dataesr/scientific-paragraphs-categorization huggingface dataset:
Moreover, to remove the possibility of a lack of membrane solubility which would have explained these results, compounds 8a-e were also assessed on various bacterial gyrases assays. No effect was seen on the DNA supercoiling activity of the whole DNA gyrases of M. tuberculosis and E. coli, even at the highest concentration tested (2. 5 mM; data not shown). D r a f t we could isolated the tricyclic derivative 22. As described below, the bridged structure of this compound was fully established by an X-ray crystallography study. The mechanism for the occurrence of this compound is quite straightforward, upon protonation of the 3,4dihydropyridine double bond of compound 20b, the resulting cation can either be quenched by the triethylsilane, to give the reduced amide 21b, or react internally with the nucleophilic nitrogen of the pyrazole ring to give 22.
A disk without any compound, and another with 10 µl DMSO were added on the D r a f t 13 plates, as negative controls. All plates were incubated at 37°C for 24h. The strain was fully impervious to the compounds 5a-e tested. DNA supercoiling assay. The M. tuberculosis DNA gyrase was purified as described previously. 32 The reaction mixture (total volume, 30 µl) contained DNA gyrase assay buffer X-ray analysis. X-ray data were collected at 293 K using CuKα (1. 54187 Å) on a Rigaku mm007 HF rotating anode diffractometer equipped with Osmic CMF mirror and a curved imaging-plate RapidII detector. The Rigaku CrystalClear-SM Expert 2. 0 r15 software package 34 was used for data collection and data reduction. The data were corrected semiempirically for absorption using multi-scan approach through the Fs Process scaling algorithm.
Acknowledgment This work was supported by the  Agence Nationale de la Recherche (ANR) , grant  ANR-11-CRNT-0004 , in the context of the investment program " GLOBAL CARE ", an association of the  Instituts Carnot  " Pasteur-Maladies Infectieuses ", " Curie-Cancer", "Voir et Entendre ", " Institut du Cerveau et de la moelle Epiniere " and the  Consortium pour l'Acceleration de.
Statistical analysis The statistical analysis was performed using the software GraphPad Prism 6. 0b. Data were first evaluated for normality with D'agostino-Pearson normality test. Appropriate parametric or nonparametric statistical tests were used to make comparisons between groups or time-points. Within group, changes from baseline were analyzed with Friedman's test for repeated measures. The drug effect was assessed on the corneal fluorescein staining which was considered as the primary outcome. The comparison of treated groups was performed with dry eye-induced and non-treated group. To take into account the baseline PRT, the CFS was analyzed between groups using Cochran-Mantel-Haenszel method with baseline PRT as stratification variable. Statistical significance was set at a p value of 0.
In the case of Paramecium bursaria chlorella virus-1 ThyX, structural data have revealed stacking of NQ against the flavin adenine dinucleotide (FAD) co-factor, partially overlapping with the dUMP-binding pocket  27. As dUMP acts in the ThyX reaction both as the activator and the substrate  32  , NQ binding at the ThyX active site results in potent inhibition of ThyX activity. Importantly, unlike human TS, ThyX produces tetrahydrofolate (H 4 folate) as a byproduct explaining why many thyX-carrying organisms do not require dihydrofolate reductase (FolA)  33. Strikingly, although mycobacteria possess two distinct families of thymidylate synthases, the canonical ThyA as well as the non-canonical ThyX, only ThyX is essential in these organisms  34. ThyX thus represents a promising target against Mtb  34, 35  , with a crystal structure available [PDB:  2AF6 36  ].
To our knowledge this represents the first target-based machine learning approach towards the identification of enzyme inhibitors in Mtb. Clearly, quinone and NQ substructures were identified as important for activity and molecules with amines and sulfonamides were less desirable. These machine learning results could help us focus on compounds to test in the future. The Bayesian model has the added advantage of being able to quickly score compounds so could narrow down potential compounds for testing. We evaluated the Bayesian model with additional NQs (Supplementary Table  7 ). Our model predicted potent new Mtb ThyX inhibitors that had some whole-cell activity against Mtb, thus attesting to the utility of our approach. In addition we have used a second software tool (CDD Models) which produces a similar leave-out-cross-validation ROC value, with the advantage that this Bayesian model can be shared openly with others so that they can benefit from these modeling efforts  53.
Data were normalised to the minimum and maximum inhibition controls to generate a dose response curve (% inhibition) from which the MIC 90 was determined. Substructure searching. The CDD database (Collaborative Drug Discovery Inc. Burlingame, CA) has been described previously and applied for TB research  14    350,000 compounds derived from patents, literature and HTS data, and we have termed this the CDD TB DB. The NQ substructure was used to query these NIAID/Southern Research Institute data. Molecules which showed previously published good whole-cell activity (MIC 90 ) were selected for testing. The data generated in this study were collected and uploaded in the CDD private Vault (http://www. collaborativedrug. com/register) from sdf files and mapped to custom protocols.
Common features pharmacophores. A set of NQs (Supplemental Table  1 ) was used to build common features pharmacophores for Mtb ThyX and GyrB with Discovery Studio 4. 1 (Biovia, San Diego, CA) from 3D conformations of the molecules generated with the CAESAR algorithm. This identified key features for each protein. The pharmacophores were then used to search various databases (for which up to 100 molecule conformations with the FAST conformer generation method with the maximum energy threshold of 20 kcal/mol, were created) such as the NIH clinical drugs set containing over 700 molecules. The pharmacophore models were updated as additional data were generated. Bayesian models. We have previously described the generation and validation of the Laplacian-corrected Bayesian classifier models for Mtb 14 using Discovery Studio 3.
5 (San Diego, CA). The models were all generated using the following molecular descriptors: molecular function class fingerprints of maximum diameter 6 (FCFP_6), AlogP, molecular weight, number of rotatable bonds, number of rings, number of aromatic rings, number of hydrogen bond acceptors, number of hydrogen bond donors, and molecular fractional polar surface area which were all calculated from input sdf files. This approach was applied to the ThyX data generated in this study using the cut off of 70% inhibition at 100 μ M to define actives. The resulting models were also validated using leave-one-out cross-validation; 5-fold validation to generate the receiver operator curve area under the curve (ROC AUC); concordance; specificity, and selectivity, as described previously. In the current study, as well as using the datasets individually, we also combined the datasets.
Acknowledgements H. M. is supported by the  Centre National de la Recherche Scientifique. The work of V. K. in the Epicentre lab was partially supported by  The Council for Frontiers of Knowledge. The work was partially supported by a grant from the  European Community's Seventh Framework Program  (grant  260872 ,  MM4TB  Consortium) to S. E. , A. M. and V. M. Work in A. M. 's lab is also supported by grant  BB/J004561/1  from  BBSRC (UK)  and the  John Innes Foundation , and work in V. M. 's laboratory by grants from the  South African Medical Research Council  and the  National Research Foundation of South Africa. The CDD TB database was made possible with funding from the  Bill and Melinda Gates Foundation  (Grant# 49852  "Collaborative drug discovery for TB through a novel database of SAR data optimized to promote data archiving and sharing").
RNA isolation and analysis Total RNAs were extracted using the TRI reagent (Sigma-Aldrich). RNA was then subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR), using the RT kit from Applied Biosystems (Foster City, CA), the fluorescent dye SYBR Green methodology and a CFX384 real-time PCR system (Bio-Rad, Hercules, CA), as previously described (Le  Vee et al. 2013 ). Gene-specific primers for drug transporters, CYP1A1, CYP1B1, aldehyde deshydrogenase 3A1 (ALDH3A1) and 18 S rRNA were exactly as previously reported (Le  Vee et al. 2010; Le Vee et al. 2013). The specificity of each gene amplification was verified at the end of qPCR reactions through analysis of dissociation curves of the PCR products. Amplification curves were next analysed with CFX Manager software (Bio-Rad), using the comparative cycle threshold method.
Western blot analysis Total protein extracts were prepared from HepaRG cells as previously reported (van  Grevenynghe et al. 2004). Proteins were then separated on polyacrylamide gels and electrophoretically transferred to nitrocellulose membranes. After blocking in Tris-buffered saline containing 4% bovine serum albumin, membranes were incubated overnight at 4°C with primary antibodies directed against transporters or AhR or against HSC70, used here as a loading control. Peroxidase-conjugated antibodies were thereafter used as secondary antibodies. After washing, immunolabeled proteins were visualized by chemiluminescence. Intensities of antibody-stained bands were finally measured by densitometry using ImageJ 1. 40g software (National Institute of Health, Besthesda, MA), allowing to normalize antitransporter or anti-AhR antibodies-related staining to anti-HCS70 antibody-labeling.
Statistical analysis Quantitative data were usually expressed as means ± SEM. Data were statistically analyzed using Student's t test, analysis of variance (ANOVA) followed by Dunnett's or Newman-Keuls post-hoc test or the nonparametric Spearman's rank correlation method. The criterion of significance was p < 0. 05. Half maximal inhibitory concentration (IC50) and half maximal effective concentration (EC50) values were determined using GraphPad Prism software (GraphPad Software, La Jolla, CA), through nonlinear regression based on the four parameter logistic function.
As shown in Fig. 8B , the global effect of CSC exposure on drug transporter expression in HepaRG cells was found to be highly correlated to that of TCDD, suggesting that CSC and TCDD may share the same signaling way for regulating transporter levels, i. e. , the AhR signaling pathway. The consequences of AhR expression extinction on drug transporter regulation by CSC were next determined. In agreement with previous data (Le  Vee et al. 2010)  Repression of OATP2B1 mRNA expression by CSC was also attenuated by AhR knock-down, knowing that the level of statistical significance was however not reached (Fig. 9B ). Transfection of siRNAs against AhR concomitantly and significantly abrogated CSC-mediated induction of MRP4 and BCRP mRNA expression, whereas CSC-triggered down-regulation of NTCP and BSEP were not impacted (Fig.
Acknowledgments KS was supported by a grant from  AZM Association-UL (Tripoli, Lebanon). analysis, normalized to HCS70 staining and expressed relative to AhR expression found in siNT-transfected cells, arbitrarily set at the value of 100%; the results are the means ± SEM of values from three independent assays. *, p<0. 05 when compared to untreated cells. (B) siAhRand siNT-transfected HepaRG cells were either untreated (control/CTR) or treated by 40 µg/mL CSC for 48 h. CYP1A1,  CYP1B1  and drug transporter mRNA expression was then determined by RT-qPCR. Data are expressed as fold factor comparatively to mRNA levels found in control untreated siNT-transfected cells and are the means ± SEM of at least three independent assays. *, p < 0. 05.
Results and Discussion The ethyl acetate soluble fraction of the acetone extract of the dried bark of M. cinnamomea was subjected to repeated silica gel column chromatography to yield four known acylphenols and dimeric acylphenols 1-4. They were identified as malabaricone A (1), malabaricone B (2), malabaricone C (3) and giganteone A (4) (Figure  1 ) upon comparison of their spectroscopic data with those reported in the literature  [9, 10]  and were further assessed for their anti-QS activity against E. coli QS biosensors. The 1 H-NMR and 13 C-NMR spectra of compounds 1-4 are depicted in Figures  2 3 4 5. Molecules 2016, 21, 391 2 of 7 Myristica cinnamomea King (Myristicaceae), commonly known as cinnamon nutmeg, is distributed in the Malayan Peninsula, Singapore, Borneo and Philippines. Locally, it is referred to as "pala bukit"  [6].
Results and Discussion The ethyl acetate soluble fraction of the acetone extract of the dried bark of M. cinnamomea was subjected to repeated silica gel column chromatography to yield four known acylphenols and dimeric acylphenols 1-4. They were identified as malabaricone A (1), malabaricone B (2), malabaricone C (3) and giganteone A (4) (Figure  1 ) upon comparison of their spectroscopic data with those reported in the literature  [9, 10]  and were further assessed for their anti-QS activity against E. coli QS biosensors. The 1 H-NMR and 13 C-NMR spectra of compounds 1-4 are depicted in Figures  2 3 4 5. Myristica cinnamomea King (Myristicaceae), commonly known as cinnamon nutmeg, is distributed in the Malayan Peninsula, Singapore, Borneo and Philippines. Locally, it is referred to as "pala bukit"  [6].
Results and Discussion The ethyl acetate soluble fraction of the acetone extract of the dried bark of M. cinnamomea was subjected to repeated silica gel column chromatography to yield four known acylphenols and dimeric acylphenols 1-4. They were identified as malabaricone A (1), malabaricone B (2), malabaricone C (3) and giganteone A (4) (Figure  1 ) upon comparison of their spectroscopic data with those reported in the literature  [9, 10]  and were further assessed for their anti-QS activity against E. coli QS biosensors. The 1 H-NMR and 13 C-NMR spectra of compounds 1-4 are depicted in Figures  2 3 4 5. In the present study, compounds 1-4 were tested for possible anti-QS properties using E. coli [pSB401] and E. coli [pSB1075] as QS biosensors. These biosensor strains respond to the QS signaling molecules N-acylhomoserine lactones by producing bioluminescence preferentially to the presence of exogenous AHLs from six to eight carbons in length (for strain E.
Acknowledgments: The authors acknowledge the  University of Malaya  for providing the  University Research Grant   RP001-2012 , the  High Impact Research Grants   UM. C/625/1/HIR/MOHE/SC/37 Grant No. H-21001-F000037 ,  UM. C/625/1/HIR/MOHE/CHAN/01 Grant No. A-000001-50001 UM. C/625/1/HIR/ MOHE/CHAN/14/1 , Grant No. H-50001-A000027  which have made this work possible.
Study Design This open-label multicenter program provided defibrotide on a compassionate-use basis or via single-patient emergency investigational new drug in response to requests from physicians for patients who developed hepatic VOD/SOS either after HCT or after nontransplantation-associated chemotherapy/radiotherapy treatment. The CUP was conducted at multiple centers globally (Supplementary Table  S1 ). There was no official protocol for the CUP; physicians requesting defibrotide through the program were asked to complete an eligibility screening form and provide detailed demographic and outcome information on each patient. Baseline data included age, gender, body weight, primary diagnosis/disease, date of hepatic VOD/SOS diagnosis, presence of MOF, hepatitis B surface antigen and hepatitis C antibody positivity, and aspartate transaminase and alanine transaminase levels, as well as any hepatic VOD/ SOS prophylaxis/treatment that had been given (eg, tPA, low-molecularweight heparin, heparin, ursodiol, prostaglandin E).
For patients who underwent HCT, details about the transplantation (type of donor/graft), date of transplantation, conditioning regimen, and graft-versus-host disease (GVHD) prophylaxis (if any) were collected. For patients who did not undergo HCT, information about the nontransplantation-associated chemotherapy/ radiotherapy regimen and related start date and the diagnosis date were collected. Requested defibrotide treatment and outcomes data included dosing information, adverse events (AEs), and survival. Treating physicians were responsible for requesting use of defibrotide as an emergency-use investigational drug from the relevant authority (eg, from the US Food and Drug Administration), securing approval from the appropriate institutional review board, and ensuring that the patient granted informed consent.
Key Outcomes Measures Physicians reported information to regulatory authorities in the context of their own emergency investigative new drug procedures. Study sites voluntarily reported data on outcome forms without on-site monitoring or query generation or resolution. Treating physicians were asked to provide outcome data that included survival status at day +100 after HCT or after nontransplantation-associated chemotherapy/radiotherapy. Exploratory efficacy analyses on day +100 survival were conducted for pediatric and adult patients and subgroups based on dose received, presence of MOF, and Bearman status (if available), and for the subgroup of patients developing VOD/SOS after nontransplantation-associated chemotherapy. Because data were reported by study sites without on-site monitoring or query generation or resolution, all AEs were considered to be treatmentemergent, regardless of their temporal relationship to dosing.
Statistical Analysis Baseline patient demographic and clinical characteristics, exposure to defibrotide, survival, and AE data (ie, overall, serious, leading to death, leading to discontinuation) were analyzed for all patients with outcome data who received at least 1 documented dose of defibrotide. All continuous variables were summarized using descriptive statistics; categorical variables were presented as frequencies and percentages for patients with available data. Survival was estimated by Kaplan-Meier analysis with 95% confidence intervals (CIs). Patients who were alive but were lost to follow-up before day +100 were censored for survival analyses.
ACKNOWLEDGMENTS This study was funded by Jazz Pharmaceuticals, Inc. Under the direction of the authors, Paul Shea and John Norwood, employees of The Curry Rockefeller Group, LLC, provided medical writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by The Curry Rockefeller Group, LLC. Jazz Pharmaceuticals, Inc, provided funding to The Curry Rockefeller Group, LLC, for support in writing and editing this manuscript. Financial disclosures and Conflict of Interest Statements: S. C. served as a consultant for and received honoraria from Gentium. E. C has served on advisory boards and the speakers bureau for, received research funding from, and provided expert testimony for Gentium. M. M. has received honoraria and research funding from Gentium and Jazz Pharmaceuticals.
Acknowledgements This work was supported by grants from the  SimonsF oundation  (Grant Number 293065t oZ. L. ) and from the  AgenceN ationaled el aR echerche  ( ANR-14-CE33-0020-01  to the  Pepti-Systems  project). The authorst hank the  COST action CM1304 Emergence and Evolution of Complex Chemical Systemsf  or facilitating the collaboration betweeno ur groupsw ith aS hort Te rm Scientific Mission for Z. L.
7 % at M0 to 7. 1 % at M12, and from 10. 7 % at baseline to 6. 5 % at M12, respectively. After multiple adjustments, opiate injection, individuals screening positive for attention deficit hyperactivity disorder (ADHD) symptoms, and those presenting depressive symptoms were more likely to regularly use cocaine. Conclusions: Although time on MMT had a positive impact on occasional cocaine use, it had no impact on regular cocaine use. Moreover, regular cocaine users were more likely to report opiate injection and to present ADHD and depressive symptoms. Early screening of these disorders and prompt tailored pharmacological and behavioral interventions can potentially reduce cocaine use and improve response to MMT. Trial registration: The trial is registered with the French Agency of Pharmaceutical Products (AFSSAPS) under the number 2008-A0277-48, the European Union Drug Regulating Authorities Clinical Trials, number Eudract 2008-001338-28, the ClinicalTrials.
Some hypotheses have been put forward regarding the possible association between psychiatric comorbidities-such as depression  [17] , attention deficit/hyperactivity disorder (ADHD)  [18] , alcohol dependence  [19] , and severe opioid dependence  [20] -and more severe patterns of cocaine use  [21, 22]. However, it would seem more relevant to investigate correlates of cocaine use more thoroughly and to provide clinicians with indications as to how they can better manage MMT patients whose cocaine use is deemed "at-risk. " We used longitudinal data from the ANRS Methaville trial, which enrolled opioid-dependent individuals starting methadone maintenance, to describe the pattern of cocaine use during MMT and to identify clinical correlates.
1 (ASRS-V1. 1) which evaluates attention deficit hyperactivity disorder (ADHD) in patients. The scoring algorithm used was the sum score obtained adding up the scores (0-4) of the first 6 items  [28]. Then, we defined the diagnosis of ADHD using 14 as a cut-off score  [29]. The second tool was the Beck Hopelessness Scale (BHS), a 20-item self-reported inventory, where a score of 9 or more indicates suicide risk  [30]. During medical visits, physicians collected data on withdrawal symptoms using the Objective Opioid Withdrawal Scale (OOWS) which comprises a list of 13 withdrawal symptoms  [31]. During the phone interviews, patients were asked about their prescribed methadone dose. At each followup visit, physicians noted the methadone dose prescribed to the patient in the medical questionnaire.
Statistical analyses From the 195 patients included in the trial, we used data of 183 patients (177 at baseline) who answered the OTI section about cocaine use at least once during follow-up, accounting for 486 visits. For these analyses, we used only the M0, M6 and M12 visits where data for most of the variables were available. First, we compared the individual characteristics of the study sample between those who consumed cocaine or crack at enrolment (i. e. before methadone initiation) and those who did not. These comparisons were performed using a chi-squared test (for categorical variables) and a Wilcoxon test (for continuous variables). To identify the factors associated with cocaine use during treatment, we used a multinomial mixed model with a 3-category outcome: no cocaine use (reference), occasional cocaine use, and regular cocaine use.
Acknowledgements The study received external funding from the  French National Agency for Research for Aids and Viral Hepatitis (ANRS)  and from the  French Ministry of Health. We thank all members of the  ANRS Methaville Study Group. We especially thank all physicians involved in the trial and all patients who took part in this study. Finally, we thank  Jude Sweeney  for the English revision and editing of our manuscript. The  ANRS Methaville Study Group Scientific Committee :  P. M. Carrieri  (principal investigator),  A. Morel  (principal investigator),  L. Michel ,  M. Mora ,  P. Roux ,  JF. Aubertin ,  S. Robinet ,  JP. Daulouède ,  JC. Desenclos ,  J. Cohen ,  A. Herszkowicz ,  C. Paul ,  I. Porteret ,  T. Sainte Marie. Safety committee:  J. Bachellier ,  P. Beauverie ,  JP Couteron ,  C.