dataesr/scientific-paragraphs-categorization huggingface dataset:
Exome sequencing, data analysis, and interpretation ES was performed at the Broad Institute of MIT and Harvard's Genomics Platform (Cambridge, MA, USA) using a 38-Mb targeted Illumina exome capture, as described previously. 8 Data were first filtered for variants in 169 NMDcausing genes (Table  S1 ), with a minor allele frequency in the ExAC control population  9  of ≤1% and a moderate to high Ensembl Variant Effect Predictor. The resulting shortlists of single-nucleotide variants (SNVs) and small insertions/ deletions (indels) were examined for pathogenicity by two independent data analysts (M. B. /J. D. /K. J. /M. M. /A. T. at the John Walton Muscular Dystrophy Research Centre [JWMDRC] and L. X. /E. M. E. /E. V. /T. M. at the Broad Institute). We deemed SNVs and indels pathogenic if they had been previously and consistently reported as pathogenic in ClinVar (two gold stars review status; https://www.
This extended gene list also included genes newly associated with muscle disease. ES data were also analyzed for copy-number variants (CNVs)  11  and SMN1 exon 7 deletions  12  (Supplementary Materials and Methods). For those cases carrying a single heterozygous pathogenic variant in the most common (exclusively recessive) genes found in our cohort (i. e. , CAPN3, DYSF, ANO5, and SGCA) we further interrogated the noncoding regions of the gene captured in the ES data. In addition, for the DYSF carriers we Sanger sequenced two previously reported pathogenic intronic variants. 13 Finally, one patient was also subjected to genome sequence (GS) and RNA sequencing (RNA-Seq), as described elsewhere. 14.
For most of the solved cases, however, who might not benefit from specific treatment, their genetic diagnosis will nevertheless allow appropriate family planning, counseling, and monitoring of their diseases. MYO-SEQ was a worldwide partnership between academia, industry, and patient organizations. Frequent communication with the referring physicians was essential for the success of the project; to reach a meaningful diagnosis, interpretation of the genetic data was always in the context of clinical, histopathological, and MRI data. The participating centers provided consent for data sharing facilitated by the European Genome-Phenome Archive (EGA) and RD-Connect (https://platform. rd-connect. eu/), and we advocate that adopting such an approach will enable future matchmaking between extremely rare cases, such as BVESrelated myopathy  34  or LGMD R21 POGLUT1-related.
ACKNOWLEDGEMENTS We thank the patients for donating their tissue samples. MYO-SEQ was funded by  Sanofi Genzyme ,  Ultragenyx ,  LGMD2I Research Fund ,  Samantha J. Brazzo Foundation ,  LGMD2D Foundation  and  Kurt+Peter Foundation ,  Muscular Dystrophy UK , and Coalition to Cure Calpain 3. Analysis was provided by the  Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG ) and was funded by the  National Human Genome Research Institute , the  National Eye Institute , and the  National Heart, Lung, and Blood Institute  grant  UM1 HG008900 , and in part by  National Human Genome Research Institute  grant  R01 HG009141.
Model simulations and evaluation 233 A simulation was performed for each pre-crop treatment and for Experiments I and II focusing on the 234 0N wheat treatment, leading to a total of 23 simulations. The model was evaluated for its ability to 235 predict the daily amount of inorganic N and water content in the soil profile. Soil core samplings in 236 the 0-60 cm soil layer were performed monthly on wheat plots for all pre-crop treatments, between 237 January and July 2015 in Experiment I, and between October 2016 and July 2017 in Experiment II, 238 with a 5 cm diameter auger. 239 The amounts of soil inorganic N and soil moisture measured from the soil samples were expressed in 240 kg N ha -1 and mm, respectively and compared with the simulated data on the same date and for the 241 same pre-crop treatment.
Data analysis 263 Statistical analyses were performed with R software version 3. 4. 2. (R Core Team, 2016). Two-way 264 analysis of variance (ANOVA) were performed to test for year effects (2015 and 2017), pre-crop 265 effects and year x pre-crop interaction effects on wheat grain yield, shoot N concentration and shoot 266 N yield, using data collected for unfertilized N wheat. ANOVAs were also performed to test for N rate 267 effects (0N and 40N), pre-crop effects and N rate x pre-crop interaction effects on the same three 268 response variables, using data collected in 2017 for fertilised and unfertilised N wheat. In both cases 269 spring and summer pre-crops were analysed separately. When no pre-crop by year or N rate The effect of year, legume growth cycle (spring and summer) and their interaction on Nleaching, was 273 also analysed.
The homoscedasticity and normality of the residuals of the response variables were 274 tested using a  respectively. 275  For all data analysis, significant differences among treatments were identified at the 0. 05 probability 276 level of significance. 277 A multivariate analysis was performed to determine the relation between pre-crop characteristics, N 278 fluxes, environmental conditions and wheat performance. Pre-crop treatments were ordered 279 through a Principal Component Analysis (PCA) using the Canoco 5. 10 program  (ter Braak and 280 Šmilaueur, 2012). The variables were standardised to obtain equal weights in the PCA. 281.
Sequence database mining using the "search for PAMs by alignment of targets" (SPAMALOT) tool  (Chatterjee et al. 2018)  predicts that even more diversity exists within CRISPR1-StCas9 systems, and two additional groups represented by strains TH1477 and MTH17CL396 potentially target NNGAAA and NNAAAA PAMs, respectively (Supplemental Fig. S3B ). By using the strategy described above, we were able to construct highly active nucleases targeting NNGAAA and NNAAAA PAMs (Supplemental Fig. S3C ). These variants also displayed a high level of specificity for their cognate PAMs despite differing by only two residues (see below) (Supplemental Fig. S3C, D ). These data highlight the modularity inherent to Cas9 the natural diversity found within S. thermophilus strains results in true reprograming toward a distinct PAM as opposed to relaxing specificity.
St1Cas9 strain variants Sequences of St1Cas9 variants were retrieved from NCBI's Identical Protein Groups (IPG) resource, which contained 29 unique protein Mice were not fasted for measurement of glycemia; data collection occurred between 9:00 and 10:00 a. m. Animals were sacrificed by cardiac puncture under anesthesia at predetermined time points or when weight loss reached 20% of body weight. Livers were snap frozen for downstream applications.
The target (turquoise) and nontarget (blue) strands are shown as sticks (the phosphate-sugar backbones are also shown as ribbons). The ribbon representation of the PI domain is orange. The hydrogen bonds between the side chain of St1Cas9 K1086 and the nucleobase of dG4 is shown as a dashed line. (C,D) The PI domains of St1Cas9 and SaCas9 (PDB: 5CZZ, gray ribbon) are superimposed. (C) The St1Cas9 Q1084 and SaCas9 R1015 occupy the same positions relative to the PAM (dA3). The St1Cas9 E1057 and SaCas9 E993 occupy the same positions relative to St1Cas9 Q1084 and SaCas9 R1015, respectively. (D) St1Cas9 T1048 and M1049 (substituted for N1048 and D1049 in some variants) superimpose onto SaCas9 N985 and N986 that specify purines in positions 4 and 5 of the PAM. See also Supplemental Figure S3.
Acknowledgments This study was supported by grants from the  Canadian Institutes of Health Research (CIHR)  to M. L. and Y. D. and by the  Banting Research Foundation  to Y. D. S. M. acknowledges funding from  NSERC. S. M. holds a Tier 1  Canada Research Chair in Bacteriophages. A. G. acknowledges funding from the  French National Research Agency  ( ANR-18-CE11-0016-01 ). UCSF ChimeraX that was used for molecular graphics and analyses is developed by the  Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco , and receives support from the  National Institutes of Health (NIH)   R01-GM129325  and  P41-GM103311. Salary support was provided by the  Fonds de la recherche du Québec-Santé (FRQS)  to M. L. and Y. D. D. A. holds a Vanier Canada graduate scholarship.
(B) Close-up view of the 5 ′ -GCAGAAA-3 ′ PAM bound to the St1Cas9 (DGCC7010) PI domain (PDB: 6RJD). The target (turquoise) and nontarget (blue) strands are shown as sticks (the phosphate-sugar backbones are also shown as ribbons). The ribbon representation of the PI domain is orange. The hydrogen bonds between the side chain of St1Cas9 K1086 and the nucleobase of dG4 is shown as a dashed line. (C,D) The PI domains of St1Cas9 and SaCas9 (PDB: 5CZZ, gray ribbon) are superimposed. (C) The St1Cas9 Q1084 and SaCas9 R1015 occupy the same positions relative to the PAM (dA3). The St1Cas9 E1057 and SaCas9 E993 occupy the same positions relative to St1Cas9 Q1084 and SaCas9 R1015, respectively. (D) St1Cas9 T1048 and M1049 (substituted for N1048 and D1049 in some variants) superimpose onto SaCas9 N985 and N986 that specify purines in positions 4 and 5 of the PAM.
Water physico-chemistry (T • C, pH, conductivity and dissolved oxygen) was measured at the beginning (0 h) and at the end (96 h) of each experimental test with control, low-, medium-and high-contaminant concentrations. The viability of juveniles was again assessed at 48 and 96 h. In order to validate our method of exposure and to validate the use of a substrate, experiments with or without the use of substrate were conducted following the same experimental protocol as described above with NaCl as a reference toxicant  [43, 44]  and Cd. Given that the juveniles in this study came from the same cohort, experiments were conducted at different times between 2017 and 2018, allowing data comparisons to be made between animal groups of the same cohort in function of juveniles age. Organisms used for toxicity tests ranged in age from 13 to 28 months post-parasitic stage and toxicity tests were not conducted on newly transformed juveniles since new pearl mussel were produced the next year.
Data Analysis Statistical analyses were performed using RStudio version 1. 1. 442. Normality and homoscedasticity were checked using the Levene test. Differences in age-related sensitivity or between the presence or absence of a substrate, were assessed by parametric testing with a two-way analysis of variance (ANOVA) with post-hoc Tukey analysis, or when necessary, by a non-parametric test using Kruskall-Wallis with a post hoc Dunn test. Values were first converted from percentages to arcsin functions for survival data. Effective concentrations (EC50) and (EC10) values were calculated from nominal concentrations for sodium chloride and from measured concentrations for all other toxicants. These toxicity thresholds were assessed with a three parameters log-logistic model allowing us to obtain where possible, the EC50 and the EC10 with corresponding to 95% confidence intervals  [45].
05) (Supplementary data, Table  S3 ). Measured physico-chemical parameters (temperature, pH, dissolved oxygen and conductivity) during Cd and NaCl acute toxicity tests were remained very similar in the two substrate conditions (Supplementary data, Table  S2 ). In fact, the percentage viability at the end of the test to medium-high concentration exposure was 80%, whereas all organisms died in the highest exposure condition. However, the data allowed us to determine a range of toxicity threshold values between 1000 to 1500 mg NO 3 -/L, which is not representative of the natural environmental conditions. EC10s were assessed for the two NaCl toxicity tests and for the cadmium acute toxicity test conducted on 16-month-old juveniles. These values were as follow with corresponding confident intervals: 0.
Age-Related Sensitivity Table  2  shows the mean survival of juveniles in 96 h acute toxicity tests to Cd for 16-and 22-month old juveniles. The viability of 16-month-old juveniles was affected at 120 µg Cd/L with 80% survival occurring, while the viability of 22-month-old juveniles was not affected even at the highest exposure concentration. For NaCl exposure conducted with sediment, the 48-h EC50 assessed for 22-month-old juveniles was 1. 5 g NaCl/L with a 95% confidence interval of between 1. 35 and 1. 66. A previous experiment conducted on 10-month-old juveniles allowed to assess 48-h EC50 of 0. 96 g NaCl/L with a 95% confidence interval of between 0. 88 and 1. 05 (Supplementary data, Figure  S1 , Table  S1 ). However, missing data of this experiment such as water-quality parameters at the end of the experiment or measured NaCl concentrations, and the short duration of the acute toxicity test (48 h) did not allow us to confirm the robustness of these results but provided interesting information concerning the sensitivity of the youngest juveniles studied in this present study.
Efficiency was within the 86-104% range, as calculated based on concomitantly analyzing serial dilutions of a plasmid including the target sequence. Exogenous luciferase was used to normalize expression between samples. Then data were normalised to the expression level in wild-type genotype. The fragments were analysed by electrophoretic migration onto a 1. 5% agarose gel. Pools of 15 fully-grown oocytes and corresponding somatic follicular cells underwent a similar protocol for RNA purification and RT, followed by PCR with BCAR4-F2/R2 and RPL19-F1/R1. For characterizing BCAR4 transcript profile during embryo development, using Picopure RNA extraction kit as above, DNAse-treated RNA was isolated from batches of at least 20 in vivo developed embryos at each stage, or 20 in vitro developed embryos at each stage (with 16 S and 23 S ribosomal RNA as carrier), after supplementation with 1 pg/embryo luciferase RNA.
Reverse transcription was performed on 10 ng RNA from in vivo developed embryos, or RNA corresponding to 5 in vitro cultured embryos at each stage, using Superscript III enzyme (Thermofisher Scientific) and random hexamers (Thermofisher Scientific) in 20 µL final volume. cDNA was diluted 12. 5-fold, then 10 µL was used in a triplicate 25 µL PCR reaction with 100 or 200 nM gene specific primers (BCAR4-F2/R2, luciferase-F2/R2) and Sybr Green PCR Master Mix (Thermofisher Scientific). Amplicon specificity was confirmed as above. Efficiencies were calculated based on concomitant analysis of serial dilutions of pre-amplified embryonic cDNA  36. Data were analysed using QbasePlus software (Biogazelle, Gent, Belgium). Exogenous luciferase was used to normalize expression between samples. Then data were normalised to expression level in ovulated oocytes.
ovarian histology. Ovarian biopsies were fixed in Bouin solution (50% saturated picric acid, 3. 7% formaldehyde, 5% acetic acid), embedded in paraffin and serially sectioned (7 µm). The ovarian sections were stained with hematoxylin and images acquired with an Axioscan Z1 (Zeiss, Le Pecq, France) slide scanner. The cortex was drawn and its area measured using the Zen software (Zeiss). Quantitative analysis of AMH. AMH was measured in 50 µL thawed plasma diluted fourfold with plasma from a castrated male using the AMH GenII ELISA (Beckman-Coulter, Roissy, France) as previously described  12. Seven twofold serial dilutions of the standard (from 0. 078 to 5 ng/mL) diluted in the same plasma from castrated rabbit were analysed in duplicate; the mean of duplicates was used to establish the linear calibration curve (r = 0.
999). All experimental values fell within the validated range. Generation of rabbits carrying an altered BCAR4. Genome editing. The vicinity of the putative translation initiation codon was selected to design a pair of Transcription Activator-Like Effector Nuclease (TALEN) with the ZiFiT Targeter program (http://zifit. partners. org)  37. A potential TALEN target sequence identified by the program was selected with a preference for an 18-16-18 combination (16 bases for the spacer). The chosen sequences were 5′-TCCCTCTAACCACCGCAG and 5′-ACCCACATTTAACCCTGA for the left and right hem-iTALEN respectively (Supplemental Fig. S6 ). A BLAST analysis onto the whole OryCun2. 0 genome did not reveal significant sequence homology with the two hemiTALENs, or with one hemiTALEN in both forward and reverse orientations, at any other location in the rabbit genome that might have represented a likely off-target site.
Acknowledgements We thank  Edouard Guitton  and the staff of the  Plateforme d'Infectiologie Expérimentale and SAAJ (Sciences de l' Animal et de l' Aliment de Jouy) unit  for animal care,  Juliette Cognie ,  Marie-Claire Blache  and the plateforme d'imagerie cellulaire, for support and helpful discussions. The project has received funding from  INRA  and from  Agence Nationale de la Biomédecine. Maud Peyny  is a PhD student supported by the  French Ministry for Higher Education, Research and Innovation.
The largest difference in incidence rates of both FRAX ® -defined MOF and all clinical fractures between treatments occurred during the 6-to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. Conclusion In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX ® -defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. Clinical trial information ClinicalTrials.
The overall incidence rate is estimated from 0 to 24 months Fig. 3  Incidence rates of pooled clinical fractures (clinical vertebral and non-vertebral) (number of events per 100 patient-years) by 6-month periods and overall (0 to 24 months). Note: data are presented as incidence rate. The incidence rate is calculated as the number of patients who experienced at least one fracture event in the respective 6-month period, divided by the total amount of person-time contributed by the population at risk during the respective time interval. a statistically significant reduction in the IRR during the 6-to 12-month period. These add to the body of evidence suggesting a more rapid and greater fracture risk reduction in patients treated with anabolic therapies compared with antiresorptives  [1, 4, 12, 13].
Demographic data In each plot, stems with a diameter at breast height (DBH) larger than 2 cm were individually tagged, mapped and their DBH was measured before and after treatment application in March 2003. Neighboring trees located within a 3m band around the blocks were also measured to assess the competitive environment of the trees inside the plots. Annual inventories of stem DBH were then conducted every winter from 2004 to 2019 with a diameter tape. Annual stem basal area increments were calculated for each year n from 2003 to 2018 as BAIn =  4 ( +1 2 -  2 ). Trees were recorded as dead when only brown leaves remained on the tree without crown regreening during the following years. Resprouts were inventoried twice, in 2008 and 2018. For each stump, the number of resprouts, the diameter of all resprouts and the height of the dominant resprout were measured.
Stool identification and clonal structure The stool clonal structure of the coppice was visually assessed during the first inventory by grouping as clones the stems that were visibly connected to the same stump and root system. This assessment was facilitated by the shallow and rocky soil of the site where the stumps are generally clearly visible above the ground. This visual census of genetically different individuals was then confirmed by genetic analyses performed in 2018 on a subsample of 166 individuals selected in the denser unthinned plots. Leaves were collected on one stem of every identified stump and frozen on dry ice. The DNA was extracted using DNeasy 96 Plant kit (QIAGEN GmbH, Hilden, Germany) and genotyping was performed using 70 validated SNPs markers  (Bonal et al. , 2019)  developed from ddRAD-Seq data by the Genome Transcriptome Facility of Bordeaux (PGTB) following the methods described in  García et al.
Competition indexes We calculated the stem-level competition index as the sum of the neighbors' basal area in a 3m radius around each stem (BAn). BAn is a distance-independent, size-symmetric competition index. Size symmetric competition occurs when each tree exerts a competitive effect proportional to its size. This is typically assumed to be the case when belowground resources such as water are the main limitation. We also computed other widely used competition indexes: two size and distance-dependent competition indexes, the Hegyi competition index  (Hegyi, 1974)  and the Weiner competition index  (Weiner, 1984)  and the size asymmetric index Basal Area of Larger trees within a 3m radius (BAL). The models including these indexes were however always less performant than with BAn (lower or similar R 2 , higher AIC, with particularly no effect of BAL, data not shown).
Data analysis Annual stem basal area increment (BAI) were averaged over the 15 years of the experiment for each tree. This mean growth variable was first analysed as a function of thinning, rainfall exclusion and their interaction using a linear model. Then, we constructed a stem growth model as a function of individual characteristics using stem size in interaction with indexes of competition intensity (BAn), competition release (percentage difference of BAn before and after thinning, see above) and rainfall exclusion as explanatory variables. Thinning was not included in these latter models because it was redundant with competition indices and strongly inflated models VIF  (Zuur et al. , 2010). We selected the best model based on the Akaike criterion (AIC). When AIC difference between two models was lower than 2, we considered the models equivalent and selected the most parsimonious one.
The variance explained by each of the predictors was assessed using the R package relaimpo  (Grömping, 2006). Finally, the temporal evolution of treatment effects on tree growth was analysed by separating the dataset in three 5-years periods and analysing stem growth as a function of treatments, period and their interactions using a linear mixed model with stem identity as a random factor in order to account for repeated measures. In all models, stem growth was log-transformed to satisfy conditions of normality and homoscedasticity. Holm oak stem and stool mortality was analysed similarly as a function of i) treatments and ii) individual characteristics. Mortality probability was modelled using a logistic regression with a logit link. Rainfall exclusion effect on the diameter of dead trees in unthinned plots was tested with a t-test.
The year 2006 had the driest spring season over the course of the experiment, with only 52mm of precipitations between April and June (average 2003 -2018 = 211mm). Spring water limitation has been shown to be the most important environmental factor for stem growth and stand productivity in our site  (Gavinet et al. , 2019; Lempereur et al. , 2015). We thus used data from the year 2006 to quantify the impact of an extreme drought event on individual stem growth. We calculated the drought resistance for each stem as the ratio of stem growth in 2006 to mean growth in the three preceding years  (Lloret et al. , 2011). Drought resistance was analyzed as described for stem BAI and mortality as a function of rainfall exclusion and thinning treatments, then as a function of individual characteristics.