dataesr/scientific-paragraphs-categorization huggingface dataset:
Results The biochemical profiles of the forebrain were measured at all ages using a combination of liquid chromatography-mass spectrometry approaches covering a broad range of hydrophilic and hydrophobic compounds. This combination of approaches measured a total of 469 metabolites in the forebrain. Principal components analysis (PCA) was performed on the forebrain profiles to identify sources of metabolic variation in the dataset. The scores plot generated from the PCA model comparing the neurobiochemical profiles of all ages shows clear separation by age (Supplementary Figure  S1 ). The largest variation in the metabolic profiles (principal component 1 (PC1), 82. 8% variance) was observed between post-natal day (P)3 and the two older age groups (P21 and P60). The main drivers behind this separation were the higher amounts of proline, taurine, phosphocholine, adenosine monophosphate, citrulline, 1-palmitoyl-2-palmitoleoyl-glycerophosphorylcholine, trans-4-hydroxyproline, threonine, and spermidine in the P3 animals compared to in the older mice and the lower amounts of glutamate, creatine, adenosine, N-acetylaspartate, glutamine, γ-aminobutyric acid (GABA), stearate, stearoyl sphingomyelin, arachidonate, glycerophosphorylcholine, oleate, palmitate, and docosahexaenoate.
Data Analysis Raw data were extracted, peak identified, and QC processed using the hardware and software of Metabolon. Compounds were identified by comparison to library entries of purified standards. Peaks were quantified according to area-under-the-curve. Metabolic data was imported into MetaboAnalyst (www. metaboanalyst. ca). Volcano plots were generated for pair-wise comparisons (P21 vs. P3/P60 vs. P21) using a two-fold change and an FDR-adjusted p < 0. 05 threshold. Metabolites found to meet these criteria were used for pathway analysis, applying the hypergeometric test (over representation analysis; p < 0. 05) and relative-betweenness centrality (pathway topology analysis), with the KEGG Mus musculus pathway library. Principal component analysis (PCA) was performed using mean centered and pareto scaled data.
Analysis of individual metabolites was performed using SPSS Statistics 26 (IBM). Metabolite abundances were compared between time points (P3, P21, and P60) by one-way ANOVA and equality of means measured by the Brown-Forsythe test. All results were confirmed by Kruskal-Wallis one-way ANOVA. Differences between each age group (P3 vs. P21/P3 vs. adult/P21 vs. adult) were assessed using post hoc pairwise comparisons with Bonferroni correction for multiple tests. The box plot hinges represent the 25th and 75th percentiles, and the median is plotted as a midline. The whiskers represent the minimum and maximum values. The significance level alpha was defined as a p value < 0. 05.
The EEHG spectrum and intensity was recorded for three values of the spreader momentum compaction, i. e. , R 56 ≅ -2; 0; þ2 mm (four-dipole chicanes have negative R 56 with this convention). The linear optics functions are shown in Fig. 1 , and the R 56 along the line is in Fig. 2. For each setting of the quadrupole magnets devoted to produce a specific R 56 value, the FEL intensity was reoptimized as a function of the electron beam optical Twiss parameters at the entrance of the undulator, seed laser parameters, and strength of the dispersive sections of the EEHG scheme. By virtue of the small correlated energy spread at the entrance of the spreader (<0. 1%, rms value), the bunch length differences between datasets due to first-and higherorder transport matrix terms were negligible (<2%).
Finally, the spreader optics was tuned to also preserve the beam bend-plane emittance from CSR emitted in the dipoles  [45]. The final emittance values reported in Table I are the largest values among all the measurements, which were repeated at each change of R 56. The EEHG output was recorded on a single-shot basis at the on-line spectrometer. In the following, the FEL data refer to the average of 41 consecutive FEL shots recorded at 50 Hz. Each dataset was measured as a function of the laser heater pulse energy, as shown in Fig. 3(a). The contribution of the pedestal to the spectrum was evaluated by fitting the central FEL line with a Gaussian. The area of the Gaussian was subtracted from the total integrated spectrum signal. Doing so, we calculated the ratio of the pedestal signal (A SB ) and the total FEL signal (A tot ), as shown in Fig.
A decision to proceed from one dose to the next was made jointly by the sponsor and the investigator on the basis of reviewing the preliminary safety and PK exposure data of the previous dose. The study comprised of a screening period of up to 26 days during which an FMD threshold of <7% was used to enrich for patients with dysfunctional endothelium. SAR247799, sildenafil and placebo capsules were taken under fasted conditions each morning from day 1 to day 28 (inclusive) and there was a 14-day follow-up period till the end of study visit on day 42. There was a 4-day in-house period (day -2 to day 3) followed by ambulatory conditions with various in-house periods for FMD assessments (day 13-14, day 20-21, day 27-28, day 34-35   and day 41-42). Patients were randomized on day 1 to receive SAR247799, placebo or sildenafil in 5:2:2 ratio if they met all inclusion/exclusion criteria (at day -1 and/or day -2).
The focus zone was set to the depth of the anterior vessel wall and depth and gain settings were optimized to identify the lumen vessel wall interface. The maximum brachial artery diameter was determined by continuously imaging from prior to cuff inflation until 2 min after cuff release. The ultrasound images were recorded directly onto the hard disk of the ultrasound machine and image analysis performed using an automated edge-detection software (Vascular Research Tools 5, Medical Imaging Applications LLC, Coralville, Iowa, USA) as previously described. 54 FMD was expressed as the percentage change in BAD following reactive hyperemia.
KG, Mainz) and was approved by the competent authority as well as two independent ethics committees (Local Ethical Committee of Düsseldorf and Local Ethical Committee of Mainz, Germany). The study was performed in accordance with the clinical trial protocol and with ethical principles having their origin in the Declaration of Helsinki. All patients provided written informed consent before participating. The trial was prospectively registered with Unique identifier NCT0346201 on 12/03/2018 (www. clinicaltrials. gov). The study dosing scheme is summarized in Fig. 3A.
ACKNOWLEDGEMENTS. The authors thank the study participants, the clinical research staff at the 2 sites,  Charlene Buffat  and  Thomas Rizard  for trial management support,  Ariane-Saskia Ries  and  Katharina Iwaniuk  for study organization at Mainz and Neuss sites, respectively,  Carol Damon  for data programming,  Anne Charlier ,  Clementine Chopin  and  Mélanie Mellerin  for compound supply,  Delphine Marin  and  Mélodie Hermier  for data management,  Michel Scemama  for pharmacovigilance support,  Helene Joyeux ,  Christine Maestrini  and  Tadashi Sugihara  for regulatory support,  Didier Simard  and  Brigitte Molinier  for biomarker evaluation,  Catherine Cadrouvele  for in vivo study support, and  Dorothee Tamarelle  for certifying preclinical statistics.
Data availability statement. All relevant preclinical and clinical data are provided within the paper and its supporting information files. Qualified researchers may request access to patient level data and related study documents including the clinical study report, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at www. clinicalstudydatarequest. com.
Acknowledgments Lots of thanks to  Thomas Pradeu ,  Jean-Francois Moreau ,  André Ariew ,  Wiebke Bretting ,  Anne Coubray ,  Jan-Pieter Konsman ,  Fridolin Gross ,  Maël Lemoine ,  William Morgan ,  Simon Okholm ,  Elena Rondeau ,  Martin Zach , and all the immunologists responding to a 250 word version of the main hypothesis:  Gérard Eberl ,  Akiko Iwasaki ,  Rob Knight ,  Bruno Lemaitre ,  Sarkis K. Mazmanian ,  Margaret McFall-Ngai , and  Philippe J. Sansonetti. I would also like to thank two anonymous reviewers for their very helpful comments and suggestions. This project has received funding from the  European Research Council (ERC)  under the European Union's  Horizon 2020 research and innovation programme  -grant agreement n o 637647 -IDEM (P. I. :  T. Pradeu ).
9 and concentrated to a final concentration of 8 mg ml -1. Equal volumes (0. 1 l) of protein-DNA complex and reservoir solution were mixed and equilibrated against 50 l of reservoir solution. A single crystal appeared after 5 days in an in-house screen (25% PEG 3350, 0. 2 M L i 2SO 4 , 0. 1 M bis-tris pH 6. 5) reaching its full size (130 × 60 × 60 m) after 5 weeks. Crystals of the Hoxb13 DR0 complex were cryoprotected with Parabar 10312 (Hampton Research) before being flash cooled in liquid nitrogen. Data were collected on a Pilatus 6M Hybrid Pixel Detector (Dectris) at the Proxima 1 beamline of the synchrotron SOLEIL. 180 • of data were collected using 0. 1 • rotation and 0. 1 s exposure per image (50% transmission). Crystals of the Rarb2 DR5 complex were transferred to 35% PEG 3350, 0. 2 M Li 2 SO 4 , 0.
1 M bis-tris pH 6. 5 before flash cooling in liquid nitrogen. Data were collected on a Pilatus 6M Hybrid Pixel Detector at the ID23-1 beamline of the ESRF using the MxCuBE software  (26). 180 • of data were collected using 0. 1 • and 0. 037s exposure per image (46% transmission). All data were indexed, integrated and scaled using XDS  (27)  before performing anisotropic truncation and correction with the STARANISO server (http://staraniso. globalphasing. org). The crystals of the complex with the Hoxb13 DR0 diffracted anisotropically to 2. 1 Å (2. 7 Å in the worst direction) and belonged to the primitive monoclinic space group P2 1 , with unit cell dimensions a = 45. Both structures were solved by molecular replacement using PHASER  (28)  in the PHENIX suite  (29). A monomer of the RXRA DBD bound to 6 bp of DNA from the structure of complex with the human Nr1d1 response element (PDB ID: 4CN5 (  23 )) was used as a search model.
Small angle X-ray scattering Synchrotron SAXS data were measured from samples of MmRXRA AB-MmRARA ABF -F11r DR5 and -Hoxb13 DR0 utilising split-flow in-line SEC-SAXS coupled to a right-angle laser light scattering (RALLS), UV absorption spectroscopy and refractive index (RI) tripledetector array (Malvern Instruments Viscotek TDA 305) on the EMBL bioSAXS-P12 beam line ( = 0. 124 nm, 10 keV) at the PETRA III storage ring, Hamburg, Germany  (34)  employing BEQUEREL SEC-SAXS control software  (35). Samples of RXR-RAR-F11r DR5 and RAR-RXR-Hoxb13 DR0 were made to an approximate injection concentrations of 4. 8 and 5. 5 mg/ml, respectively, in 20 mM Tris, 75 mM NaCl, 75 mM KCl, 5% (v/v) glycerol, 1 mM CHAPS, 4 mM MgSO 4 , 1 mM TCEP, pH 8 and 100 l of each sample were successively injected onto a GE Healthcare Superdex 200 10/300 column (equilibrated in the same buffer) at a flow rate of 0.
5 ml min -1. The SAXS data were collected every 1 s for a total of 2900 s for each sample elution profile. Data were processed using the SASFLOW pipeline (36) that included the identification of an appropriate solute-free blank for buffer subtraction purposes. Structural parameters and additional evaluations of the SAXS data were performed using the ATSAS 2. 8 software package  (37). The R g was determined from the Guinier approximation  (38)  (ln I(s) versus s 2 , for sR g < 1. 3) and from the p(r) profiles that were calculated using GNOM (39) which also provided estimates of D max. In all instances, PRIMUS (40) was used to manually evaluate the appropriate Guinier range and to calculate the R g (Supplementary Figure  8 ) while the consistency of R g of the individual SAXS data frames through the SEC-elution peaks for either complex were automatically determined using AUTORG  (41).
The molecular mass of the complexes were evaluated from the TDA measurements -calibrated relative to monomeric bovine serum albumin -using the Malvern Omnisec software where the refractive index increment, dn/dc, was set to 0. 185 mL g -1 (Supplementary Figure  8 ). Concentration-independent MW estimates extracted directly from the SAXS data were evaluated using Bayesian inference  (46). The modelling program CORAL (47) was used to rigid-body refine the structures of the RXR-RAR-F11r DR5 and RAR-RXR-Hoxb13 DR0 complexes. The resulting models were constructed by combining the highresolution models of the LDBs and DBDs (PDB 6XWG, 6XWH, 1XDK and 3A9E) with the respective response element and connecting the domains with appropriate length linkers, modeled as a string of dummy amino acids, and allowing the domains and linkers to refine their spatial position(s) against the SAXS data (47).
The CORAL rigidbody modelling routines were run several times to assess the stability of the results in context of the ambiguity of the SAXS patterns (Table  1 ). The final fits of the model scattering to the experimental data were computed using CRYSOL  (48)  and the model/data similarity evaluated using the reduced χ 2 test and CorMap P values. All data and models have been deposited to the SASBDB (SASBDB; www. sasbdb. org; (49) ) with the accession codes SASDFT8 and SASDFU8, including the unsubstracted SEC-SAXS data frames, the RALLS/RI MW analysis and all CORAL models that fit the SAXS data.
The instrumental response function (IRF) was recorded using a polished aluminum reflector, and its full-width at half-maximum was ∼30 ps. Fluorescence emission was recorded at 520 nm through a 4 nm band-pass monochromator (HORIBA Jobin-Yvon) on a micro-channel plate photomultiplier (Hamamatsu) coupled to a pulse pre-amplifier HFAC (Becker-Hickl GmbH). The single-photon events were recorded on a time correlated single photon counting board SPC-130 (Becker-Hickl GmbH). The software SPCM 9. 75 (Becker-Hickl GmbH) was used to record the data and build the photon distribution over time. Fluorescence decays were deconvoluted from the IRF and fitted by the maximum entropy method using the Pulse 5 software  (51, 52)  to retrieve the most probable lifetime distributions. In all cases, the 2 values were close to 1 and the weighted residuals, as well as the autocorrelation of the residuals were randomly distributed around zero, indicating an optimal fit.
All measurements were performed at 25 • C. Analysis was performed with the switch-ANALYSIS software from Dynamic Biosensors. Normalized Dynamic Response values were obtained by subtracting the signal measured upon injection of a volume of buffer corresponding to injections performed in each titration measurement. The association and dissociation rate constants (k on and k off ) of the RXR-RAR interaction with DNAs were derived from a single-exponential fit model. Measurements were performed in duplicate, and values reported represent the mean k on and k off of the datasets, leading to an average K D by: K D = k off,avg /k on,avg.
Functional data showed that RXR-RAR bound to DR0s are not able to modulate gene expression in a transcriptional reporter assay  (18). The complementary approaches reported here provide important information for understanding the structural basis of DNA recognition of DR5 and DR0 elements and the allosteric control of RXR-RAR activity. In this study, we determined the crystal structures of the RXR-RAR DBDs with Rarb2 DR5 and of the RXR-RXR DBDs with Hoxb13 DR0 response elements. The only previously reported structures of RXR-RAR DNA complex was obtained with the idealized DR1 element  (20, 21). In the DR5 complex reported here, although most of the residues involved in DNA binding are conserved, additional specific contacts are observed. More importantly, binding to the Rarb2 DR5 induces a DNA curvature that allows the two DBDs to interact.
ACKNOWLEDGEMENTS We are grateful to  Jacob Piehler  ( University of Osnabr ück, DE ) who kindly provided  OG488-TrisNTA ,  Guillaume Bec  and  Eric Ennifar  ( IBMC, France ) for the Switchsense experiments. We thank the staff of Proxima 1 at synchrotron SOLEIL and of ID23-1 at  ESRF  for assistance in using the beamlines.
FUNDING Agence Nationale de la Recherche  [ ANR-11-BSV8-023 ]; Fondation ARC [SFI20121205585];  French Infrastructure for Integrated Structural Biology (FRISBI)  [ ANR-10-INBS-05 ]; Instruct-ERIC;  Agence Nationale de la Recherche  under the  program Investissements d'Avenir  [ ANR-10-LABX-0030-INRT ,  ANR-10-IDEX-0002-02 ];  French Proteomic Infrastructure ProFI  [ ANR-10-INBS-08-03 ]; Portions of the research received funding from the  European Community 's  Seventh Framework Programme  [FP7/2007-2013] under BioStruct-X [283570 to D. I. S. ] and from the  Bundesministerium f ür Bildung und Forschung (D. I. S. award nos. BIOSCAT [05K12YE1 ]);  Horizon 2020 programme  of the  European Union , iNEXT [653706 to D. I. S. ]; the authors thank  GIS IBiSA and Région Alsace  for financial support in purchasing a Synapt G2 HDMS instrument; M.
1) 2. 5 (4) Flat/modular (13. 3) 2. 9 (4) #shape topologies 330 853 Uniqueness Highly ambiguous Highly ambiguous Atomistic modelling Method  ‡ ‡ CORAL CORAL Final model fit evaluation  ‡ ‡ ‡ CRYSOL CRYSOL Model R g (nm) 3. 8 4. 0 Model fit to data (χ 2 , CorMap P)  † 1. 2, 0. 03-0. 13 1. 8, 0. 36-0. 59 Small angle scattering biological data bank Accession code SASDFT8 SASDFU8 Automation Manager (Waters), while chromatography was carried out on Acquity UPLC system with HDX technol- ogy (Waters, Manchester, UK). Samples were incubated at 20 • C for five deuteration timepoints including 0. 5, 2, 10, 30 and 60 minutes in 95% of 20 mM Tris, 75 mM NaCl, 75 mM KCl, 2 mM CHAPS, 4 mM MgSO 4 , 1 mM TCEP, pD 8 deuterated buffer. The labelling reaction was then stopped by adding 1:1 (v/v) 2 M guanidine-HCl, 100 mM glycine, 100 mM TCEP, pH 2.
Isolation and growth conditions In 2014, we isolated an unidentified bacterial strain from a stool sample collected from a 7-month-old healthy girl from Niger with a weight-for-height z score of 0. 15. The child's parents gave an informed consent to participating in the study. Screening was made by MALDI-TOF MS on a Microflex LT spectrometer (Bruker Daltonics, Bremen, Germany) as previously described  [7]. The obtained spectrum (Fig. 1 ) was imported into the MALDI Biotyper 3. 0 software (Bruker Daltonics) and analysed against the reference spectra of bacteria included in two databases (Bruker and the constantly updated URMS databases (https://www. mediterranee-infection. com/urms-data-base/)). The study was validated by the ethics committee of the Institut Fédératif de Recherche 48 under number 09-022.
Strain identification The 16S rRNA gene was sequenced to classify this bacterium. Amplification was done using the primer pair fD1 and rP2 (Eurogentec, Angers, France) and sequencing used the Big Dye® Terminator v1. 1 Cycle Sequencing Kit and ABI Prism 3130xl Genetic Analyzer capillary sequencer (Thermofisher, Saint-Aubin, France), as previously described  [8]. The 16S rRNA nucleotide sequence was assembled and corrected using the CODONCODE ALIGNER software (http://www. codoncode. com). In 2017, strain Marseille-P1935 was considered as a representative of a new bacterial species within a new genus for which the name Khelaifiella massiliensis was proposed  [9]. However, this name was not validly published and, in the present study, we obtained a 99. 12% 16S rRNA nucleotide identity between strain Marseille-P1935 and Haloimpatiens lingqiaonensis strain JCM-19210 T (GenBank accession number KC869664), the phylogenetically closest species with standing in nomenclature (Fig.
Genome sequencing Genomic DNA was extracted using the EZ1 biorobot (Qiagen, Courtaboeuf, France) with the EZ1 DNA tissue kit and then sequenced on the MISEQ technology (Illumina, San Diego, CA, USA) with the Nextera Mate Pair sample prep kit (Illumina), as previously described  [12]. The assembly was performed with a pipeline incorporating different softwares (VELVET  [13] , SPADES  [14]  and SOAP DENOVO  [15] ), on trimmed data (MISEQ and TRIMMOMATIC  [16 -19]  softwares) or untrimmed data (only MISEQ software). GAPCLOSER was used to reduce assembly gaps. Scaffolds <800 bp and scaffolds with a depth value < 25% of the mean depth were removed. The best assembly was selected by using different criteria (number of scaffolds, N50, number of N). The genome of strain Marseille-P1935 was 4 214 685 bp long with a 29.
8 mol% G + C content and 28 contigs. The degree of genomic similarity of strain Marseille-P1935 with closely related species was estimated using the ORTHOANI software  [20] [21] [22]. Strain Marseille-P1935 exhibited an 87. 18% ORTHOANI value with H. lingqiaonensis (Fig. 4 ). An ANI value < 95% between two strains suggests that they belong to distinct species. Using the Genome-to-Genome Distance Calculation software  [23] [24] [25] , the digital DNA-DNA hybridization (dDDH) of strain Marseille-P1935 with H. lingqiaonensis was 34. 9% (Table  2 ). This value was lower than the 70% threshold used for delineating prokaryotic species. Finally, the phylogenetic tree based on the genometo-genome distance showed that strain Marseille-P1935 and H. lingqiaonensis belonged to distinct species (Fig. 5 ).
However, negative reactions are obtained for glycerol, erythritol, D-arabinose, L-arabinose, D- ribose, Kd-xylose, L-xylose, D-adonitol and methyl-βD-xylopyranoside. The genome is 4 214 685-bp long and its G + C content is 29. 8%. The type strain, Marseille-P1935 T , isolated from a stool sample collected from a 7-month-old healthy girl from Niger with a weight-for-height z score of 0. 15, was deposited in the CSUR and DSMZ collections under accession numbers CSUR P1935 and DSM 100591, respectively.
Images were captured at 433 nm monochromatic excitation wavelength. The acquisition rate was 20 images/min. Image analysis was performed with ImageJ software  [14]  using a homemade macro, and the fluorescence emission ratios were derived after subtracting the background. We observed that during acquisition, photobleaching gradually decreased the steady-state ratio with a linear kinetic (not shown). This drift was thus, when necessary, corrected in the function of time with a constant factor. All spectra were acquired using an Orbitrap Fusion Tribrid Mass Spectrometer controlled by Xcalibur 3. 0 software (Thermo Scientific) and operated in data-dependent acquisition mode using an SPS-MS3 workflow. FTMS1 spectra were collected at a resolution of 120 000, with an automatic gain control (AGC) target of 400 000 and max injection time of 100 ms.
Data analysis The raw data files were processed and quantified using Proteome Discoverer software v2. 1 (Thermo Scientific) and searched against the UniProt Rat database (downloaded in January 2019; 35759 entries) using the SEQUEST algorithm. Peptide precursor mass tolerance was set at 10 ppm, and MS/MS tolerance was set at 0. 6 Da. Search criteria included oxidation of methionine (þ15. 9949) as a variable modification and carbamidomethylation of cysteine (þ57. 0214) and the addition of the TMT mass tag (þ229. 163) to peptide N-termini and lysine as fixed modifications. Searches were performed with full tryptic digestion and a maximum of 2 missed cleavages were allowed. The reverse database search option was enabled and all data were filtered to satisfy false discovery rate (FDR) of 5%.