dataesr/scientific-paragraphs-categorization huggingface dataset:
1 ). However, the gibbon (NOMGA) NAT1 and (NOMGA)NAT2 isoenzymes provided relatively low specific activities too, despite their more robust recombinant expression and purification. Compared with other primates, NAT enzymatic activities may be lower Table  1. Description of NAT gene constructs and their primate species of origin. a The current scientific names of species with synonymous names in parentheses (first column) and a common name (second column), are from the UniProt Taxonomy database (http://www. uniprot. org/taxonomy/). Official taxon mnemonics (third column) and taxon identification numbers (fourth column) are from the same source. According to current consensus nomenclature (http://nat. mbg. duth. gr/), taxon mnemonics are attached to the symbols of NAT genes to identify their specific organism of origin  22.
b All NAT gene annotations (fifth column) are as first described by  6  , except for the NAT2 gene of M. mulatta  60  , and the NAT1 and NAT2 genes of H. sapiens  66. The recombinant proteins expressed in this study were as predicted by translation of the nucleotide sequences for which GenBank identification numbers are provided (sixth column). c The complete coding sequence of each NAT gene was amplified for cloning, using combinations of the following primers, as indicated (seventh column): Primer #1 (forward), GCGGCAGCCATATGGACATTGAAGCATA; Primer #2 (reverse), TCGAGTGCGGCCGCCTAAATAGTAAAAAATCTATCACC; Primer #3 (reverse), GTGCTCGAGTGCGG CCGCCTAAATAGTGAAGGATC; Primer #4 (reverse), TCGAGTGCGGCCGCCTAAATAGTAAGGG ATCCATC; Primer #5 (reverse), TCGAGTGCGGCCGCCTAAATAGTAAAGAATCCATC. The recognition sites for restriction endonucleases NdeI (forward primer) and NotI (reverse primers) are underlined.
Clones for the NAT2 genes of M. mulatta and H. sapiens were available in our laboratories from previous studies  61. The NAT1 constructs of C. tantalus and E. patas were generated from the NAT1 construct of C. diana via site-directed mutagenesis with Primer #6 (forward), CCATGGACTTAGGCTTAGAGGCCAT, and Primer #7 (reverse), ATGGCCTCTAAGCCTAAGTCCATGG (in bold, the mutagenised nucleotide representing the only non-synonymous SNP differentiating the NAT1 gene of C. diana from the other two homologues). Amplification of the NAT2 genes of A. nigroviridis (GenBank ID: KU640981) and S. apella (GeneBank ID: KU640976) was not possible due to limited availability of genomic DNA. in human and other apes. This similarity, further supports the utility of (NOMGA)NAT1 and (NOMGA)NAT2 as in vitro models of the more poorly expressed human NATs.
The dark grey bars are the specific activities of (MACMU/MACSY)NAT1, and each measurement is also provided relative (%) to the corresponding specific activity of (ERYPA)NAT2 per each substrate tested. Assays were performed in duplicate and variability between replicates was within 10% from the average specific activity shown. A presentation of enzyme activity data is provided in Expanded Data Supplementary Fig. 2  at the end of the Supplementary Information file. Two parallel sets of assays were performed with acetyl-, n-propionyl-, malonyl-, succinyl-or hexanoyl-CoA as donor substrates. The first set employed (MACMU/MACSY)NAT1 protein with p-aminobenzoate (PABA) as acceptor substrate, while the second utilised (ERYPA)NAT2 protein with p-anisidine (PANS). On the graph, the bars of each series are the relative specific activities measured with each one of the five acyl-group donor substrates tested, presented as percentage (%) of the corresponding specific activity measured with acetyl-CoA (100%).
31% homologous (MACSY)NAT2 (Tyr232). The NAT1 and NAT2 homologues of non-human primates were modelled against the crystal structure of (HUMAN)NAT1 (PDB ID: 2PQT) and (HUMAN)NAT2 (PDB ID: 2PFR), respectively. to 3-fold higher relative to (MACMU)NAT2 (Fig. 2b ). Among all investigated NAT2 proteins, (MACSY)NAT2 provided highest and (MACMU)NAT2 lowest Tm values which were different by about 6 °C (Fig. 5b  and d ). Moreover, recombinant expression of (MACSY)NAT2 was considerably more efficient compared with (MACMU) NAT2 (Fig. 1 ). The two homologues are different by only two amino acids at positions 155 and 232, where (MACSY)NAT2 has glutamate and tyrosine, and (MACMU)NAT2 has glutamine and histidine, respectively (Supplementary Fig. S2 ). Among all primate NAT proteins investigated, glutamine is found at position 155 only in (MACMU)NAT2 (Supplementary Fig.
Molecular modelling of protein structures. The published crystal structures  23  of human NAT1 (PDB ID: 2PQT) and NAT2 (PDB ID: 2PFR) proteins were used to model the secondary and tertiary structures of NAT homologues from other primates. Alignments of non-human NATs to the secondary structure of human NATs were performed with T-COFFEE Expresso (http://tcoffee. crg. cat/apps/tcoffee/do:expresso)  64 and graphically visualised with ESPript3. 0 (http://espript. ibcp. fr)  65. The tertiary structure of non-human NATs was modelled to the three-dimensional structure of human NATs using SWISS-MODEL (http://swissmodel. expasy. org/) and graphically visualised on PyMOL (Schrödinger, LLC). Docking analysis was performed as described  39. In the available structure of human NAT1, the catalytic Cys68 appears modified as S-(2-anilino-2-oxoethyl)-L-cysteine and this modification was removed to restore the functional residue.
Residue 232 is predicted to functionally differentiate (MACMU)NAT2 (His232) from its 99. 31% homologous (MACSY)NAT2 (Tyr232). The NAT1 and NAT2 homologues of non-human primates were modelled against the crystal structure of (HUMAN)NAT1 (PDB ID: 2PQT) and (HUMAN)NAT2 (PDB ID: 2PFR), respectively.
Acknowledgements This work was supported by the  Bodossaki Foundation, Greece. For work at Oxford (U. K. ), G. F and S. B. were supported by an  EU - FP7 Coordination & Support Action "Capacities" REGPOT-2008-1 programme (acronym "BioStrength "). T. T. was recipient of Ph. D. scholarships from the  Onassis Foundation  and the  State Scholarships Foundation of Greece. Her work at Oxford was additionally supported by an  LLP Erasmus Scholarship. We thank  Professor Robert Sim ,  Dr. Areej Abuhammad  and  Dr. Edward Lowe  ( University of Oxford, U. K. ) for helpful advice and technical assistance during protein purification and crystallisation efforts.
Scientific name (synonym) a Common name a Taxon mnemonic a Taxon ID a Gene b GenBank ID b Amplification primers c Allenopithecus nigroviridis Allen's swamp monkey ALLNI 54135 NAT1 KU640972 #1 and #2 Cercopithecus diana Diana monkey CERDI 36224 NAT1 KU640973 NAT2 KU640982 #1 and #2 #1 and #3 Chlorocebus tantalus (Cercopithecus tantalus) Tantalus monkey CHLTN 60712 NAT1 KU640974 NAT2 KU640983 #6 and #7 #1 and #3 Erythrocebus patas (Cercopithecus patas) Red guenon ERYPA 9538 NAT1 KU640975 NAT2 KU640984 #6 and #7 #1 and #3 Homo sapiens Human HUMAN 9606 NAT1 X17059 (allele NAT1*4) NAT2 X14672 (allele NAT2*4) #1 and #2 Clone available Macaca mulatta Rhesus macaque MACMU 9544 NAT1 KU640969 NAT2 AJ504440 (allele NAT2*1) Clone available #1 and #2 Macaca sylvanus Barbary macaque MACSY 9546 NAT1 KU640970 NAT2 KU640978 #1 and #2 #1 and #3 Mandrillus sphinx (Papio sphinx) Mandrill MANSP 9561 NAT1 KU640971 NAT2 KU640980 #1 and #2 #1 and #3 Nomascus gabriellae Red-cheeked gibbon NOMGA 61852 NAT1 KU640967 NAT2 KU640985 #1 and #2 #1 and #4 Sapajus paella (Cebus apella) Brown-capped capuchin SAPAP 9515 NAT1 KU640966 #1 and #2 Trachypithecus cristatus (Presbytis cristata) Silvered leaf-monkey TRACR 122765 NAT1 KU640968 NAT2 KU640977 #1 and #2 #1 and #5.
Neuroblastoma Cell-Based Assay (CBA-N2a) CBA-N2a analyses were conducted following the procedure previously described in  Roué et al. (2016)   [17]  as adapted from  Manger et al. (1993)   [48]. All dry fractions were carefully weighed and re-suspended in methanol to reach a final concentration of 1 mg of dry extract/100 µL prior to CBA-N2a assays. Fractions were tested at a concentration range of 5-9524 pg/µL in eight distinct concentrations and three independent experiments (each run in triplicate). Absorbance data were fitted to a sigmoidal dose-response curve (variable slope) based on the four-parameter logistic model (4PL) allowing the calculation of EC 50 values using Prism v6. 0. 7 software (GraphPad, San Diego, CA, USA). The half maximal effective concentration values (EC 50 ) ± standard deviations (SD) were expressed in g tissue equiv.
Five microliters of sample were injected onto the column. The instrument control, data processing and analysis were conducted using Analyst software. The API4000 QTRAP was operated in positive mode using Multi Reaction Monitoring (MRM). The pseudomolecular ions [M+NH 4 ] + and [M+H] + were selected as precursor ions. The ions resulting in the successive losses of NH 4 and/or water molecules were selected as product ions (see  Roué et al. (2016)   [17] ). The MRM experiments were established by using the following source settings: curtain gas set at 25, ion spray at 5500 V, a turbogas temperature of 300 • C, gas 1 set at 40 and gas 2 set at 60 psi with an entrance potential of 10 V. Calibration was carried out using P-CTX3C standard purchased from Wako chemical. In addition, three P-CTX standards: P-CTX1B, P-CTX3B, and P-CTX3C, obtained from the Institut Louis Malardé's bank of standards were injected to obtain a toxin profile for verification of retention times.
Acknowledgments: The work described in this paper was supported by funds from the  countries of France and French Polynesia (Contrat de Projet "Caractérisation écotoxicologique des  lagons exploités" CELEX-No. 8192-2012/VP/DBP ). The authors greatly acknowledge  Nicolas Maihota  (IRD),  Philippe Cruchet  (ILM) and  Laura Dufranc  ( IRD/ILM ) for their technical assistance.
The plot of the computed and experimental  values or the C-H bonds of methane, ethane, propane and isobutane is shown in Figure  1 , assessing a good correlation between calculations and the competition experiments outcome. A data set collection of computational results is available in the ioChem-BD repository. 29 ne concern that might arise at this point refers to the role of the alkane as nucleophile, which could be called into doubt, in the event that this transformation involves radical species, derived from homolytic scission of the C-H bond. However, we have collected some experimental evidence related to this issue. The competition experiments are carried out in pressure vessels that are not purged from initial air. In the event that radicals are formed, oxygen would avoid the formation of the desired products,  [ 30 ]  at variance with the experimental observation.
Acknowledgements We thank  MINECO  for support with Grants  CTQ2017-82893-C2-1-R ,  CTQ2014-62234-EXP ,  CTQ2015-73693-JIN ,  CTQ2017-87792-R, Severo Ochoa Excellence Accreditation 2014-2018  ( SEV-2013-0319 ),  Red Intecat  ( CTQ2016-81923-REDC ). Junta de Andalucía  is also acknowledged for Grant  P12-FQM-1765. R. G. and A. O. thanks  MINECO  for  FPI  and  Juan de la Cierva  fellowships, respectively. The CNRS is thanked for support.
An illustration is shown in Fig. 3 , where the photon yield and the microphone average acoustic power signal are plotted as a function of time. The data have been recorded with the device A at ΔP = 10 bar (i. e. u o = 35. 8 ms, Q = 377 µl/s, σ = 0. 16, σ/σ cav = 0. 55). The valve was opened at t = 8 s and a tiny increase of the sound level indicates the delivery of the flow in the metastable liquid phase. No signal increase is recorded by the PMT. The valve was often switched off and on in an attempt to induce cavitating flow (at t = 60 s, 65 s, 75 s for example). The jump from the metastable single phase flow to the cavitating flow occurred at t = 85 s, when a strong increase of the noise level was recorded. Simultaneously, there is a strong increase of photons yield. An average emission of 183 photons per second has been recorded.
Acknowledgments The authors acknowledge helpful assistance of the technical support of the staff of the Nanofab facilities from the  Neel Institute of Grenoble. J. -M. Barnoud , from  LEGI , is greatly acknowledged for his contribution in the mechanical design and realization of mechanical structures. The assistance of  Dr E. F. C. Driessen  and  A. Barbier , from Iram, was helpful for the deep RIE process. The authors thank the  NanOptec center (Lyon, France)  for access to the optical facilities and  Jean-Marc Ingargiola  from  ILM  for having designed and manufactured the microphone setup. much shorter run off length in this channel. D. P. performed the experiments and wrote the paper D. C. micromachined the samples and performed the hydrodynamics characterization G. L. designed the electrooptical set up and monitored the experiments F.
Acknowledgements Financial support:  Russian Foundation of Basic Research (RFBR) , grant  16-33-60086  for I. T. ,  Russian Ministry of Science and Education (S. G. and A. M. ), an  Edinburgh Global Research Scholarship  (A. M. ),  EPSRC CMAC EP/I033459/1  (A. M. ), project  0301-2018-0007  of the ISSCM SB RAS (E. V. B. ). R. M. P. and N. B. participated in this work during their summer training course at  Novosibirsk State University. They thank  ESCOM  for providing this opportunity to undertake an internship in Novosibirsk and are grateful to the  Région Picardie of France  whose funding made it possible. A. M. thanks  Prof C. R. Pulham  for on-going support. S. A. thanks  T. N. Drebushchak  for helpful advises. Additional thanks are given to  Prof. V. V. Boldyrev  for fruitful discussions.
For NMR samples with directly added deuterated solvent, the tubes were inverted 20 times for mixing. for a good S/N ratio (typically >300) was applied. After NMR data processing, integration ratios ρoct and ρaq (ρoct is defined as the integration ratio between the compound and the reference compound in the octanol sample; likewise for ρaq) were obtained, and used in the equation (logP X = logP ref + log[ρoct/ρaq]) to obtain the logP value of the compound. The logP measurement of each compound was run in triplicate. LogP values of non-fluorinated compounds were taken from the literature.
Calculations The theoretical calculations were carried out with the Gaussian16 program. 49 2] [53]  Scans along the various rotatable bonds: C-C, C-O, and O-H bonds of the compounds have systematically been conducted. The solvent effects (octanol and water) were taken into account using the SMD solvation continuum model. 54 The vibrational spectrum of each optimized conformer was computed to confirm its nature of true minimum and to obtain free energies. The relative populations, pi, of the various conformers were evaluated at 298K from the computed free energies through a Boltzmann distribution (Eq. (  1 )). ( The various theoretical descriptors (molecular dipole moments, partial atomic charges) computed for each conformer were weighted according to these populations. The Polar Surface Area of each compound was computed using the QikProp module of the 2018 Schrödinger suite (Schrödinger release 2018-2, QikProp; LLC, New York, 2018).
Acknowledgements We are grateful to  AstraZeneca  for a CASE award, and to the  EPSRC  for a  CASE Conversion grant  ( EP/M508147/1 ), a  standard grant  ( EP/P019943/1 ), and a core capability grant ( EP/K039466/1 ). Apollo Scientific  is gratefully acknowledged for the donation of chemicals. The  CCIPL (Centre de Calcul Intensif des Pays de Loire)  is acknowledged for provision of computer time. resonance; pKa, logarithm of the acid dissociation constant; PPB, plasma protein binding;  Rat Heps , rat hepatocytes; ppm, parts per million; PSA, polar surface area; rt, room temperature; SMD, solvation model based on density; Tf, trifluoromethylsulfonyl; TLC, thin layer chromatography; TOF, time of flight; Ts, tosyl; UV, ultraviolet.
Materials The data was extracted from the Detec't database  [26] , a database developed by Kappa Santé [27] that collects messages from several French forums using a Web crawler. Detec't extracts messages from forums based on a named entity recognition module using a drug lexicon made by Kappa Santé and a fuzzy matching algorithm. The lexicon was based on Racine Pharma and the Anatomical Therapeutic Chemical (ATC) classification system  [28]. Racine Pharma is an extensive source of drug names that covers all medications available on the French market, including brand names and active ingredients. Racine Pharma entries are mapped to the ATC. More precisely, we extracted two corpora from Detec't: the first one corresponding to the messages related to escitalopram, an antidepressant drug, the other one related to aripiprazole, an antipsychotic drug.
Rationale for choosing these drugs is that nonadherence cases are more likely to be found in chronic diseases and is a major concern in psychiatric disease management  [29]. Moreover, these drugs belong to two different therapeutic classes: escitalopram is in a class of antidepressants called selective serotonin reuptake inhibitors; aripiprazole belongs to the so-called atypical second generation antipsychotics and acts as a partial dopamine agonist. All messages extracted from Detec't database in this study were posted from 2004 to 2013 on three of the most popular French forums (doctissimo, atoute, and santé médecine). The metadata accompanying each message that form the corpus were as follows: (1) an identifier, (2) the date of publication on the forum, and (3) the forum from which the message was extracted.
Datasets Characteristics Table  1  shows the number of messages in each corpus. The preliminary preprocessing of escitalopram corpus returned a DTM of 3650 messages and 155,883 tokens (unigrams and bigrams). Setting the sparsity threshold at 99. 35% (3626. 275/3650), we obtained a DTM of 3649 messages and 1497 tokens. One message was removed because the terms it contained were particularly misspelled. The processing of the aripiprazole corpus yielded a DTM of 2164 messages and 81,371 tokens. On the basis of a sparsity threshold of 99. 25% (2147. 77/2164), we obtained a DTM of 2164 messages and 1062 terms. The tokens that appeared least frequently in the corpora were removed (Table  2 ).
Limitations Our study focused on two drugs from two distinct classes. Both drugs are used to treat psychiatric disorders. A review currently including 50 clinical studies and 9476 participants taking antipsychotic drugs revealed an overall attrition from the included studies of 49%  [44]. Consequently, our results regarding the noncompliance rate and the reasons for not being compliant cannot be extrapolated to other patient profiles. Further studies on other therapeutic classes must be conducted. Manual review was required to distinguish between true and false positives in each dataset. The vocabulary used to describe dosage modifications or treatment interruptions in messages is commonly employed for characterizing other kinds of general variations or cessations (diet, smoking, etc). Topic models demonstrated their ability to identify potential noncompliance messages (average recall 98.
5%, 272/276). Syntactic and semantic methods could be developed to recognize the experiencers, the temporal features, and the object concerned by the action in the sentences. Such methods could be applied to the datasets identified by the topic models to reduce the number of false positives and improve the precision score. Another limitation of our work is the empirical determination of the thresholds used in our method. The thresholds concern the reduction in the size of the DTM and the significance of the association of messages to topics: 1. The choice of a sparsity threshold under 97% for DTM does not guarantee the best compromise between the calculation cost and the preservation of information for all the corpora we used. 2. The threshold for association between message words and topics, which was set at 25%, led to 23.
Experimental Designs and Data Analysis Experimental designs were used in order to determine the optimized formulations based on HPβCD and HPγCD. In this study, the goal of optimization was respectively focused on maximization of the DXMa solubility and adjustment of osmolality within acceptable physiological range from 250 to 450 mOsm/Kg  [23]. Experimental domain was obtained by fixing the minimum and maximum proportions of each component (% w/w) as presented in Table  2. Design-Expert software version 10. 0. 8 (State Ease, Inc. , Minneapolis, MN, USA) package was used to establish a special cubic mathematical model which exhibits the relationships between response and formulation components, allowing the optimum operational conditions to be obtained via a statistical analysis. Two experimental designs (1 and 2) were performed, one per CD derivative (Table  2 ).
Special Cubic Mixture Designs Using the DXMa solubility and osmolality of each experiment (Tables  S1  and S2 ), the experimental designs for both cyclodextrin derivatives were analyzed using Design-expert software and the results are reported in Table  6. Based on these results, the R 2 , R 2 adj , and R 2 pred values for the osmolality and [DXMa] for HPβCD are higher than 0. 98, indicating that the refined model has high regression accuracy. For HPγCD, the R 2 , R 2 adj , and R 2 pred statistics values are higher than 0. 85, indicating that the refined model has good regression accuracy. For all considered responses, the AdeqPrec values are up to 31. 45, which indicates an adequate signal to noise. The analysis of variance (ANOVA) results are described in supplementary materials (Table  S3 ) and evidenced that the reduced models were highly significant (p-value < 0.
Pharmacological Treatments All treatments were administered acutely via the i. p. route 14-16 days after surgery, when hyperalgesia and allodynia remained stable at their maximal levels in both CCI-SN and CCI-ION rats  (Latrémolière et al. , 2008; M'Dahoma et al. , 2015). Behavioral tests were performed just before injection, and then at 30 min intervals for 4 h after injection, always by an experienced person blind to treatment groups. When gabapentin was co-administered with agomelatine, melatonin, RS 127445, SB 206553 or SB 242084, injections of each drugs'duo were made within less than 1 min. Other pharmacological treatments  (ICI 118551, idazoxan, propranolol, S22153)  were administered 30 min before injection of the combination of agomelatine + gabapentin. Doses were chosen from relevant data in the literature: agomelatine, 10, 20 and 45 mg/kg (M'  Dahoma et al.
Determination of zeaxanthin IC 50 in A2058 melanoma cells Purified zeaxanthin (1) was solubilized in DMSO at 6 mM (stock solution) and diluted in cell culture medium to obtain 5 to 60 µM solutions. The final DMSO concentration in the cell culture medium was lower than 1%, tested as a negative control and validated as a non cytotoxic concentration. The antiproliferative activity of zeaxanthin was determined using the MTT assay (Sigma-aldrich, France) as previously described  (Putey et al. , 2007; Baudelet et al. , 2013; Hedidi et al. , 2016). IC 50 was determined using the free Graph pad Prism software using the "sigmoidal dose response" (variable slope) function.