dataesr/scientific-paragraphs-categorization huggingface dataset:
Overlap of the genetic makeup of early growth traits with adult and childhood phenotypes To gain insights into the potential overlap in the genetic makeup of early growth traits with adult and childhood phenotypes, we searched databases and the literature for the phenotypic implications of our four GWAS SNPs. First, we retrieved from the Gene Atlas (9) PheWAS in the UK Biobank data all phenotypic associations (P < 5 × 10 -8 ) with our four GWAS SNPs (table  S4 ). Second, we retrieved from the PhenoScanner (10) database all SNPs in the literature with phenotypic associations (P < 5 × 10 -8 ) and in high LD (R 2 > 0. 8) with our four GWAS lead variants (table  S5 ). Third, we systematically searched in the GWAS catalog (48) database all SNPs with phenotypic associations (P < 5 × 10 -8 ) in the chromosomal regions of our four GWAS lead variants.
Bayesian colocalization Colocalization analyses were performed using our stage 1 GWAS results with multitissue eQTL results from GTEx data (www. gtexportal. org/home/datasets)  (15). For each GTEx tissue (n = 48 tissues), we first identified all genes with significant cis-eQTLs at <5% of FDR. For each such gene, we retrieved the GWAS summary statistics for each of the three traits (BMI-AP, BMI-AR, and Age-AR), for all SNPs in common between the GWAS and the eQTL data [typically everything within 1 megabase (Mb) of the gene transcription start site]. If the GWAS locus contained one or more eQTL variant at P < 5 × 10 -6 , then we implemented the computational procedure outlined in the coloc package in R (https://github. com/chr1swallace/coloc/blob/ master/R/coloc-package. R)  (50)  with default parameters and using the MAFs of European ancestry individuals from 1000 Genomes study.
nlm. nih. gov/ probe/). If the probe IDs were not available in the ProbeDB, then we aligned the probe sequence to HG38 with blast algorithm available at https://blast. ncbi. nlm. nih. gov/Blast. cgi and then annotated the transcripts overlapping the genomic coordinates using consensual information in GenBank, RefSeq, ENCODE (Encyclopedia of DNA Elements), and UCSC (University of California, Santa Cruz) databases.
Genetic correlations using LD score regression analyses We used the LD hub (57) available at http://ldsc. broadinstitute. org to quantify the genetic correlation between each of the six early growth traits and a selection of 49 disease/traits of interest from 33 GWAS studies in the following precompiled categories: education, anthropometric traits, lipids, glycemic traits, bone mineral density, neurological/psychiatric diseases, and other traits (including adiponectin, coronary artery disease, type 2 diabetes, and menarche). We carried out the LD score regression analyses for blood pressure traits using the Python scripts provided on the developer's website at https://github. com/bulik/ldsc. Before running the LD score regression analyses, each summary statistics file was reformatted using the munge_sumstats.
SNP heritability We estimated the SNP heritability, the proportion of variance explained by common SNPs (MAF > 1%), with LD score as implemented in LD hub and using our six stage 1 GWAS meta-analyses on early growth traits (see the next paragraph for detailed information on postprocessing of GWAS data for LD score analysis). LD score regression estimates were obtained using a regression model with intercept, which aims at correcting for systematic confounders in GWAS summary statistics such as population stratification. In addition, we provided SumHer (21) SNP heritability estimates due to the current debate on the (mainly downward) bias of LD score regression estimates. SumHer estimates were obtained using a regression model including an intercept. The estimates of heritability using family and twin studies were obtained from the literature using PubMed searches complemented with Google scholar.
The other parameters are taken from oxygen self-diffusion data since the anion diffusion represent the slowest mechanism in MgO, and are listed in Table  2. Starting from this equation it is possible to calculate the oxygen self-diffusion coefficient as a function of temperature for a fixed pressure. This was made for pressures ranging from 100 to 140 GPa and temperatures between 1500 and 4000 K. Each curve was sampled every 100 K and the retrieved values were plotted as a function of the homologous temperature in order to obtain a dataset to be fit with the homologous temperature relation highlighted in eq. (  4 ). The obtained dataset along with the relative fit using the homologous temperature relation is showed in Figure  1 , together with other experimental data on intrinsic anion selfdiffusion for oxides and halides from the literature.
Study sponsoring The study was sponsored by Clevexel Pharma. Study protocol was reviewed and approved by an ethics committee and the Competent Authorities (CT-CVXL-0107-01, EudraCT Number 2015-004103-23); all participants gave written informed consent. The steering committee (J. C. C. , O. R. , J. P. A, F. D. , W. G. M. ) had full access to the data, was responsible for interpretation of the results, and the redaction of the manuscript.
Acknowledgements D. M. acknowledges the  Materials Institute Carnot Alsace  (project  ProtRemote ) and the  Canceropôle Est  (project  VIVIRMAG ) for the financial supports. Bing LI would like to thank the  Chinese Scholarship Council (CSC)  for the grant during her PhD in  University of Strasbourg. Received: ((will be filled in by the editorial staff)) Revised: ((will be filled in by the editorial staff)) Published online: ((will be filled in by the editorial staff)).
On the contrary, the activation of the lower limbs was achieved by a switch controlling a humanoid walk program 21,22 , without equilibrium, requiring ceilingmounted gravitational compensation. The paradigms, software, and decoding algorithms were developed and integrated into the Adaptive Brain Signal Decoder (ABSD) framework software  23  to provide adaptive high-resolution decoding of EpiCoG activity within 350 milliseconds, comparable with reaction times measured in normal subjects  24. Initially, Recursive Exponentially Weighted N-way Partial Least Squares 23 (REW-NPLS) regression algorithm was the decoder. Switching Markov Linear Model 25 (SMLM) was later added to improve decoding stability and resting state support (Timeline, Figure  6 ). The subject had permanent access to all Degrees of freedom of the currently used model, and can control any Degrees of freedom at any moment.
C: The EMY Exoskeleton was designed as a wearable humanoid universal neuroprosthesis mimicking the human body shape and its mobility. It is self-supporting, wireless, and autonomous for 2. 5 hours. Equilibrated walking is not currently available nor achievable, but it can be achieved with a software that produces a humanoid walk and a ceiling suspension system (Vector Elite model, Bioness. http://bionessvector. com/vector). This proof-of-concept prototype will evolve toward lighter, more practicable, and higher-skilled versions. When the patient repeated motor tasks (e. g. real or virtual ) metabolic changes were detectable by fMRI (A) as BOLD signals. These signals were used to produce task-related functional images visualized using Brainvisa software (3D projections in statistical parametric mode (SPM), Supplementary Figure  1 ) of the contralateral SMC and ipsilateral cerebellum.
Similar MEG images (B) were obtained, using the Brainstorm software, for both real (upper line) and virtual (lower line) flexion of the right and left elbows. fMRI and MEG data from all limb segments were combined; the results were projected onto stereotactic atlas maps and a 3D rendering of the subject's brain. fMRI and MEG data were combined to determine the coordinates of the "hottest" SMC target (white disks, red circles) (C. 1), centered near the Rolandic sulcus (red line. These coordinates were transferred to the Image-Guided SurgiScope IGS (D. 1). According to Penfield's homunculus, the 4x4 cm ECoG grid covers the cortical primary motor M1 and sensory S1 functional areas controlling the upper limb (C. 2), but not the lower limb (located in the interhemispheric fissure). Photographs taken during the surgical procedure showed placement of implants before closing (D.
Statistical analyses All statistical analyses were performed using SAS Enterprise Guide V5. 1 (SAS Institute, Cary, USA). Statistical significance was set at p<0. 05 for all analyses with the biostatistician blinded to the treatment groups. The analyses were performed and presented as per the revised CONSORT 2010 Statement  (Schulz et al. , 2011). The Shapiro-Wilk test was used to test the normality of quantitative variables. Non-parametric tests were used to compare the FLACC scores between the two groups because they did not follow a normal distribution. The FLACC scores assessed at bag removal in the two groups were compared using the Mann-Whitney U test on the unpaired data. Missing data were imputed with best-worse case method. FLACC scores were grouped (0-3, no pain/mild discomfort; 4-6, moderate pain; 7-10, severe pain).
Frames A frame is a schematic representation of an event or scenario together with the participating actors/objects/locations and their (semantic) role  (Fillmore, 1982). For instance, the sentences 1. (a) Mary bought a car from John (for 5000$). (b) John sold a car to Mary (for 5000$). activate the same COMMERCIAL TRANSACTION frame, consisting of a SELLER (John), a BUYER (Mary), a GOOD which is sold (car), and the MONEY used in the transaction (5000$ ). Semantic frames are the standard meaning representation in CxG, which represent them as symbolic structures. The source of this information is typically FrameNet  (Ruppenhofer et al. , 2016) , a lexical database of English containing more than 1,200 semantic frames linked to more than 200,000 manually annotated sentences. The not negligible problem of FrameNet is that entries must be created by expert lexicographers.
| INTRODUC TI ON In the GEMINI 2 pivotal phase 3 clinical trial of vedolizumab (VDZ) for Crohn's disease (CD), approximately one-third of patients with active CD achieved corticosteroid-free remission at week 52. 1  Similar results were recently reported in a meta-analysis of observational studies with an estimated 1 year corticosteroid-free remission rate of 31% (95% confidence interval [CI] 20-45%). 2, 3 These data underscore that while a substantial proportion of treatment-resistant patients respond to VDZ therapy, the majority do not. Although this circumstance is likely multifactorial, variability in VDZ pharmacokinetics (PK) is a potential explanation in some patients. Specifically, high drug clearance resulting in inadequate drug exposure may be responsible for suboptimal results in some.
Accurate identification of these patients could allow a personalised medicine approach to induction therapy and greater treatment efficiency. The VICTORY consortium investigators previously developed and validated a clinical decision support tool (CDST) that classifies CD patients according to low, intermediate and high probability of response to VDZ. 13  In the current analysis, we used the GEMINI 2 clinical trial data (NCT00783692) to assess whether these differences were related to differences in measured VDZ concentrations (exposure-efficacy) and whether the CDST predicts differences in rapidity of onset of action. We subsequently performed a second external validation of the CDST based on data from a prospective cohort study (GETAID) and then, using data from both the GETAID and VICTORY cohorts, assessed whether the CDST accurately identified patients who might benefit from dose intensification.
| Data Sources and Participants Methodology for the development and validation of our CDST has been published previously. 13 In the current study, individual participant data from the phase 3 VDZ in CD trial (GEMINI 2) were used in combination with observational cohort data from the VICTORY consortium and GETAID collaboration. 14, 15 A treat-straight-through cohort was created from the GEMINI 2 clinical trial programs to mimic an observational cohort design. Patients from VICTORY and GETAID were included if they had started VDZ therapy for clinically or endoscopically active CD, had a follow-up clinical or endoscopic assessment of disease activity after VDZ initiation, and had baseline data available to calculate the CDST.
| Outcomes Our main objectives were to determine whether the previously created and validated CDST predicted measured VDZ concentrations (trough and peak) in the 52-week GEMINI 2 clinical trial and whether differences in measured drug exposure corresponded to differences in drug efficacy and rapidity of onset of action as assessed by reductions in Harvey-Bradshaw Index (HBI) over time (exposure-efficacy). The HBI was chosen given its widespread use internationally in routine practice, its availability in the GETAID cohort dataset, and its good correlation with the Crohn's Disease Activity Index. 16 Secondary objectives were to (a) externally validate the CDST in an independent multicentre cohort (GETAID collaboration) and (b) determine whether the CDST identified patients most likely to benefit from VDZ dose intensification for benefit from interval shortening and those most likely to require surgery while on active therapy.
| Statistical analysis First, we evaluated the relationship between CDST-defined probability groups, changes in HBI scores and measured VDZ concentrations using the entire 52-week GEMINI 2 study dataset (exposure-efficacy relationship). Differences in median concentrations at each time point among the three probability groups were first assessed using nonparametric testing (Kruskal-Wallis); pairwise comparisons were subsequently performed for each group at each time point. A closed testing procedure was used to control the overall type I error such that each of the pairwise comparisons was conducted at the 0. 05 level with no P value adjustments if the initial omnibus hypotheses that all of the probability groups showed equal (a) mean HBI scores and (b) median measured VDZ concentrations were first rejected at the 0.
17 Secondary analyses were performed comparing changes in HBI over time and rates of clinical remission and corticosteroid-free remission at weeks 6, 14, 22 and 30. Sensitivity analyses were done limiting the analyses to patients receiving Q8 week VDZ maintenance, as European labelling allows for an additional dose to be given at week 10 in patients with a suboptimal induction response. Categorical data were compared using chisquare or Fisher's exact test. We then assessed response to VDZ dose intensification in the GETAID cohort and VICTORY consortium according to the CDSTdefined baseline probability of response (low vs intermediate-high) to confirm whether the exposure-efficacy relationship observed could be modified by higher predicted drug exposure. The decision to dose escalate was made clinically by treating providers without consideration for CDST-defined probability of response as the providers were unaware of how the different variables were used to generate a score and how that CDST score might classify a patient's probability of response.
Using data from the most recent VICTORY consortium cohort database, we assessed differences in 52-week cumulative rates of endoscopic remission (absence of ulcers) across probability groups among patients undergoing endoscopic follow-up, and whether these differences in endoscopic remission corresponded to differences in rates of surgery between the high-probability group and the intermediate-or low-probability groups (exposure-efficacy-complication relationship). This relationship was initially assessed by groupwise and pairwise log-rank analyses and univariable Cox proportional hazard analyses. Adjustment for hazard ratio (HR) estimates was then performed for the covariates known to influence risk of surgery that were not already included in the baseline prediction model, including disease duration >2 years, ileal disease location, age >60 years, prior CD-related hospitalisation and smoking status.
| Patient characteristics The VICTORY consortium and GETAID populations had higher proportions of TNF-antagonist-exposed and female patients, and the participants were slightly older with longer disease duration at the time of VDZ treatment than subjects in the GEMINI 2 clinical trial (Table  1 ). Importantly, of the 173 CD patients in the GETAID cohort, only 55 had all the necessary baseline variables for calculation of the CDST. However, the patients with complete data had characteristics similar to the excluded patients (P > 0. 20 for all comparisons; Table  1 ).
Accordingly, we previously developed and validated a CDST for predicting response to VDZ therapy in CD. In the current study, we extend the clinical utility of this CDST through several additional analyses and an international collaboration between the VICTORY consortium and GETAID investigators, which also benefited from access to the phase 3 GEMINI trial data. In the GEMINI 2 trial dataset, the CDST-defined response categories predicted highly significant differences in measured VDZ exposure throughout the 52-week study, and this was observed irrespective of whether VDZ exposure was measured at trough  Most notably, the measured week 6 trough VDZ concentrations in the CDST-defined low-and high-probability response groups from the GEMINI 2 cohort had non-overlapping interquartile ranges, with a twofold higher median concentration being observed in the high-probability group.
In the GEMINI 2 trial dataset, we also observed that the CDST-defined response categories predicted highly significant differences in rapidity of onset of action and absolute reductions in HBI throughout the 52-week study. Specifically, throughout the first 14 weeks of VDZ treatment, the high-probability response group had at least a twofold increased reduction in HBI from baseline compared with the low-probability response group (P < 0. 001). Together these observations demonstrate a relationship between CDST-defined probability groups, VDZ exposure, and rapidity of onset of action and an ability to identify patients undergoing VDZ therapy who will have low drug exposure and slower onset of action, and therefore may benefit from early dose intensification. F I G U R E 2 GEMINI In the VICTORY and GETAID cohorts, we observed the CDST to predict differences in VDZ response comprising both rapidity of onset of action and overall effectiveness as defined by both symptomatic and endoscopic remission rates.
Our study has several strengths, including the multinational validation in mixed practice settings and extension of CDST predictions to VDZ exposure, onset of action, response to interval shortening and risk of surgery. Several limitations, however, require acknowledgment. Post hoc analyses of clinical trial datasets have inherent limitations that prevent definitive conclusions, and real-world data have inherent limitations in collection methods and consistency of assessments that may have biased the results. No specific or consistent timing was applied for the assessment of response to interval shortening in the VICTORY consortium, and the physician global assessment was used, which carries a risk for misclassification. The GETAID cohort was an early, treatment-refractory population, and only a subset had all necessary data to calculate the CDST.
The enzymatic characterization and the structure solved in the presence of calcium confirm the importance of this ion in catalysis, as observed for sGDH. The structural characterization of TrAA12 was completed by modeling PQQ and L-fucose in the enzyme active site. Based on these results, the AA12 family of enzymes is likely to have a catalytic mechanism close to that of bacterial sGDH. IMPORTANCE Pyrroloquinoline quinone (PQQ) is an important cofactor synthesized by prokaryotes and involved in enzymatic alcohol and sugar oxidation. In eukaryotes, the benefit of PQQ as a vitamin has been suggested but never proved. Recently, the first eukaryotic enzyme using PQQ was characterized in the basidiomycete Coprinopsis cinerea, demonstrating that fungi are able to use PQQ as an enzyme cofactor. This discovery led to the classification of the fungal PQQ-dependent enzymes in auxiliary activity family 12 (AA12) of the Carbohydrate-Active Enzymes (CAZy) database (www.
No three-dimensional structure of mGDH has been determined yet, but the sequence similarity with MDHs has allowed the modeling of an eight-blade ␤-propeller domain and the identification of the putative catalytic residues  (9). The second family, sGDH, corresponds to soluble GDHs, which fold as a six-blade ␤-propeller  (10). The active site of sGDH is wide, commensurate with the broad substrate specificity of the enzyme  (11) , and it was shown that sGDHs use a general base-catalyzed hydride transfer assisted by calcium  (12). Carbohydrate-active enzymes (CAZymes) are classified in sequence-based families in the Carbohydrate-Active Enzymes (CAZy) database (www. cazy. org) (13). A new category of CAZymes, named auxiliary activity (AA) enzymes, was recently introduced into the CAZy database after the oxidative cleavage of glycosides was established  (13) (14) (15) (16).
The glycosylation was confirmed by SDS-PAGE following peptide-N-glycosidase treatment (data not shown) and was observed on Asn94, Asn147, Asn184, Asn306, and Asn341 in the crystallographic structures. Various monosaccharides were tested to evaluate the enzyme activity and specificity. Several monosaccharides were tested under standard conditions requiring calcium and PQQ as cofactors. No detectable activity against D-glucose or D-fucose was found. TrAA12 preferentially oxidizes L-fucose, and weak activity was measured against D-arabinose (11. 6% relative activity), D-galactose (5. 7%), L-arabinose (2. 8%), and D-lyxose (2. 2%) (Fig. 2A ). The activity against D-glucosone was also tested, but the activity of TrAA12 was 10 times lower than that measured with L-fucose. Unfortunately, the reductive activity of D-glucosone on cytochrome c was not stable enough to yield reliable activity.
5 and above 7, only 50% and 10% of the maximum activity, respectively, was attained (Fig. 2D ). For stability in relation to pH, TrAA12 was stable from pH 3. 5 to pH 8. Below pH 3. 5, only 50% of the activity could be measured (Fig. 2E ). Three-dimensional structures of TrAA12. Three structures of TrAA12 were solved, namely, the structure of the iodide adduct for phasing, that of the native protein, and that of the catalytic calcium-containing protein (PDB accession numbers 6I1Q, 6H7T, and 6I1T, respectively). The three structures superimposed very well, and no major differences in the main chains were observed. The polypeptide chain observable in the crystal structure of TrAA12 covers amino acids Gln24 to Asn435. This domain folds as a 6-blade ␤-propeller (Fig. 3A ). This fold is frequently found in various enzyme families, where the number of blades varies from 4 to 12  (26).
The two longer N-glycans, on Asn94 and Asn306, come close to the symmetric molecule and participate in crystal packing. To understand the enzymatic mechanism, we tried to solve the structure of TrAA12 in the presence of the cofactor and of the substrate. Soaking experiments were performed on native crystals in crystallization buffer supplemented with calcium, PQQ, and L-fucose. Several crystal soaking experiments were performed, and eight data sets were collected. A large additional electron density inside a pocket and a reorganization of the amino acids surrounding this electron density were observed in each of the eight structures (Fig. 4 ). Only the best-resolution structure was deposited in the Protein Data Bank (PDB) and is presented here (PDB accession number 6I1T). Based on the difference map peak intensity, a part of the additional electron density was assigned to a second calcium ion.