dataesr/scientific-paragraphs-categorization huggingface dataset:
Here, we holistically review the available data on the elicitation of specialized metabolites by NPs, along with their exposure, uptake, mechanism of elicitation and possible phytotoxic effects on plants. For this purpose, a systematic review of the literature was conducted by searching information published in original articles, technical reports or conference proceedings in scientic databases such as PubMed, Bentham Science, Direct Science Direct Science, Springer, Google Scholar, BMC, MED-LINE, ScopeMed.
Screening drugs for bone fracture risk: a nation-wide longitudinal study using the national SNDS claims database Bacry, E 1* 1 Health Data Hub Large observational healthcare databases (LODs) offer the potential to produce inexpensive studies on patients' real-world behaviour and drug use. While carefully designed risk quantification studies using LODs are well established, adverse drug reactions (ADR) screening remains an unsolved challenge. Black-box or fully-automated approaches for screening often fail to tackle the many methodological and statistical issues that can be raised. We propose a methodology halfway between black-box screening and carefully tailored studies, by studying many drugs at a time, without precise a priori on the shape and timing of the potential ADRs. We use this methodology to study the dynamics of antidepressants, hypnotics, neuroleptics molecules and fracture risk as a proxy for fall risk in the elderly, using data from the SNDS, a French large healthcare claims database.
Acknowledgments This work was supported by  Ministère de l'Enseigenement supérieur et de la Recherche  ( R. Membrat PhD  grant,  French Ministry). We thank  Dr. Valérie Monnier  and  Dr. Christophe Chendo  for HRMS analysis (Spectropole,  Fédération des Sciences Chimiques de Marseille). Special thanks to  Arnaud Treuvey  for his efficient technical support.
Structure Design Considerations and Docking Analyses In all newly designed analogues, a halogen substituent was retained, since it was shown previously that such a substitution motive is important for DYRK1A inhibitory activity  [34]. When the so-designed molecules 11-16 were docked into the structure of the DYRK1A-10 complex (PDB:4YLJ), all congeners fitted nicely into the ATP binding pocket and displayed similar poses as the actual ligand 10. For example, the docked cyclohexenone analogue 13 was located near the hinge region in the adenine binding area, displaying a hydrogen bond to the terminal amino group of the conserved Lys188. Similar to 10, 13 is not forming direct hydrogen bonds to the hinge, but straightens its halogen substituent towards the backbone carbonyl oxygen of Leu241, albeit the.
Structure Design Considerations and Docking Analyses In all newly designed analogues, a halogen substituent was retained, since it was shown previously that such a substitution motive is important for DYRK1A inhibitory activity  [34]. When the so-designed molecules 11-16 were docked into the structure of the DYRK1A-10 complex (PDB:4YLJ), all congeners fitted nicely into the ATP binding pocket and displayed similar poses as the actual ligand 10. For example, the docked cyclohexenone analogue 13 was located near the hinge region in the adenine binding area, displaying a hydrogen bond to the terminal amino group of the conserved Lys188. Similar to 10, 13 is not forming direct hydrogen bonds to the hinge, but straightens its halogen substituent towards the backbone carbonyl oxygen of Leu241, albeit the distance of 4.
predicted by a docking analysis in DYRK1A (pdb: 4YLJ). (c) Result of an X-ray structure analysis of DYRK1A in complex with 11 (pdb: 6T6A). Note that the orientation of the ligand is very similar to the poses of 13 and (S)-16 as predicted by the docking analyses. (d) Orientation of (R)-16 predicted by a docking analysis in DYRK1A (pdb: 4YLJ). Note that the orientation of the tetrahydrocarbazolone ring system is flipped so that the indole nitrogen points inward and the carbonyl oxygen points outward of the binding pocket.
Kinase Inhibitory Activity The new compounds 11-16 were tested on an array of protein kinases of the CMGC family. First, the kinases were incubated with 10 µM solutions of the test compounds and the residual activities compared to controls were measured. The IC50 values of promising compounds were then determined from concentration-response curves (Table  1 ). Standard deviation of data points of single concentrations was typically below 10%. Assays were performed by radiometric methods, with the exception of 16, which was tested using the ADP-GloTM assay kit (Promega, Madison, WI). Data for 10 taken from Falke et al. [34]. The results of the kinase inhibition assays show that with exception of the Mannich base 16, all other tested derivatives are inhibitors of DYRK1A with IC50 values in the low micromolar or submicromolar concentration range.
Crystallization of DYRK1A-11 Complex, Data Collection and Structure Determination Crystallization of the DYRK1A-11 complex was carried out as described previously  [34] , albeit with using solution containing 31% PEG 400, 0. 2 M lithium sulfate and 0. 1 M tris, pH 7. 5. Diffraction data collected at Diamond Light Source, I04-1 were processed using Xia2  [46]  and scaled with Scala  [47]. Molecular replacement was performed using Phaser  [48]  and the coordinates of DYRK1A  [34]. Model rebuilding was performed in COOT  [49] , alternated with refinement in REFMAC  [50]. The final structure was validated for geometric correctness with Molprobity  [51] , and was deposited under accession code 6T6A.
Funding: This research was supported by grants from the  "Fonds Unique Interministériel" (FUI)   TRIAD  project (LM), the  "Fondation Jérôme Lejeune" (LM) , and an  FP7-KBBE-2012  grant (BlueGenics) (LM). AC and SK are grateful for support by the  SGC , a registered charity (number  1097737 ) that receives funds from  AbbVie ,  Bayer Pharma AG ,  Boehringer Ingelheim ,  Canada Foundation for Innovation ,  Eshelman Institute for Innovation ,  Genome Canada ,  Innovative Medicines Initiative  ( EU/EFPIA) [ULTRA-DD  grant no. 115766 ],  Janssen ,  Merck KGaA, Germany ,  MSD ,  Novartis Pharma AG ,  Ontario Ministry of Economic Development and Innovation ,  Pfizer ,  São Paulo Research Foundation-FAPESP, Takeda ,  Wellcome  [ 106169/ZZ14/Z ]. AC is supported by the  Collaborative Sonderforschungsbereich 1177 Autophagy  ( SFB1177 ).
Purpose: To review knowledge on therapeutic uses of ethanol and the latter's effectiveness and safety profiles in a range of indications. Methods: MEDLINE and PubMed databases were searched for relevant peer-reviewed papers published in English between 1888 and 2018 using the following search terms: ethanol, therapeutic, alcohol withdrawal syndrome, antiseptic, antidote, methanol, ethylene glycol, neurolysis, embolization, cyst, sclerosing agent, sclerotherapy, arteriovenous malformations, ablating agent. Studies providing information about association between alcohol and therapeutic indications, or mechanic explanation for the association were included for review. Results: According to the World Health Organization, approximately three millions deaths worldwide are attributable to alcohol consumption each year.
In this review, MEDLINE and PubMed databases were searched for relevant papers published in English between 1888 and 2018 using the following search terms: ethanol, therapeutic, cyst, alcohol withdrawal syndrome, antiseptic, antidote, methanol, ethylene glycol, neurolysis, embolization, sclerosing agent, ablating agent, arteriovenous malformations, sclerotherapy. Studies providing information about association between alcohol and therapeutic indications, or mechanic explanation for the association were included for review. THERAPEUTIC USES OF ETHANOL Interestingly, scientists in the late 19th century regarded alcohol as a therapeutic agent  [35, 36]. Their knowledge of ethanol's metabolism and toxicity was summed up by Fermie in 1894 by the nuanced phrase "It can save as well as destroy". The use of alcohol was advocated empirically in indications of insomnia, fever, and cholera  [36].
5-17 min: 30% B. The column oven temperature, the injection volume and the flow rate were set at 40 °C, 2 μL and 600 μL/min, respectively. To check the specificity of the method, another UHPLC system was used. Analyses were carried out in the "Service HPLC-MASSE" of the Institut de Chimie des Substances Naturelles, CNRS, 91198, Gif sur Yvette, France on an Acquity UPLC system (Waters, Mildford, MA, USA), driven by a MassLynx 4. 1 software, coupled with a Acquity DAD 996 UV/Visible detector (200-400 nm) and a triple quadrupole (QqQ) Acquity mass spectrometer (Micromass-Waters Manchester, England) (m/z mass ranging from 50 to 800), with an ESI source operated in positive ionization mode at 3. 2 kV capillary voltage.
Phytochemical profiling of aristolochic acids and aristolochic acid analogues (AAAs) in "Chiniy-tref" and A. trilobata leaves by UHPLC-DAD-HRMS/MS. The qualitative analysis of AAAs present in CT was carried out by UHPLC-DAD-HRMS/MS on sample CT_2016 that was considered representative. Anyway, all samples of CT showed similar chromatographic profiles. Compounds detected by reverse-phase chromatography with UV detection at the characteristic band of 310 nm were further characterized by tandem mass spectrometry. Some of them were unambiguously identified in the analyzed sample by comparison of chromatographic and spectral data (i. e. Retention time (tR), wavelengths of maximum absorption (λ max), m/z values of the pseudomolecular ions and of the MS or MS 2 fragment ions) (Table  2 ) with those of reference compounds, namely AA I, AA Ia, AA II, AA IIIa, AA IVa and AL I (Fig.
Acknowledgements The Authors thank  O. Thoison  ( Institut de Chimie des Substances Naturelles CNRS ) for her technical support;  C. Locatelli-Jouans  ( ARS Martinique ),  C. Bottai ,  J. Kai  and  K. Ma Chou  ( Faculté de Pharmacie de Paris ) for their substantial help in the preparation of this manuscript;  F. Achille  ( Collections végétales du Muséum National d'Histoire Naturelle ) for providing the herbal reference standard of A. trilobata (Voucher number  C87793-63 ) and the  "Agence Régional de Santé Martinique"  for financial support.
Raman spectroscopy measurement Raman spectra were recorded by Xplora microspectrometer (Horiba Scientifics, France) via the LabSpec 6 software, which equipped with liquid N 2 -cooled CCD detector. A near infrared laser (785 nm and ~20 mW) was used for excitation. Samples were packed in an aluminium sample holder and spectra were collected at a resolution of 2-3 cm -1 with × 50 microscope objectives at room temperature. A baseline correction was applied as pretreatment with the LabSpec 6 software.
Results & discussion Antimicrobial activity of the aurone derivatives was first tested using MRSA (Methicillin-Resistant S. aureus, Gram positive) and P. aeruginosa (Gram negative) with the determination of MIC values as detailed in the Experimental section. Bacteria were exposed to increasing concentrations of compounds 5-38 (from 0 to 500 µM) and MICs were determined as the lowest concentration of the molecule able to prevent bacterial growth (Table  1 ). On the 34 derivatives tested, 15 were found active (i. e. compounds 8-10, 15, 16, 23-25, 27-33) against MRSA (MIC MRSA <250 µM) but not against P. aeruginosa, suggesting a specific activity against Gram positive bacteria. The determination of the Minimal Bactericidal Concentration (MBC) on MRSA showed that for all active derivatives, MBC and MIC were similar, suggesting a bactericidal mechanism of action as previously demonstrated for other aurones (data not shown)  [11].
Quantication of echinomycin by HPLC Quantication of echinomycin was performed by HPLC system (DIONEX TM Ultimate TM 3000, Thermosher) using reversed phase C18 column 150 Â 4. 6 mm, 5 mm (KNAUER). The mobile phase containing 60% acetonitrile (HPLC grade) and 40% water was prepared according to a method described by the National Center for Biotechnology Information (PubChem Database; Echinomycin). Chromatographic conditions were as per the following: the prepared mobile phase was provided in an isocratic mode at ow rate 1 mL min À1 , detection by UV at 243 nm, 20 mL of each sample was used for injection, the retention time was 4. 6 min. The calibration curve was constructed using known concentrations of standard echinomycin in the range 0. 000587-0. 3 mg mL À1 in absolute ethanol. Echinomycin has been quantied using the linearity regression equation was The mean hydrodynamic diameter of the liposomes was determined by Dynamic Light Scattering (DLS) using a Nano ZS (Malvern Instruments, UK).
Acknowledgements The authors would like to the thank  Hamdi Mango Center for Scientic Research, The University of Jordan  (Grant# 4200053 ). Scientic Research Fund  (Grant# MPH/2/8/2013 ). We also would like to thank  Ms Hanan Azzam  and  Ms Rula Buqaien  ( The University of Jordan ) for assistance on HPLC and TEM, respectively.
Differential Scanning Calorimetry (DSC) Samples were further assessed by a differential scanning calorimeter on a DSC 3 (Mettler Toledo, Greifensee, Switzerland). The samples were cut in small pieces and 5 to 9 mg was placed in a 40 µL aluminum pan with a pierced lid. A heating rate of 10 • C/min from -10 • C to 140 • C was applied, while the surrounding sample cell was purged with nitrogen 200 mL/min. Moreover, the combination of heating, cooling and heating cycles was used to fully evaluate the samples. For the assessment of the initial form, the first heating was used. The thermograms and glass transition temperatures (T g s) were analyzed with the STARe Evaluation-Software Version 16 (Mettler Toledo, Greifensee, Switzerland). All thermograms show exothermic events as upward peaks.
Hot Stage Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) A Cary 680 Series FTIR spectrometer (Agilent Technologies, Santa Clara, CA, USA) was used, which was equipped with a heatable attenuated total reflectance accessory (Specac Limited, Orprington, UK) and the control panel 6100+ by WEST (West Control Solutions, Gurnee, IL, USA). The scanning range of 4000-600 cm -1 was selected with 1500 scans over a period of 30 min and a resolution of 4 cm -1. The heating rate was set to 5 • C/min going from 30 • C to 130 • C. For the evaluation, a spectrum was extracted and evaluated by the software ACD/Spectrus Processor 2016. 1. 1 (Advanced Chemistry Development, Canada) every minute (i. e. , every 5 • C). Every spectrum shows a 5 • C temperature increase going from the front to the back of the figures.
Synchrotron Powder X-ray Diffraction X-ray powder diffraction data were recorded at the ID22 beamline at the European Synchrotron Radiation Facility (ESRF, France) using a two-dimensional detector (PerkinElmer XRD 1611CP3) and an incident X-ray energy of 60 keV (λ = 0. 20678 Å, Qmax = 24 Å -1 ). A beam size of about 0. 5 mm × 0. 5 mm was used. Reference samples were packed in 0. 7-mm diameter borosilicate capillaries. Extrudate samples were mounted directly on capillary supports and measured as is. In order to minimize any possible radiation damage, samples were cooled down to 100 K using an Oxford Cryosystem Cryostream. To improve the overall statistics, 200 two-dimensional images were recorded (2 s per frame) and averaged. The one-dimensional diffraction patterns were retrieved after integration using the PyFAI software  [31].
PXRD data collected at the synchrotron source featured Bragg peaks that could be related directly to the crystallinity of the respective additive. Pronounced crystallinity evidenced in the histidine evaporate was in accordance with the initial X-ray and DSC assessment and was still detectable after extrusion, which is pointed out by the peaks at 1. 07 A -1 , 1. 71 A -1 , 2. 11 A -1 , 2. 60 A -1 , 2. 81 A -1 , 3. 06 A -1 , 3. 61 A -1 (Figure  2 ). Moreover, the measurement at five different locations throughout the extrudate showed the inhomogeneous distribution of the crystalline additive in the extrudate (Figure  2 ), which can potentially lead to more recrystallization. The diffraction pattern of the arginine extrudate indicated a more homogeneous distribution of the additive compared to histidine, although peaks at 3.
Therefore, to obtain high quality data that is sensitive to extremely low amounts of crystalline phase in the sample, it was necessary to perform the diffraction and scattering experiments at a synchrotron source. Thus, synchrotron X-ray diffraction offered a more thorough assessment of the amorphous form to complement the DSC and benchtop PXRD data, which indicated that the raw substances were crystalline except for the polyelectrolyte NaCMC (Figure  S1 ). PXRD data collected at the synchrotron source featured Bragg peaks that could be related directly to the crystallinity of the respective additive. Pronounced crystallinity evidenced in the histidine evaporate was in accordance with the initial X-ray and DSC assessment and was still detectable after extrusion, which is pointed out by the peaks at 1.
Conclusions The application of additives and targeted molecular interactions together with an initial solvent step enabled the extrusion of the polyelectrolyte, NaCMC. Differences in melting behavior and loading highlighted the suitability of the investigated additives to form as a fully amorphous polyelectrolyte matrix after extrusion. The additives, lysine and meglumine, in a concentration of 50% (w/w), have proven to be beneficial for extrusion and formation of a fully amorphous polymer matrix. Moreover, the application of synchrotron X-ray diffraction helped to further differentiate between the formulations by examining the distribution of the additive throughout the matrix and residual crystallinity in the sample. PXRD data collected at the synchrotron source proved the amorphous state of the lysine, meglumine, and urea formulations compared to arginine and TRIS, for which crystallinity was not detectable by means of benchtop PXRD or DSC.
Study Design and Setting This non-interventional cohort study collected data from adult patients initiating agomelatine treatment in routine clinical practice in Denmark, France, Germany and Spain. The selection of countries was driven by the sales volume of agomelatine in Europe, the distribution of prescriptions according to specialties and practice settings, and the desire for a diverse geographic representation of European countries. Figure  1  presents an overview of the study scheme. The prescriber's guide and the patient booklet were disseminated in countries participating in this study from December 2014 through July 2015. The study comprised two independent components: a retrospective MRA and a cross-sectional patient survey. The MRA included two periods. The 'before-RMM' period collected information from January 2013 to November 2014, corresponding to a time period before adoption of the latest aRMMs.
Study Population Eligible patients were aged ≥ 18 years at treatment initiation and were not participating in a clinical trial of agomelatine. For the MRA, eligible patients had initiated agomelatine during at least one of the study periods and provided written informed consent (except in France, where not objecting to the processing of the personal data was acceptable for the MRA). Patients with documented use of agomelatine in the 6 months before the first recorded prescription in a study period were ineligible. All eligible patients were identified and received information on the study, and sites were instructed to collect the data of the first ten or 15 patients who returned their signed informed consent. Overall, 600 patients were initially targeted for each period. However, according to the calculated precision estimates, a study size of 400 patients per study period was considered acceptable to meet the study objective (Electronic Supplementary Material, Figure S-1), with an absolute precision of 6% for the worst precision scenario of 50% adherence to liver testing recommendations, yielding a 95% confidence interval (CI) of 44-56.
Statistical Analyses All statistical analyses were performed using SAS ® version 9. 4 (SAS Institute, Cary, NC, USA). Frequency distributions for categorical variables and summary statistics for continuous variables were calculated. Analyses were conducted by country and overall. Data on agomelatine treatment duration were derived from prescription dates and drug supply information. Considering the observational study design and the possibility for missing data, two treatment duration definitions were used: theoretical and empirical. The theoretical treatment duration-the more conservative approach-was calculated from the first prescription start date to the earliest date among end date of the last prescription, discontinuation date or end of the concerned study period. For the dose-escalation analysis, the theoretical treatment duration before dose escalation was derived from the start date of the first prescription to the start date of the first dose-escalation prescription.
Results A total of 19,301 physicians were invited by telephone, mail or e-mail to participate in the study. Of these, 91. 4% were non-responsive and 7. 6% refused to participate. Of the 191 physicians (1. 0% of those contacted) who initially expressed interest in participating, 63 were contracted and trained for the study. Of these, 54 physicians became active sites (21 GPs and 33 specialists) and recruited 437 patients in the before-RMM period and 404 patients in the after-RMM period of the MRA (35 patients contributed data to both periods). Owing to recruitment challenges and the aim to meet the regulatory agreed timelines for study completion, the target samples of 600 patients by period were not reached, but the study size was considered sufficient to meet the study objective. Females represented 65.
Compliance with Contraindications and Precautions of Use Based on data recorded in the medical records, no patient in either the before-RMM or after-RMM period had records of cirrhosis at initiation or during agomelatine treatment. Overall, 98% of patients in each period were free of any chronic or acute liver disease at initiation or during agomelatine treatment (Table  2 ). Compliance with contraindicated medications (fluvoxamine and ciprofloxacin) was above 99% in both study periods (Table  2 ). No patients with a liver test before or at initiation had a transaminase result > 3 × ULN. Regarding co-morbidities identified as risk factors for hepatic injury and precautions of use, 99% of patients in either period had no records of non-alcoholic fatty liver disease and approximately 95% had no alcohol use disorder and no diabetes mellitus (either type 1 or type 2).
Similarly, a study conducted by the French Medical Agency (ANSM) in the French Health Insurance database (SNIIRAM) to evaluate the hepatotoxicity of antidepressants found no increased risk of serious liver injury associated with agomelatine relative to selective serotonin reuptake inhibitors  [16]. These two studies, performed while the RMMs were in force, showed the risk of hepatotoxic reaction among agomelatine users is not higher than that for users of citalopram or other antidepressants. Additional assessments of the usefulness of the RMMs (patient booklet and prescriber's guide) are also planned. Results from these analyses are expected in the next Periodic Safety Update Report for agomelatine, anticipated in February 2021.
Acknowledgements The authors gratefully acknowledge  Manel Pladevall-Vila  of  RTI Health Solutions  for his contributions to designing the study and developing the protocol,  John Forbes  of  RTI Health Solutions  for medical editing services, and  Kate Lothman  of  RTI Health Solutions  for assistance with developing the manuscript under the authors' direction. The authors gratefully acknowledge  Kantar Health  for their contributions to field operations for this study.