dataesr/scientific-paragraphs-categorization huggingface dataset:
If missing data are not completely at random, a patternmixture model will be used. Analysis of the secondary end points will focus first on comparison of overall survival. Overall survival is defined as the time from study registration to death of any cause. Patients who are lost to follow-up will be counted at the date of their last follow-up. For all time-to-event end points, the 95% CI of the median survival will be calculated with the Brookmeyer and Crowley method  [30]. The two treatment arms will be compared with the log-rank test. Hazard ratios with 95% CI will be estimated by using Cox's univariate proportional hazards model. Follow-up will be estimated by using reverse Kaplan estimation. A multivariate Cox regression model will be performed to investigate potential prognostic factors.
Acknowledgements This study received financial support from the  National Cancer Institute  through the  2011 Clinical Research Hospital Program  grant. The authors thank the  ALIM-K study investigational group :  Dr Géraldine CAPODANO  ( Institut Paoli-Calmettes, Marseille ),  Dr Gisèle CHVETZOFF  ( Centre Léon Bérard, Lyon ),  Dr Nathalie CRETINEAU  ( Centre de Cancérologie de Lorraine, Vandoeuvre-lès-Nancy ),  Dr Olivier DUBROEUCQ  ( Institut Jean Godinot, Reims ),  Dr Cathie FISHBACH  ( Centre Paul Strauss, Strasbourg ),  Dr Laure FAVIER  ( Centre Georges François Leclerc, Dijon ),  Dr Jean-Michel FRASIE  ( Centre Paul Strauss, Strasbourg ),  Dr Vincent GAMBLIN  ( Centre Oscar Lambret, Lille ),  Dr Marie-Christine GRACH  ( Centre François Baclesse, Caen ),  Dr Bruno RAYNARD  ( Institut Gustave Roussy, Villejuif ),  Dr Christophe TOURNIGAND  ( Hopital Henri Mondor, Créteil ).
In vivo development of EEFs C57Bl/6j mice, 4 weeks old, were injected intravenously with 150,000 sporozoites and 24, 48 and 65 h postinfection mice were killed by cervical dislocation. The large liver lobe was removed, washed and images of developing EEFs were acquired using 50× Oil emersion objective on a Nataxix Inverted Objective Microscope. EEF size measurement was performed with ImageJ software  (Schneider et al, 2012).
Immunolocalization of ZIPCO-HA HepG2 cells were infected with WT-F or ZIPCO-HA sporozoites, and samples were fixed with 4% PFA at 48 h postinfection. After incubation with rat monoclonal anti-HA (Roche) and a rabbit anti P. berghei MSP1 polyclonal serum (de Koning-Ward et al, 2003) followed by Alexa Fluor 568 and 647 conjugated antibodies, samples were stained with DAPI and mounted in ProLong Antifade kit (Molecular probes). 16-bit images were acquired at the Imaging Platform of the Pasteur Institute (PFID) on a laser scanning confocal microscope (LSM 700 Zeiss) with a 63× Plan-APOCHROMAT/oil objective (Zeiss). Images were processed using the ImageJ software  (Schneider et al, 2012).
Statistical analyses Quantitative RT-PCR data in Supplementary   S4  was conducted within treatments across replicates using a non-parametric test, followed by combination of P-values from independent tests of significance using the meta-analytical approach of Fisher  (Fisher, 1932). Briefly, each treatment condition was compared to the control condition (DMEM) for each biological replicate independently, using the exact two-sided Wilcoxon rank sum test. Then, the P-values for each treatment were combined using Fisher's method. The threshold for significance was defined as P = 0. 001. All computations were done using the R statistical software (version 2. 14. 1; R Development Core Team, 2011; http://www. r-project. org/) and the exact Rank-Tests package  (version 0. 8-22). See also Supplementary Table  S4.
Acknowledgements The team of the  'Centre de Production et d'Infection des Anophèles' (Institut Pasteur)  are thanked for mosquito rearing. J. Pham  and other members of the laboratory are thanked for helping with mosquito infections. We are extremely grateful to  Dr. J-C. Barale  for providing the protein extracts of P. berghei SUB1-HA merozoites prior to publication and the anti MSP1 antibody. Dr. G. Badis-Breard ,  L. Decourty  and  Dr. C. Saveanu  are thanked for their advice and help with attempts to express ZIPCO in yeast. TS was supported by an  HHMI  grant awarded to RM. BB was supported by the  Fonds dédiés 'Combattre les maladies Parasitaires ' financed by the  Ministère de la Recherche and Sanofi-Aventis. This work was supported by funds from the  Institut Pasteur , the  Howard Hughes Medical Institute  and the  European Commission  ( FP6 BioMalPar Network of Excellence ).
We further excluded 6 cases and 9 controls for missing data on fingernail selenium, and a batch of 8 cases and 33 controls for which all measures of any elements in the fingernails were returned as null. The final analytic population was 215 cases and 331 controls. The French Polynesian Ethics Committee approved the study, and written informed consent to participate in the study and to contact his or her physician was obtained from each participant. Detailed characteristics of cases and controls are, as well as thyroid cancer risk factor estimates are reported elsewhere (de  Vathaire et al. 2010 , Xhaard et al. , 2014).
Data collection Home addresses for cases and controls were obtained through the territorial medical insurance plan that offers coverage for all inhabitants. In-person interviews were conducted in the participants' homes (though some cases were interviewed at the hospital on the day of their usual follow-up consultation) by trained interviewers and medical staff using a structured questionnaire which included questions regarding ethnicity, education, smoking, weight at various ages, personal history of thyroid disease and cancer, places of residence, reproductive and hormonal exposures, history of medical X-rays and diet. We used a French food composition table  (Favier et al. , 1995)  for the calculation of iodine and selenium intake because data were lacking in the Pacific Islands food composition tables  (Dignan et al.
Acknowledgements This study was supported by the  Association pour la Recherche contre le Cancer , the  Ligue Nationale Contre le Cancer , the  Direction Generale de la Sante , the  Comite de radioprotection de Electricite de France ,  Agence Française de Securite Sanitaire et Environnementale et du Travail, CHILD-THYR EEC  programme and the  Fondation de France. The first author  Yan Ren  has a scholarship from the  Fondation de France  for her Ph. D study.
Products For the experiments, we used Recombinant Human soluble form of Klotho and Recombinant intact Human FGF23 (R&D Systems, Minneapolis, USA). Endothelial Cell Growth kit-BBE was obtained from ATCC (Manassas, VA, USA). Phosphate (NaH 2 PO 4 ), Dulbecco's Modified Eagle's Medium (DMEM) and penicillin/streptomycin (P/S) were purchased from Sigma Aldrich (Saint Louis, USA). GlutaMAX TM (Glut) and Fluorescent probe, 29, 79dichlorodihydrofluorescein diacetate (DCF) were obtained from Invitrogen, (Saint Aubin, France) and fetal calf serum (FCS) from Dominique Dutcher Laboratories (Brumath, France). FACS Canto II flow cytometer and FACSDiva software were obtained from BD Biosciences (Rungis, France). 4-amino-5-methylamino-29, 79-difluorofluorescein diacetate (DAF-FM DA) was obtained from Merck Millipore (St.
Measurement of intracellular reactive oxygen species (ROS) production by HUVEC or HVSMC using flow cytometry To evaluate ROS production, hydrogen peroxide (H 2 O 2 ) levels were monitored using fluorescent probe, DCF. After overnight serum starvation, confluent cells were incubated with the different drugs. H 2 O 2 production was measured by flow cytometry on detached cells resuspended in PBS and analyzed in a FACS Canto II flow cytometer. The analysis was focused on the whole cell population. Mean fluorescence intensity was calculated using FACSDiva software and expressed as percentage of control value.
Measurement of intracellular NO production by HUVEC using flow-cytometry NO production by HUVEC was assessed by measuring the fluorescence of DAF-FM DA, a specific NO probe. After overnight serum starvation, HUVEC were loaded with DAF-FM DA (1. 0 mM) for 30 min. Subsequently, cells were stimulated with the different drugs for 10 min. The stimulated cells were then trypsinized and using flow-cytometry (FACSCantoII), a population of 10,000 cells was gated and segregated based on its relative fluorescence intensity. Analyses were done using FACSDiva software.
Induction of vascular relaxation by Klotho in phosphatepreconstricted aortic rings, probably via enhanced NO generation In contrast to the vasoconstrictor effect of Klotho alone, the addition of Klotho induced a concentration-dependent relaxation in phosphate preconstricted vessels (Figure  4A ) or in phenylephrine preconstricted vessels (data not shown). Maximal Klotho induced vascular relaxation was obtained within 200 sec. This relaxant effect was abolished by endothelium removal (data not shown), indicating the involvement of endothelium-derived factors. Consistent with this hypothesis, the relaxation effect of Klotho on phosphate-preconstricted vessels was blocked by the addition of L-NNA, a competitive inhibitor of NOS with selectivity for the neuronal and endothelial isoforms of the enzyme (Figure  4A ).
Experimental design This randomised, double-blind reference-controlled, six-period cross-over study was performed in a single clinical site (Biofortis, Nantes, France). The six different dairy desserts were randomly administered orally to the subjects during six different experimental sessions with at least 2 washout weeks between them. A randomisation table was generated using SAS software version 9. 3 (SAS Institute Inc. , Cary, NC, USA). A minimum of 2 weeks was kept between each test. During each experimental visit (V1-V6), the subjects arrived at the clinical site after 12 h fasting and were subjected to a clinical examination and a medical enquiry. For the subjects participating in the tolerance test only, the test meal started directly after the clinical examination at T0. When relevant, the tolerance questionnaires filled since the last visit were recovered.
Statistical analyses Summary results are presented as means ± s. d. Variables were assessed for normality of distribution. If the normality assumption was violated, a log transformation of data was performed. A repeated measures analysis of variance model using visit, dessert type and visit × dessert type interaction as fixed effects was used to compare the effects of dairy desserts containing different formulations of maltitol and scFOS on the composite score of GI symptoms within the 24 h following consumption. In case of statistically significant product effect, a Dunnett's test was conducted to compare each test dessert with the control and a Tukey's test to compare each test dessert with all the desserts. The same statistical model was applied to evaluate the effects on secondary end points: composite score of GI symptoms at 48 h, individual GI symptoms at 24 and 48 h, stool frequency (number of bowel movements per 24 h) and stool consistency (according the Bristol stool scale).
The incremental area under the curve (AUC) between 0 and 120 min (AUC 0-120 min ) for blood glucose and insulin concentrations was computed following the Food and Agriculture Organization recommendation. 14 UC 0-120 min and Cmax for glucose and insulin were analysed with an analysis of covariance (ANCOVA) model taking the baseline value for glucose or insulin accordingly as a covariate followed by a Dunnett's post hoc test (each test dessert was compared with a reference); in case of statistically significant product effect, a McNemar's test was performed to compare the frequency of adverse event between treatment groups. A statistical analysis was conducted on both intention to treat (ITT) and per protocol (PP) populations using SAS software version 9. 3 (SAS Institute Inc. ). For all the statistical tests, the 0.
Therefore, the aims of the present study were to estimate whole grain intake from all dietary sources in French children and adults and to compare it with recommendations. In addition, the associations between whole grain consumption, daily nutrient intakes and body weight status were examined. The intake data were obtained from the Comportements et Consommations Alimentaires en France (CCAF) survey carried out in 2009-10 by the Centre de Recherche pour l'Etude et l'Observation des Conditions de Vie (CREDOC). The CCAF survey collected data on anthropometry, socio-economic status, lifestyle, and consumption of foods, energy, and macro-and micronutrients in a representative sample of French consumers characterised by age, sex, education level and body adiposity status.
The participants then completed a 7 d food survey. Data for children were obtained either from the parents (children aged , 9 years) or from the children themselves (aged $ 9 years). The estimated energy intake reported by the included participants was consistent with the estimated energy requirements (1•55 times the metabolic rate), according to Schofield's equation  (36). Adult participants were excluded if their reported intake was inconsistent with the estimated energy requirements. The proportion of overweight and obese individuals (BMI. 25 kg/m 2 ) among the excluded participants was greater than that among the included participants (x 2 ; P, 0•05). There were no differences in sex distribution and education level between the included and excluded participants. To control for seasonal differences in intake, the survey was carried out in four successive phases (October -December, January -March, April -mid-June, and mid-June -July), during each of which approximately a quarter of the participants were included.
Assessment of 7 d food intake Food intake was assessed on the basis of a 7 d food diary in which details regarding the consumption of all foods and beverages were recorded. The participants were provided with a validated photographic booklet  (37)  showing various common foods and beverages in different portion sizes. Data on the energy and nutrient contents of consumed foods and drinks were obtained from a French food composition table  (38). Daily intakes were evaluated for the whole day and for individual eating occasions (main meals and snacks). The circumstances of intake (time of day, day of the week and location) were recorded.
In a few cases, intakes from the 'sandwiches' food group contributed to whole grain intake. In these rare cases (n 12 events), the whole grain intake was calculated and added to the intake from the 'bread and toasts' food group. Minimal whole grain intake (n 1) was identified for the 'cakes and pies' food group, and this intake was not included in the analysis. Details regarding the whole grain content of consumed foods were obtained from brand information and quantitative nutrient declarations (QUIDs) on food labels (52 % of all whole grain foods consumed). QUIDs were obtained from MINTEL, a market research database  (39)  , manufacturer's websites or online shopping websites. If brand or QUID information was not available, then details of the whole grain content of similar products were used (products of the same brand with available QUIDs (14 % of foods consumed), or similar ingredient list, or similar name and description (34 % of foods)).
For ease of analysis and due to the low number of consumers of certain foods, pasta and rice were grouped together, and 'mixed dishes', popcorn and cereal bars were merged into one group called 'Other'. Total whole grain consumption, computed as the total intake from the various sources mentioned above, was determined in amounts (g/d) and frequency (eating occasions per week) for the total population and for only consumers. Consumers were defined as respondents who reported consumption of a whole grain product at least once in the 7 d food diary. Tertiles of whole grain intake were defined for children and adults. Whole grain intake data were analysed in terms of age, sex, education level, geographical region, physical activity level, smoking status and BMI. The daily distribution of intake was examined in terms of time and place of consumption.
Statistical analyses The SAS 9. 2 software was used for statistical analyses (SAS Institute, Inc. ). The means and standard errors for whole grain intake were calculated according to sex, age group, education level, eating occasion, geographical location, and day of the week for the total population and for only consumers. Differences between the proportions were tested using x 2 tests. Differences in quantitative variables (such as intakes) were tested using the generalised linear model (PROC GLM) adjusted for energy (ANCOVA) or age and sex (multivariate ANCOVA). Tertile analysis was also carried out according to the levels of whole grain consumption. Multiple comparison tests were carried out with Bonferroni correction. Multiple logistic regression analysis was carried out to explore eventual associations between whole grain consumption and body adiposity status.
The prevalence of obesity in children and in adults was too low to allow any logistic regression; therefore, obesity status was aggregated with overweight. The OR and associated 95 % CI for overweight/obesity for each level of whole grain intake were calculated using multiple logistic regressions, adjusted for age, sex, education level, geographical region, physical activity level (only adults due to missing data in children), smoking status (only adults) and energy intake. Data are reported as means with their standard errors and/ or medians and percentiles. The statistical significance level was set at P,0•05. In statistical analyses with subsamples of sufficient size, data were analysed separately for children and adolescents. In all other circumstances, data obtained for children and adolescents were combined into one group.
Acknowledgements The present study was funded by  Cereal Partners Worldwide (CPW) SA, Switzerland. B. R. and S. H. are employed by  CPW. J. C. and P. H. are employed by the  CREDOC , which received funding from  CPW  to carry out the present study. F. B. contributed as a scientific consultant and received an honorarium from  CPW  for her participation. The statistical analyses were carried out by the CREDOC. The authors' contributions are as follows: B. R. and S. H. designed the study; F. B. was responsible for manuscript preparation. All authors participated in data analysis and interpretation and reviewed the manuscript.
Construct Design of Recombinant CrISA1-An Escherichia coli codon optimized gene encoding for amino acids 57-875 of C. reinhardtii isoamylase 1 (CrISA1) (GenBank TM accession number AAP88032. 1) was obtained from GenScript (NJ). The first 56 N-terminal amino acids of CrISA1 were predicted to encode a chloroplast transit peptide by ChloroP  (24)  and subsequently excluded from the construct. The pET28a-CrISA1 plasmid was constructed by inserting the codon-optimized gene into the pET28a expression vector at NdeI/XhoI restriction sites in-frame with an N-terminal His 6 tag and thrombin cleavage site. Purification of Recombinant CrISA1-BL21(DE3) E. coli cells transformed with pET28a-CrISA1 were grown at 37 °C until an A 600 of 0. 5 was reached. Cells were then induced with 0. 4 mM isopropyl ␤-D-1-thiogalactopyranoside and incubated at 30 °C for 4 h.
2A ). CrISA1 Crystallization and Maltoheptaose Soak-CrISA1 crystals were grown at 20 °C by hanging well vapor diffusion using a 1:1 volume ratio of protein (10 mg/ml) to well solution (0. 2 M triammonium citrate, pH 7. 0, and 14 -20% PEG3350). Crystals were cryoprotected using 30% glucose (w/v) (dissolved directly in crystallization buffer), 5% glycerol before flash freezing in liquid nitrogen. Maltoheptaose (M7) soaks were achieved by incubating crystals with 50 mM M7 dissolved in crystallization buffer, which were then cryoprotected in 30% glucose, 5% glycerol, 50 mM M7. X-ray Data Collection and Refinement-Diffraction data of the CrISA1 and M7 soaked crystals were collected at the ESRF ID23-1 and ID23-2 beamlines, respectively. Diffraction data were processed and scaled using XDS  (25).
Data collection statistics are summarized in Table  2. Precision-indication merging R factor values (R pim ) (26) calculated using Aimless  (27) , along with data completeness and CC 1/2  (28)  were considered in the determination of high-resolution cutoffs used for structural refinement. The CrISA1 structure was determined by a molecular replacement method using Phaser (29) and a CHAINSAW (30) trimmed structure of glycogen debranching enzyme TreX (PDB code 2VNC) as a search model  (31). Two molecules were found in the asymmetric unit, which corresponded to a solvent content of 65%. The resulting model was rebuilt using ARP/ wARP  (32) , which traced 97% of the structure. The remaining residues were manually built using Coot (33) and refined using restrained refinement and TLS refinement  (34)  in REFMAC  (35).
The refined model was subsequently used as a starting model for refinement of the M7-soaked CrISA1 structure. After rigid body refinement and restrained refinement in REFMAC, water was added using ARP/wARP solvent and glucose units were manually built using Coot. Using link restraints generated by JLigand (36), M7 was refined as a covalently bound intermediate. Refinement statistics are summarized in Table  2. Coordinates and structure factors for the CrISA1 and M7 soaked CrISA1 structures were deposited into the Protein Data Bank (PDB) with accession codes 4J7R and 4OKD, respectively. Activity Assay of Recombinant CrISA1-CrISA1 activity was measured using soluble potato AP (Sigma), glycogen (Oyster Type II, Sigma), ␤-limit dextrin (Megazyme), and pullulan (Megazyme) substrates. Substrates stock solutions of 10 mg/ml were prepared in 150 mM NaCl, 50 mM MES, pH 6.
These include the highly conserved catalytic (␤/␣) 8 A-domain (aa 184 -750), N-terminal ␤-sandwich domain (aa 76 -183), and C-terminal ␤-sandwich domain (aa 751-875) (Fig. 2B ). In the crystal structure, the N-terminal region, including the His tag and residues 57-77 of CrISA1, are disordered. The overall architecture of the CrISA1 monomer is very similar to that of TreX (r. m. s. deviation 1. 46 Å, PDB code 2VNC), Pseudomonas isoamylase (r. m. s. deviation 1. 54 Å, PDB code 1BF2)  (40) , and glycogen debranching enzyme (r. m. s. deviation 1. 55 Å, PDB code 2WSK)  (41). Calcium ions, observed in the TreX and isoamylase structures at non-conserved positions, were not observed in the CrISA1 structure. This is consistent with the experimental data that suggest that these ions are not required for ISA1 activity  (17).
3a ). Following the nomenclature described by Davies et al. (43) , the electron density spans the substrate binding groove corresponding to putative subsites Ϫ7 to Ϫ1. The glucosyl moieties of the M7 residue are numbered from the reducing to non-reducing end from G1 to G7. Moreover, connective density observed between G1 and OD1 of the catalytic nucleophile Asp-542, suggests M7 forms a covalent glycosyl intermediate with CrISA1 (Fig. 3B ). Except for a weak density in subsite ϩ2, interpreted as a glucose molecule from the cryoprotectant (Fig. 3A ), no extended density is observed at the potential ϩ1 to ϩ7 subsites. Subsite assignment was determined from structural alignment of CrISA-M7 with the structure of Trex in complex with acarbose (PDB code 2VNC). Overall, there is substantial hydrogen bonding of the M7 to the side chains of residues Glu-640, Arg-450, Asp-620, His-619, Asn-704, Tyr-314, Tyr-706, Arg-389, Trp-229, Thr-228 and the main chain of residues Tyr-331, Gly-417, Asn-387, and Tyr-315.
Acknowledgments-We acknowledge the European Synchrotron Radiation Facility  and beamline scientists at ID23-1 and ID23-2 for beam time and assistance,  Dr. Jose Antonio Cuesta-Seijo  for collecting diffraction data and assisting in the data processing of the CrISA1⅐M7 crystal,  Dr. Alexander Striebeck  for assistance with the enzymology, and we thank DANSCATT for access to synchrotron beam time.