dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical analyses Statistics were performed using R Studio. Differences in origin usage between repeats of a given condition and datasets for distinct conditions were analyzed by conducting independent-samples T-tests (two-sided) (S2 Table ). These assessments showed that the alterations in origin usage observed upon modulating CDK timing and activity are statistically significant, while this is not the case for individual repeats of a given condition. The Spearman's rank correlation coefficient was evaluated for the comparisons in Figs  1F  and 2E , Figs 3B, 3D and S6. For DNA combing analysis, differences in interorigin distances between conditions were evaluated by conducting independent-samples T-tests (two-sided) (S5D Fig).
Accession number The array data reported in this paper have been deposited in the NIH GEO database and has been assigned the accession number GSE88714. efficiencies. Left panel: x-axis: efficiencies in G2B, y-axis: efficiencies in G1+15; right panel: x-axis: efficiencies in G2B, y-axis: efficiencies in G1+5. Each dot represents an origin. The dashed lines represent efficiencies if they were identical in the two compared backgrounds. C) Analysis of origin efficiencies in cells that have undergone different lengths of HU treatment. Cdc13-Cdc2 cells were synchronized as in Fig 1A but treated with 24 mM HU for either 60 min (G2B) or 90 min (G2B+30) (specifically, cells were harvested 70 min and 100 min after release from G2, respectively). G2B data are as in S2B Fig. Origin  efficiencies in the two conditions are virtually identical despite significant differences in the duration of the HU treatment (see also S2 Table ).
x-axis: efficiencies in G2B; y-axis: efficiencies in G2B+30. Each dot represents an origin. The dashed line represents efficiencies if they were identical in the two compared backgrounds. D) Regional analysis of origin efficiencies in individual replicate experiments in the G2B (Top), G1+5 (Middle), and G1+15 (Bottom) conditions. Average origin efficiencies were determined in continuous windows of 1000 probes (~250 kb). Black: experiment 1, red: experiment 2. Dashed line indicates the mean efficiency of all origins in each experiment; the corresponding experiment is indicated by the color. The average efficiency values are as follows: G2B: 25. 4% and 24. 5%; G1+5: 33. 0% and 30. 8%; G1+15: 29. 4% and 29. 5. x-axis: chromosome coordinates, y-axis: average origin efficiencies. These results show the high level of reproducibility of our datasets.
S6 Fig. Comparisons of origin efficiencies from individual experiments for each condition. A-J) Graphs comparing the two repeats of origin mapping experiments performed in all conditions in this study. The Spearmans' rank correlation coefficient (ρ) for each comparison is displayed. ÃÃÃ : p < 0. 001. The dashed black lines represent efficiencies if they were identical in the two repeats. x-and y-axes: origin efficiencies in the indicated conditions. These results show the high level of reproducibility of our datasets. (PDF) S1 Table. List of origins identified in all experimental conditions along with their efficiencies. (XLSX).
Acknowledgments We thank members of the  Genome Duplication and Maintenance team  for helpful discussions. We are grateful to  Feriel Baïdi  and  Damien Coudreuse  for sharing unpublished strains. We thank  Biogenouest Genomics  and the  Human Environmental Genomics core facility of Rennes (Biosit/OSUR)  for technical support. We also thank  Damien Coudreuse  for invaluable discussions and critical reading of the manuscript.
Funding: This study was supported by grants to PYJW from the  Centre National pour la Recherche Scientific (CNRS , www. cnrs. fr)/ Institut national de la santeet de la recherche medicale (INSERM, www. inserm. fr)through the  ATIP-Avenir program  and the  Fondation pour la Recherche Medicale (FRM , www. frm. org)through the  "Amorcage de programsfunding  from the  Region Bretagne  (www. bretagne. bzh), the  Fondation ARC  (www. fondation-arc. org),and the  Institute of Genetics and Development of Rennes  (igdr. univ-rennes1. fr). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Introduction Marfan syndrome (MFS; OMIM #154700) is an autosomal dominant connective tissue disorder with an estimated prevalence of 1/5000 individuals. It is a multisystemic disease that affects the ocular, skeletal, and cardiovascular system as well as lung, skin, and dura. Thoracic aortic aneurysm (TAA) is the main cardiovascular feature that can lead to dissection or rupture of the aortic wall, the major life-threatening event in MFS. In most cases, MFS is due to mutation in the FBN1 gene encoding fibrillin-1, an extracellular matrix protein. To date, over 3000 mutations have been reported in the FBN1 database  [1, 2]. The syndrome displays great clinical variability, regarding age of onset and number and severity of the symptoms that cannot be explained by the few genotype-phenotype correlations identified between FBN1 mutations and MFS.
PCR was carried out on a thermal cycler for 40 cycles using a 55 • C annealing temperature and fluorescent level of each droplet was read using the QX100 Droplet Reader (BioRad, Marnes-la-Coquette, France). Data were analyzed and the concentration of mRNA levels for both genes and the ratio of gene of interest/reference gene were calculated using QuantaSoft software (BioRad, Marnes-la-Coquette, France). Each DNA sample was run in two technical replicates and three biological replicates.
Mimic and micro RNA (miRNA) Transfection TargetScan  [9]  was used to predict biological targets of micro RNAs (miRNAs) by searching for the presence of conserved sequenced corresponding to miRNA binding site. P CT (probability of conserved targeting) estimates the probability of the site being preferentially conserved because it is targeted by the cognate miRNA  [10]. For the transfection assay, 6 × 10 5 skin fibroblasts were seeded in each well of 4-well plates (21. 8 cm 2 /well). Transfection was performed using Hiperfect Transfection Reagent (Qiagen S. A. , Courtaboeuf, France), 150 ng miScript miRNA Mimic (Syn-hsa-miR-9-5) (Qiagen S. A. , Courtaboeuf, France) or 1500 ng miScript miRNA Inhibitor (Anti-hsa-miR-9-5) (Qiagen S. A. , Courtaboeuf, France), according to the manufacturer's recommendation.
Supplementary Materials: The following are available online at http://www. mdpi. com/2073-4425/9/9/421/s1: Table  S1 : Primers for gene expression quantification; Funding: This research was funded by DHU FIRE (Emergence 2 project for MA), Programme Hospitalier de Recherche Clinique (AOM10108 and CRC15014 for CB), Agence Nationale de la Recherche (NONAGES, ANR-14-CE15-0012-01 for GJ), Fédération de Cardiologie (for GJ), Société Française de Cardiologie (for GJ).
Data analysis The dose-effect relationships of the individual and combined mycotoxins were biometrically modeled using the Median-Effect Equation of the Mass Action Law as already described  (Alassane-Kpembi et al. , 2013 , 2015). We verified that the linear regression correlation coefficients of the median effect plots were greater than 0. 95  (Chou, 2006). Toxin interactions were analyzed by the isobologram and combination-index (CI) methods. For all toxic combinations, CI values were generated over a range of fractions of cell viability affected (fa) from 0. 05-0. 97 (5-95% toxicity). CI = 0. 9-1. 1, CI < 0. 9, and CI > 1. 1 indicate additive, synergistic, and antagonistic effects, respectively  (Chou, 2006). f a /f u =(D/D m ) m.
Statistical analysis The reported values were expressed as means ± standard deviation (SD) of at least three independent experiments, each with triplicate wells per dose level. Statistical analyses were performed using GraphPad Software (La Jolla, CA, USA). Significant differences between groups were analyzed using the Bonferroni's multiple comparison test. The level of p < 0. 05 was considered statistically significant. The dose-effect relationship analysis for individual compound cytotoxicities, combination index (CI) and their 95% confidence intervals, the dose reduction index calculation, isobologram plots and fa-CI plots for combined effects were all performed using Compusyn software version 3. 0. 1 (ComboSyn Inc. , Paramus, NJ, USA).
All the dose-effect experiments demonstrated good linear correlation coefficients (r > 0. 95), which are required for the interaction analysis using the Median-Effect principle  (Chou, 2006). Dm, m, and r are the median-effect dose (e. g. , the EC50), slope, and coefficient of linear correlation of the experimental data to the mass-action law, respectively The types of interactions were analyzed by drawing an isobologram and calculating CI values. The isobologram for the DON/Cd combination at ratio 1/1 is presented in Figure  3  for three different cytotoxicity levels (30%, 50% and 80%). In this type of graph, the additive combined effect follows the diagonal line between the effective concentrations of each single contaminant. If the measured combined effect of two contaminants is above or below the diagonal line, it indicates an antagonistic or a synergistic effect of the combination, respectively.
In this study, sND technology has been used to incorporate a membrane protein, the ATP-binding cassette (ABC) transporter protein MsbA, into sNDs, exploiting the effective invisibility of the carrier system to obtain high-quality SANS data from MsbA in a lipid environment. The SANS experiments were accompanied by synchrotron small-angle X-ray scattering (SAXS) measurements. These data allowed further validation of the methodology and permitted the reconstruction of hybrid and ab initio models, as well as the detection of structural transitions between different conformational states. MsbA is a prokaryotic ABC transporter located in the bacterial inner membrane where it acts as lipid flippase, translocating lipid A, glycolipids, and lipopolysaccharides from the inner to the outer leaflet  (Raetz et al.
, 2017)  (calculated R g 37. 7 A ˚), rather than the open V-shaped apo structure from Escherichia coli  (Ward et al. , 2007)  (calculated R g 45. 9 A ˚). The pair distance distribution function of MsbA has a bilobed shape, consistent with a multi-domain particle of maximum dimension (D max ) of 130 A ˚. The R g derived from the indirect Fourier transform of the entire SANS curve (40. 95 A ˚) is in agreement with the value calculated from the Guinier approximation, reflecting again the high quality of the experimental data acquired. The Kratky plot indicates a compact multi-domain structure with minimal flexibility (Figure  S1D ). The ab initio reconstruction of the particle using the program DAMMIF  (Franke and Svergun, 2009)  produced a model that fits very well with the molecular shape of the closed MsbA model  (Ward et al.
In parallel with this, rigid body modeling was undertaken using SASREF  (Petoukhov and Svergun, 2005 ) and a single MsbA monomer (Figure  4 ). We imposed several structural restraints, assuming residues in the TMD to be in close proximity with one another in the dimeric assembly. The modeled conformation fits the scattering data well, with a c 2 of 1. 68, and a calculated R g of 39. 4 A ˚. In this model, the NBDs are not in contact but rather approximately 20 A ˚apart, resembling an overall confirmation as observed for P-glycoprotein  (Szewczyk et al. , 2015)  (PDB: 4Q9H) and its homologues ABCB1/ABCB10  (Shintre et al. , 2013)  (PDB: 4AYX). These findings are consistent with a recent cryo-EM report where a subset of MsbA particles showed a slight opening of the TMDs  (Mi et al. , 2017) , as well as electron paramagnetic resonance studies showing that the cavity is accessible to water  (Dong et al.
, 2017). However, ADP is able to interact with NBDs as well as competitively inhibit ATP hydrolysis of MsbA  (Doshi et al. , 2013). An inspection of crystal structures solved in the presence and absence of ADP in the NBD of MsbA homologues reveals that small (but significant) structural rearrangements within the domain are evident (PDB IDs: 5IDV and 5DGX). These structural rearrangements were confirmed using SAXS data with isolated NBDs in the presence and absence of ADP, showing characteristic differences in the mid q-range (Figure  S4C ) (Table  2 ). In summary, this study demonstrates that subtle differences between conformation states of integral membrane proteins can be detected by SANS measurements of IMP-incorporated stealth nanodiscs. A parallel use of SAXS provides important control information and further enhances the reliability of the structural models built from the solution scattering data.
Small-Angle Neutron Scattering (SANS) Data from apo MsbA-sND and MsbA-sND (ADP) were collected using the small-angle scattering instrument D11 at the Institut Laue-Langevin (ILL, Grenoble, France), while data from ADP and ADP-vanadate bound MsbA-sND were collected at the SANS-1 instrument at Heinz Maier-Leibnitz Zentrum (MLZ) in Munich (Heinz Maier-Leibnitz Zentrum (MLZ), 2015). All measurements were performed in 100 % D 2 O buffer (30 mM Tris pH 7. 5, 150 mM NaCl) at 1-6 mg/ml protein concentration at 10 C. Data recorded using D11 at ILL were measured in two different configurations of 1. 5 m / 1. 5 m and 8 m / 8 m (collimation length / sample-detector distances) to cover a sufficiently wide q-range (0. 03 < q > 0. 58 A ˚-1 ), with a fixed neutron wavelength (l) of 4. 6 A ˚. Overview of the experiments at D11 is available at DOI:10.
5291/ILL-DATA. 8-03-894. Measurements at SANS-1 were performed at 5 A ˚with a sample-detector distance of 5. 5 m and 20 m (0. 01 < q > 0. 23 A ˚-1 ) were the detector was moved by 400 mm perpendicular to the beam. Water reference sample (H 2 O), buffers, empty cell, the direct beam and the total absorber boron-cadmium were measured as well to perform data reduction using the GRASP software (D11) or BerSANS (SANS-1) to obtain one-dimensional scattering intensities I(q). The scattering curves of all samples were buffer subtracted using the software PRIMUS  (Konarev et al. , 2003)  and the radii of gyration extracted by the Guinier approximation. The R g and scattering intensities were back-calculated from the atomic models of MsbA using the program CRYSON  (Svergun et al. , 1998)  and scored in a c 2 fit against the respective experimental SANS data.
For SANS data sets at 100% D 2 O molecular mass estimates were obtained from the forward scattering (I0), with the contrast and partial specific volume as determined from the solution components and protein sequence using the MULCH server (http://smb-research. smb. usyd. edu. au/NCVWeb/) (Whitten et al. , 2008). All SANS and SAXS scattering parameters have been included in Tables  1  and 2  according to the recommended publication guidelines for small-angle scattering studies  (Trewhella et al. , 2017). Small-Angle X-ray Scattering (SAXS) MsbA-sND were characterized by small-angle X-ray scattering (SAXS) using the Bio-SAXS instrument P12 on the storage ring PETRA III (DESY, Hamburg, Germany) and the beamline BM29 at the European Synchrotron Radiation Facility (ESRF, Grenoble), respectively.
The scattered intensity was recorded as a function of the scattering vector q with jqj = 4psinq/l, using a wavelength of 0. 124 nm. All SAXS measurements were carried out at 10 C in 30 mM Tris (pH 7. 5), 150 mM NaCl, and 0. 5 mM TCEP at protein concentrations ranging from 1-6 mg/ml with exposure times of 20 x 0. 050 s. The average of the data were normalized and background subtracted using automatic procedures on the beamline  (Konarev et al. , 2003). Calibration of the scattering intensity into absolute units of cm -1 was performed using the forward scattering intensity of bovine serum albumin. The radius of gyration was evaluated from the experimental SAXS pattern using the Guinier approximation and as well from the entire scattering curve using the program GNOM  (Svergun, 1992). The latter also provided the distance distribution function, P(r), and the maximal dimension, D max.
ACKNOWLEDGMENTS We are grateful to the staff at beamlines D11 (ILL, Grenoble), SANS-1 (MLZ, Munich),  P12  ( EMBL, Hamburg ), and  BM29  ( ESRF, Grenoble). We acknowledge access to the  Sample Preparation and Characterization (SPC) Facility of EMBL. V. T. F. acknowledges the  UK Engineering and Physical Sciences Research Council (EPSRC)  for grants  GR/R99393/01  and  EP/C015452/1  that originally funded the  Deuteration Laboratory within ILL's Life Sciences Group  that produced deuterated material for this study. This work is partially based upon experiments performed at the SANS-1 instrument operated by HZG and FRM II at the  Heinz Maier-Leibnitz Zentrum  (MLZ), Garching,  Germany. The authors gratefully acknowledge the financial support provided by  HZG  to perform the neutron scattering measurements at the  Heinz Maier-Leibnitz Zentrum  (MLZ), Garching,  Germany.
JAB-1 colonies were small, smooth, and oxidase and catalase positive. The API32GN system was unable to identify Shewanella sp. even at the genus level. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was used for species identification, yielding S. putrefaciens, with a best score value of 2. 0, Shewanella profunda with a score of 1. 7, and Shewanella baltica with a score of 1. 5. Since MALDI-TOF MS discrepancies for the identification of Shewanella spp. are known, sequencing of 16S rRNA gene was performed. The 1,406-bp 16S rRNA gene sequence was 98% identical to Shewanella seohaensis S7-3T GU944672, making this strain the closest relative based on patristic distances  (18). As the 16S rRNA gene sequence may not be discriminatory enough to differentiate closely related Shewanella species (9), we used whole-genome sequencing (WGS) data to dive deeper into the identification of this isolate.
193 kb. pSHE-CTX-M was fully sequenced using PacBio technologies. The overall structure of the plasmid indicated that it belonged to the IncA/C incompatibility group (Fig. 3 ). The plasmid backbone shares features of IncA/C-type plasmid, i. e. , partitioning, replication, and conjugation apparatus. In the variable region, several antibiotic resistance genes have been identified in addition to bla CTX-M-15 , bla SHV-2a , and bla OXA-1 ␤-lactamase genes, the four aminoglycosidemodifying enzyme genes [aph(3Љ)-Ib, aph(6)-Id, aac(6=)-Ib-cr, and aac(3)-IIa], the tetracycline resistance gene (tetA), the sulfonamide resistance gene (sul2), and the chloramphenicol resistance gene (catB3). E. coli JAB-1 carried three plasmids, as observed following Kieser extraction (data not shown). Electroporation in E.
pneumoniae JAB-1 carries three plasmids (data not shown). Electroporation into E. coli TOP10 and selection on ticarcillin conferred an ESBL phenotype, and the transformant carried a plasmid of 60 kb, called pKP-CTX-M, which belonged to the IncR incompatibility group and was fully sequenced (Fig. 3 ). We identified in this plasmid five resistance genes encoding three ␤-lactamases (bla CTX-M-15 , bla TEM-1b , and bla OXA-1 ), an aminoglycoside acetyltransferase gene [aac(6=)-Ib-cr], and the chloramphenicol resistance gene catB3. A comparison of the three bla CTX-M-15 gene-harboring plasmids revealed major differences in size, backbone, and incompatibility group, thus ruling out in vivo plasmid exchanges between these three species (Fig. 3 ). There was no plasmid deposited in the NCBI database that shared the same structure as pSHE-CTX-M and pKP-CTX-M, but we found one plasmid called tig00003056 (accession no.
Total Shewanella DNA was also sequenced using PacBio long-read technology (Macrogen, Seoul, South Korea). Illumina read de novo assembly was performed using CLC Genomics Workbench 9. 0, according to the manufacturer's recommendations (Qiagen, Courtaboeuf, France). PacBio subreads were assembled with both Canu  (38)  and the RS_HGAP_Assembly. 3 protocol from the SMRT Analysis toolkit version 2. 3, while consensus accuracy was further polished using Quiver (39), as was previously described  (40). PCR sequencing was used to complete the assembly of pECO-CTX-M and pKP-CTX-M plasmids. A phylogenetic tree based on the gyrB-rpoB concatemer was drawn with the MEGA7 software using the maximum likelihood method based on the Tamura-Nei model  (41). Phylogenetic analysis based on whole-genome sequences of Shewanella spp.
close to Shewanella sp. JAB-1 was done using the Parsnp program from the Harvest Suite  (42). tRNAs were detected by ARAGORN (http://mbio-serv2. mbioekol. lu. se/ARAGORN/)  (43). Circular representation was performed by CGview  (44). Shewanella sp. JAB-1 was compared with three closely related strains: Shewanella MR-4 (accession no. CP000446. 1), MR-7 (accession no. CP000444. 1), and ANA-3 (accession no. CP000469. 1). Accession number(s). The nucleotide sequence of the bla OXA-535 gene of the assembled chromosome sequence of Shewanella sp. JAB-1 and of its 10. 5-kb plasmid, with no antibiotic resistance features, have been deposited at the EMBL/GenBank nucleotide sequence database under the accession numbers KX828709, CP022358, and CP022360, respectively. The three assembled ESBL-encoding plasmids (pSHE-CTX-M, pECO-CTX-M, and pKP-CTX-M) have been deposited at the EMBL/GenBank nucleotide sequence database under the accession numbers CP022359, MF510423, and MF510424, respectively.
ACKNOWLEDGMENTS We thank the  Institut Pasteur Collection  (https://www. pasteur. fr/fr/crbip)for providing strains S. algae CIP 103562 and S. putrefaciens  CIP 67. 65. This work was supported by the  Assistance Publique-Hôpitaux de Paris , by a grant from the  Université Paris Sud  ( EA 7361 ), and by the  LabEx LERMIT  supported by a grant from the  French National Research Agency  ( ANR-10-LABX-33 ) and by the  LabEx IBEID. This work was also funded in part by a grant from the  Joint Programming Initiative on Antimicrobial Resistance  ( ANR-14-JAMR-0002 ). L. D. is coinventor of the Carba NP test, the patent for which has been licensed to bioMérieux ( La Balme -les-Grottes, France).
Acknowledgments The authors thank  Alain Jauneau  and his collaborators of the  Imagery Platform of the Federation de Recherche "Agrobiosciences, Interactions et Biodiversite"  for their kind help during the microscopic observations. They also thank  Christophe Bressac  and  Francisco Garcı ´a-Gonza  ´lez for their scientific advices,  Jean-Francois Garrigues , and  Nathalie Dardenne  for technical assistance, and  Celia Nave  for her help in protocol design. We thank the three anonymous reviewers for their helpful comments on the manuscript.
Background: While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials. gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. Methods: Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of.
Methods This is a randomized, double-blind, placebo controlled, parallel group study of patiromer for the enablement of spironolactone use for blood pressure control in patients with RHTN and CKD (AMBER; ClinicalTrials. gov identifier NCT03071263). This multicenter, multinational study will compare patiromer versus placebo with concomitant spironolactone in patients with RHTN and CKD. AMBER is ongoing, and began enrolling patients on January 23, 2017. The study consists of a screening/run-in period of up to 4 weeks, a double-blind treatment period of 12 weeks, and a followup visit scheduled 2 weeks after the treatment period or early termination (Fig. 1 ).