EU-funded  ' ZF-Models '  Integrated  Project. We thank  E. Moro  and  F. Argenton  ( University of Padova ) for providing TCF:nls-mCherry and TCF:eGFP transgenic lines, and  R. Kelsh  ( University of Bath ) for providing the sox10 m618 mutant in Tg[sox10:gfp] background. We thank  D. Soroldoni ,  A. Oates  ( University College London ) and  G. Gillet  ( University of Lyon ) for providing the paact-GFPI2 plasmid and pCS2 þ flag-zBcl-XL plasmid, respectively. We thank  Mylene Lancino  for her help to analyse three-dimensional data, and  Ana Cumano ,  Anne Schmidt  and  Estelle Hirsinger  for their critical reading of our manuscript. This work was supported by grants to P.
H. from the  European Commission  through the  FP6  ' ZF-Models '  Integrated Project and E-RARE  ' Neutro-Net ' project, from the  Fondation pour la Recherche Medicale  (FRM 2012 team, # DEQ20120323714 ), and from the  Laboratoire d'Excellence Revive (Investissement d'Avenir ;  ANR-10-LABX-73 ).
0 3 10 À14 ), as was the consensus TEAD/TEF1 binding motif (Figure  S2A ), consistent with TEAD family proteins being the key partners for YAP in the liver  (Liu-Chittenden et al. , 2012). We identified candidate direct YAP targets by integrating the expression analysis and chromatin immunoprecipitation (ChIP) data for TEAD binding in hepatic cells (HepG2 cells, ENCODE database; Figure  S2B ; Table  S1 ). This gene set was highly enriched for predicted targets of HNF4A and FOXA1, which are master regulators of hepatocyte differentiation that cooperatively regulate many common targets (Figure  S2B ;  Alder et al. , 2014; Bochkis et al. , 2012; Li et al. , 2012). Notably, YAP has been shown to act as a switch for enhancer occupancy of HNF4A and FOXA2 in the liver, preventing expression of mature hepatocyte genes and promoting expression of liver stem cell (hepatoblast) genes  (Alder et al.
To identify the transcriptional program underlying YAPmediated tumor maintenance, we conducted RNA-sequencing (RNA-seq) on siLuc-and siYAP-treated tumors following 9 days of treatment. GSEA revealed that YAP silencing caused potent inactivation of the E2F/cell proliferation pathway  (Figures 4G and S4D, left panel). Reciprocally, there was a pronounced induction of a hepatocyte differentiation signature (Figure  4H , left panel), including activation of a program of specific pericentral hepatocyte markers (Figure  4H , right panel), and enrichment of predicted HNF4A targets (Figure  S4D , right panel). We integrated the set of genes that were altered by siYAP-LNP treatment in HCCs with ChIP data for TEAD occupancy in liver cancer cells in order to identify candidate direct YAP/TEAD target genes in these tumors (see Experimental Procedures).
To gain further insight into transcriptional circuits, we then searched this YAP/TEAD signature for enrichment of known binding sites for other transcription factors using the ENCODE database (Figure  S4E ; Table  S2 ). In line with our observations in the DKO liver, the YAP/TEAD signature was greatly enriched for HNF4 and FOXA1 binding sites, which were ranked first and second among all transcription factors analyzed, consistent with the interplay between these factors in dictating the balance between tumor maintenance and hepatocyte differentiation (Figure  S4E ). A comparison of the day 4 and day 9 time points indicated that the differentiation markers were gradually induced. At day 4, multiple HCC nodules with patchy staining for GS and nuclear b-CATENIN were observed in siYAP-LNP-treated mice, with positively stained regions correlating with areas of more complete YAP knockdown (Figure  S4F ).
YAP-Mediated Control of Proliferative and Hepatic Differentiation Programs in Primary Tumor Cultures We used a series of early-passage HCC tumor cultures derived from independent DKO and TKO mice to examine in vitro the relationship between Yap activity and proliferation and (E) GSEA showed strong induction of a proliferation gene signature including established E2F targets. Liver-derived gene sets are indicated in red. NES, normalized enrichment score; FDR, false-discovery rate. Gene sets were obtained from the Molecular Signatures Database, except for (HNF4a_LIVER_SPECIFIC), which is a curated list of liver-specific HNF4A targets  (Saha et al. , 2014). See also Figure  S2  and Table  S1. differentiation pathways. Consistent with our in vivo data, DKO tumor cultures grew more rapidly than TKO cultures and were characterized by higher expression of multiple E2F-regulated cell-cycle genes and lower expression of a set of HNF4A targets involved in specialized hepatocyte functions (Figures  6A  and 6B ).
, 2014). We sought to extend these data by using our YAP activity signature to identify HCC subtypes potentially driven by YAP. We derived this signature of presumptive direct YAP targets by integrating the set of genes that were altered by siYAP-LNP treatment in HCCs with ChIP data for TEAD occupancy in liver cancer cells (see Figure  S4E  and Experimental Procedures). To this end, we calculated enrichment for the YAP activation signature for each of the 111 HCC patients included in our human cohort. Correspondingly, nearest template prediction (NTP) revealed that the YAP geneexpression signature had a strong negative correlation with the CTNNB1 mutation signature in this set of human HCCs  (Lachenmayer et al. , 2012; Figure   7A ). We corroborated these findings using three additional, independent HCC classification systems (Figures  S7A-S7C ).
GSEA We used GSEA (http://www. broadinstitute. org/gsea/index. jsp) of the expression data to assess enrichment of gene signatures. Depending on the data set, we used several different methods to rank genes. In the siRNA-LNP studies, we performed a pairwise GSEA by creating ranked lists of genes using the log2 ratio of siYAP-LNPs to siLuc-LNPs, and obtained p values by permuting the gene set. To identify direct target genes (Figures  S2B  and S4E ), we downloaded TEAD ChIP peaks for HEPG2 cells from ENCODE (http://genome. ucsc. edu/ENCODE/) and generated TEAD-target lists by associating genes with TEAD peaks using PeakAnalyzer  (Salmon-Divon et al. , 2010)  with the ''closest-TSS'' routine. We defined YAP signatures by comparing the differentially regulated genes in D8 or D9 and TEAD targets.
ACKNOWLEDGMENTS We thank members of the  Bardeesy lab ,  A. Kimmelman , and  W. Kim  for helpful comments, and  F. Camargo  for generously providing the Yap fl mice. We also thank the  Novartis siRNA formulation group  for preparing the siLNPs,  K. Ross  for bioinformatics assistance, and  D. Zhou  for initiation of the mouse cohort. This work was supported by grants from the  NIH/NCI  ( R01CA136567  and  P50CA127003  to N. B. and J. A. ),  NIH/NIDDK  ( R01DK099558  to Y. H. ), and the  TargetCancer Foundation  (to N. B. ). N. B. holds the Gallagher Chair in Gastrointestinal Cancer Research at  Massachusetts General Hospital. N. B. and J. M. L. are members of the  Waxman Institute without Walls. J. F. and S. B. are recipients of long-term postdoctoral fellowships from  EMBO  and the  International Human Frontiers Science Program , respectively, and both were supported by  ECOR Fund for Medical Discovery postdoctoral fellowships.
In addition, cells are located at variable optical depths and have varying shapes and protein levels, all of which introduces variability. This hampers identification of real variation in protein dynamics and prevents the common procedure of pooling data from multiple cells to reduce noise. In this study, we assess human Dystrophin dynamics in muscle cells of host zebrafish embryos, using a new approach to perform and analyse FRAP in the context of the living muscle fibre that specifically deals with the challenges of in vivo protein analysis. We thoroughly characterize the expression of the exogenous human Dystrophin within zebrafish host muscle cells. Overexpression often results in an excess of cytoplasmic Dystrophin, which is taken into account on the analysis of Dystrophin binding dynamics.
Under these conditions, we acquire a consistent signal both for GFP and huDysGFP. However, using a high laser power to image over large areas results in significant photobleaching during imaging, and, even at 100% laser power, bleaching is so slow that significant diffusion occurs during bleaching  (Weiss, 2004). We compensate for both using a mathematical model applied to the FRAP experimental data ('Materials and methods'). This was integrated in a user-friendly application written to allow easy data analysis of multiple experiments (see 'Materials and methods'). To validate our experimental conditions and FRAP analysis method in the muscle cells of zebrafish embryos, we first analysed GFP diffusion within the cytoplasm. We studied diffusion along the long axis of the muscle cell (Figure  4B ).
, 2000; Kinsey et al. , 2011) , which indicates that our approach for in vivo FRAP analysis is able to achieve similar results to those previously reported for isolated cells in culture. We used the FRAP method described above to analyse cytoplasmic huDysGFP dynamics. The Dystrophin profile immediately after bleaching, similar to that of GFP, is not a top-hat but a Gaussian, wider than the region actually bleached, and consistent with diffusion during the bleaching phase (Figure  5C ). However, the Gaussian's amplitude is narrower and the depth greater for huDysGFP than GFP, consistent with slower diffusion (compare Figure  5A, C ). Indeed, D huDysGFP best-fit values (fitted to data over ∼40 s) ranged from 1. 4 to 10. 1 μm 2 s -1 , with a mean of 4. 4 μm 2 s -1 (Figure  5D ; Table  1 ). Again, the Gaussian profile and our ability to fit a simple diffusion model to the recovery are strong evidence for huDysGFP diffusion, and rule out large scale (above μm) directed motion along the long axis of the cell, or significant binding of huDysGFP to immobile structures.
Second, the normalized intensity difference between the unbleached and bleached regions in most tips (black crosses in Figure  6C-E ) reaches a plateau above zero (Table  2 ). At the end of the experiment, both halves of the tip have received the same amount of light (and thus bleaching) for ∼250 s after the intentional bleaching phase, so the difference observed is created by the huDysGFP bleached earlier that did not turn over. Third, in the unbleached half of the tip, which receives the same bleaching-dueto-imaging as the cytoplasm, both the normalized and the absolute drops in intensity from start to end of the experiment are much larger than in the cytoplasm (compare drops in the tips with those in the cytoplasms in Figure  6F ). Thus, our FRAP data consistently confirm that a population of huDysGFP is effectively bound and immobile at zebrafish muscle fibre tips.
Two bound populations also characterize the dynamics of zebrafish Dystrophin-GFP We asked whether the labile membrane-bound pool may be a consequence of weaker binding between the human Dystrophin protein and the zebrafish endogenous protein complexes. To address this question, we analysed the dynamics of overexpressed zebrafish Dystrophin: GFP-tagged zebrafish Dystrophin (zfDysGFP). Similar to huDysGFP, the overexpression of zfDysGFP results in mosaic expression and variable levels of accumulation both at the muscle fibre tips and cytoplasm (Figure  9A ; Table  4 ). The cytoplasmic zfDysGFP diffusion dynamics was analysed by FRAP. D zfDysGFP best-fit values (fitted to data over ∼40 s) ranged from 0. 6 to 6. 7 μm 2 s -1 , with a mean of 2. 9 μm 2 s -1 (Figure  9B ). zfDysGFP has statistically significantly lower D than GFP (p < 0.
Microscopy and analysis software An upright Zeiss Exciter laser scanning microscope (LSM) with a 40×/1. 1 W Corr LD C-Apochromat objective, and an inverted Zeiss 710 LSM with a 20×/1. 0 W Plan-Apochromat and a 40×/1. 3 Plan-Apochromat objective were used for FRAP and Z-stacks. Acquisition and maximum intensity projections were made with  ZEN 2009 /2010 (Zeiss, Jena, Germany). Volocity version 6. 0. 1 (PerkinElmer, Waltham, MA, United States) was used for XYZ projection, to which a fine Gaussian filter was applied and brightness corrected for visualization purposes only. Images were uniformly contrasted with Adobe Photoshop CS4. Illustrations were made in Adobe Illustrator CS3. GraphPad Prism 6 was used for statistical analysis and graph plotting.