dataesr/scientific-paragraphs-categorization huggingface dataset:
NMR Data Acquisition NMR data were collected on a Bruker AVIII HD 500 MHz NMR spectrometer (Bruker UK Ltd. , Coventry, UK). Samples were shimmed until the w 1 2 for the residual CDCl 3 solvent signal was 0. 5 Hz or better through a combination of sequential iterations of "TopShim" gradient shimming with additional manual intervention, as required. 1 H spectra were collected with TD = 65,536 points and SW = 14 ppm (o1p = 5. 0 ppm); zero-filling afforded digital resolution of 0. 05 Hz/point. 19 F spectra were collected with TD = 262,144 points and SW = 50 ppm (o1p proximal to 19 F signal); zero-filling afforded digital resolution of 0. 09 Hz/point. 19 F{ 1 H} spectra were collected with TD = 262,144 points and SW = 200 ppm (o1p proximal to 19 F signal; inverse-gated decoupling with o2p = 5. 0 ppm); zero-filling afforded digital resolution of 0.
Acknowledgments: The  EPSRC  ( EP/K039466/1  (core capability)), the  European Community (INTERREG IVa, AI-Chem , project  4494/4196 ), and the  ANR  ( JCJC "ProOFE" grant  ( ANR-13-JS08-0007-01 ), are gratefully acknowledged for their financial support. The current work was granted access to the  HPC resources of (CCRT/CINES/IDRIS)  under the allocation c2015085117 made by  GENCI. We thank the  CCIPL  for grants of computer time.
Gene Expression microarray raw data were normalized using limmaGUI software (R/Bioconductor, Boston, MA, USA). Data can be accessed through the GEO repository accession number GSE90831. Microarrays data were analyzed with the ingenuity pathway analysis (IPA) software (Qiagen). Quantitative real time PCR analysis was performed with Applied Biosystems PRISM 7700 Sequence Detection System. The primers used are: mouse IL-10 forward: 5′-CAGCAGACTCAATACACACT-3′; mouse IL-10 reverse: 5′-TGGCCCAGAAATCAAGGAGC-3′; mouse RPS16 (housekeeping) forward: 5′-CTTGGATTCATCCACATA-3′; mouse RPS16 reverse: 5′-ATTTGCTGGTGTGGATATTCG -3′.
statistical analysis Statistical analysis for cytokines levels and liver damage were performed with GraphPad Prism software. When several conditions were to compare, we performed a one-way ANOVA, followed by Tukey range test to assess the significance among pairs of conditions. When only two conditions were to test, we performed Student's t-test or Welch t-test (according to the validity of homoscedasticity hypothesis). Statistical analysis on survival curves were performed using log-rank test, followed by Benjamini-Yekutieli correction when required.
FUnDing The laboratory received financial support from the Innate Immunocytes in Health and Disease collaborative project between CIML, AVIESAN, and SANOFI. The laboratory is "Equipe de la Fondation de la Recherche Médicale" (FRM) sponsored by the grant DEQ20140329536. The project was also supported by grants from l' Agence Nationale de la Recherche (ANR), "ANR-12-BSV2-0025-01," "ANR-FCT 12-ISV3-0002-01" and "INFORM Labex ANR-11-LABX-0054," "DCBIOL Labex ANR-11-LABEX-0043" and ANR-10-IDEX-0001-02 PSL* and A*MIDEX project ANR-11-IDEX-0001-02 funded by the Excellence Initiative of Aix-Marseille University-A*MIDEX, a French "Investissements d' Avenir" program. The research was also supported by the Ilídio Pinho foundation. JP received financial support from "PACA Region" and INSERM. We acknowledge financial support from no.
Since the main interest here is to monitor the ratio of H 2 O/D 2 O in the sample, we focus on the ratio of these two peaks and its significance for exchange in solvent and protein side-chain groups. This of course also has implications for the exchange of labile protium atoms on the backbone amide groups. For example, at the data collection stage it is possible to record FT-IR data from the mother liquor held in the sample capillary. A fundamental (but reasonable) assumption is that a spectrum recorded in this way will reflect both the solvent content in the crystal and the deuterium exchange in the protein.
8 A ˚. X-ray diffraction data were recorded on the beamlines MASSIF-1  (Bowler et al. , 2015)  and ID30B at the ESRF  (Mueller-Dieckmann et al. , 2015)  for crystals A and B, respectively. Data were recorded at room temperature on the same capillary-mounted crystals as used for data collection on LADI-III. Data were processed to the same maximum resolution of the corresponding neutron data, i. e. 1. 8 A ˚. PDB code 5clx was used as the starting model for joint X-ray and neutron refinement. The neutron R work and R free values for the final model of crystal A were 0. 202 and 0. 238, respectively, while the X-ray R work and R free values were 0. 173 and 0. 205, respectively. For crystal B, the R work and R free values were 0. 211 and 0. 260 for neutrons, and 0. 172 and 0. 210 for X-rays, respectively.
Discussion and conclusion This paper demonstrates that FT-IR spectroscopy can be used in a routine way to assess back-exchange during sample preparation and also both before and after data collection. It is highly desirable to avoid back-exchange that could occur during data collection, since the final dataset may then contain a mixture of exchanged populations. conceive of an in situ FT-IR system on neutron diffractometers that would allow back-exchange to be monitored during data acquisition, and this could help to optimize the use of beamtime. Complementary spectroscopic arrangements of this type are widely used on X-ray crystallography beamlines (von  Stetten et al. , 2015). While it is clear that solvent back-exchange occurs almost uniformly throughout the protein, that of the amide groups of the protein backbone is highly dependent on the region of the protein structure.
Acknowledgements AWY is supported by an  ILL  PhD studentship and  Keele University. The authors acknowledge the use of the FT-IR facility at the Partnership for Soft Condensed Matter (PSCM) at  ILL/ESRF , and  David Hess  for his help with the measurements. VTF acknowledges support from the  EPSRC  which funded the creation of the  Deuteration Laboratory (D-Lab) in the Life Sciences Group  at the ILL. The authors also thank the  ILL  for the provision of beamtime on the LADI-III diffractometer. Matthew Bowler  (EMBL) and  Daniele de Sanctis  ( ESRF ) are thanked for help with X-ray data collection on the MASSIF-1 and ID30B beamlines, respectively.
Acknowledgments: Clément Ghiazza held a doctoral fellowship from la Région Rhône Alpes. The authors are grateful to the CNRS and the French Ministry of Research for financial support. The French Fluorine Network is also acknowledged for its support. Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b). Eluent for flash chromatography: pentane 100%. 1 H-NMR (300 MHz, CDCl 3 ) δ = 7. 60 (m, 2H), 7. 53 (m, 2H). 19 F-NMR (282 MHz, CDCl 3 ) δ = -36. 03 (s, 3F). The results are in accordance with the literature  [61].
Acknowledgments: Clément Ghiazza held a doctoral fellowship from la Région Rhône Alpes. The authors are grateful to the CNRS and the French Ministry of Research for financial support. The French Fluorine Network is also acknowledged for its support. Synthesis of 1-methoxy-4-[(trifluoromethyl)selanyl]benzene (3c). Eluent for flash chromatography: cyclohexane/toluene 9:1. 1 H-NMR (300 MHz, CDCl 3 ) δ = 7. 66 (m, 2H), 6. 91 (m, 2H), 3. 83 (s, 3H). 19 F-NMR (282 MHz, CDCl 3 ) δ = -37. 18 (s, 3F). The results are in accordance with the literature  [61]. Molecules 2017, 22, 833 5 of 8 Synthesis of 1-bromo-4-[(trifluoromethyl)selanyl]benzene (3b). Eluent for flash chromatography: pentane 100%. 1 H-NMR (300 MHz, CDCl3) δ = 7. 60 (m, 2H), 7. 53 (m, 2H). 19 F-NMR (282 MHz, CDCl3) δ = -36. 03 (s, 3F).
Acknowledgments: Clément Ghiazza held a doctoral fellowship from la Région Rhône Alpes. The authors are grateful to the CNRS and the French Ministry of Research for financial support. The French Fluorine Network is also acknowledged for its support. Synthesis of methyl 4-[(trifluoromethyl)selanyl]benzoate (3d). Eluent for flash chromatography: cyclohexane/EtOAc 97:3 to 95:5. 1 H-NMR (300 MHz, CDCl 3 ) δ = 8. 04 (m, 2H), 7. 81 (m, 2H), 3. 94 (s, 3H). 19 F-NMR (282 MHz, CDCl 3 ) δ = -35. 21 (s, 3F). The results are in accordance with the literature  [57].
Acknowledgments: Clément Ghiazza held a doctoral fellowship from la Région Rhône Alpes. The authors are grateful to the CNRS and the French Ministry of Research for financial support. The French Fluorine Network is also acknowledged for its support. Synthesis of 3-[(trifluoromethyl)selanyl]-1-benzothiophene (3f). Eluent for flash chromatography: cyclohexane/toluene 98:2. 1 H-NMR (300 MHz, CDCl 3 ) δ = 8. 02 (d, J = 7. 7 Hz, 1H), 7. 96 (s, 1H), 7. 92 (m, 1H), 7. 51 (m, 1H), 7. 44 (m, 1H). 19 F-NMR (282 MHz, CDCl 3 ) δ = -35. 66 (s, 3F). The results are in accordance with the literature  [57].
Characterisation of mineral oils and waxes The dermal penetration potential of the following substances, characterized by their INCI name (International Nomenclature of Cosmetic Ingredients), will be assessed in this report. Respective carbon chain length, molecular weight and approximate log Kow ranges are provided in Table  1. In the EU chemicals inventory, these substances are generically described as 'paraffin waxes and hydrocarbon waxes' with CAS No. 8002-74-2. In addition, the European Cosmetic Ingredient databases  (CosIng, 2016)  and/or the International Cosmetic Ingredient Dictionary & Handbook  (INCI, 2016)  provide the following specifications: • Paraffinum liquidum (CAS No. 8012-95-1 or 8042-47-5) is a highly refined petroleum mineral oil consisting of a complex combination of hydrocarbons obtained from the intensive treatment of a petroleum fraction with sulfuric acid and oleum, or by hydrogenation, or by a combination of hydrogenation and acid treatment.
Tape stripping allows establishing the concentration profile of the chemical substance across the stratum corneum. In experimental animals, where generally radiolabelled chemicals are being used, the dermal penetration of chemicals and/or their metabolites is determined by skin biopsy and the measurement of the compounds in all tissues, blood and excreta. The results are reported as rate, amount or percentage of skin absorption of the test material  (OECD, 2004a (OECD, ,b, 2011;; EU, 2008). In the context of studying the dermal penetration of chemicals in humans, spectroscopic methods are increasingly applied. These methods are rapid, non-invasive and can provide real time data on the penetration of chemicals through the skin  (Kezic et al. , 2008 (Kezic et al. , , 2010;; Ali et al. , 2013).
The latter incorporates detailed descriptions of the skin structure, the related barrier properties and the resulting transport processes in the predictions. QSAR approaches such as the one applied by the Dermwin programme of the US EPA's EPISuite software are based on statistically determined correlations between the physicochemical properties of a range of permeants and solvents (i. e. , molecular weight, water solubility and octanol-water partition coefficient 'log Kow') and their experimentally determined permeability coefficients as originally established by  Potts and Guy (1992). Kezic et al. (2010)  examined the suitability of commonly used QSAR modelling programmes Dermwin and Skinperm (tenBerge, 2013,  Wilschut et al. , 1995; ten Berge, 2006)  particularly with regard to predicting the dermal penetration potential of highly lipophilic petroleum products.
Data acquisition A comprehensive desktop search was carried out in handbooks, monographs and electronic scientific databases such as PubMed, Google Scholar and the commercial expert database ToxPlanet. Within ToxPlanet, ChemEXPERT™ was used which interfaces with databases such TOXLINE, TSCATS, ECIS and accesses websites/databases of global regulatory bodies and institutions including those of the European Union (e. g. ECHA, EFSA, EMA), the US EPA, the US National Toxicology Program (NTP), the US Agency for Toxic Substances and Disease Registry (ATSDR), the International Agency for Research on Cancer (IARC) or the World Health Organisation (WHO). To identify relevant literature on the dermal penetration behaviour of mineral oils and waxes, targeted search strings including the 'chemical name/CAS No.
', and targeted key words (such as 'dermal OR percutaneous penetration' 'dermal OR percutaneous absorption') were applied in the desktop searches. The identified literature was reviewed for information relevant to the dermal penetration of the substances under consideration. In addition to mineral oils and waxes, the literature searches included searches for dermal penetration data on individual hydrocarbons with carbon chain lengths being at the lower end of the carbon chain length distribution of the substances covered in this assessment, i. e. hexadecane (C16; CAS No. 544-76-3), octadecane (C18; CAS No. 593-45-3) and docosane (C22; CAS No. 629-97-0). Owing to their smaller molecular size and log Kow, these substances are likely to have a higher potential to penetrate the skin barrier compared to the longer chain hydrocarbons, and therefore represent a worst case scenario  (Brown et al.
Results The following sections summarize the design and outcome of identified experimental studies investigating the dermal penetration of mineral oils and waxes as well as their longer chain aliphatic hydrocarbon surrogates in vivo (i. e. , humans and experimental animals) and in vitro. The experimental data are supplemented with predicted quantitative penetration parameters (i. e. , dermal permeability coefficient Kp, dermal maximum flux Jmax, dermal absorbed dose per event 'DAD-event') using the Dermwin model included in the US EPA's EpiSuite software (US EPA, 2016).
Dermal penetration predicted by QSAR-based modelling To complement the experimental information available on the dermal penetration of mineral oils and waxes along with long chain aliphatic hydrocarbon surrogate compounds, the ability of mineral oils and waxes to penetrate the skin was modelled using the Dermwin v2. 02 programme of the US EPA EPISuite v4. 1 software (US EPA, 2016). As introduced in Section 2. 3, the modelled parameter used for quantitative dermal penetration assessment is the permeability coefficient (Kp; cm/h). This parameter is based on key physicochemical parameters of the compound such as molecular weight (MW), water solubility and lipophilicity (log Kow). However, it has been observed that the predicted Kp data from the usual QSAR programmes are not suitable for lipophilic substances as the underlying experimental data are based on hydrophilic substances  (Kezic et al.
Similar to the German BfR, Health Canada concluded that petrolatum is neither carcinogenic nor mutagenic in short term genotoxicity studies. It further stated that based on their log Kow there is a high probability that any residual levels of PAHs would tend to remain in the lipophilic environment of petrolatum rather than traverse into the dermis  (ECHC, 2016). In a recent industry analysis, alkylated partially hydrated (i. e. , tetraor octahydro) naphthalene, phenanthrene or anthracene were predominantly identified in the MOAH fraction of petrolatum  (Kirchoff, 2015). The total carbon number in branching varied but was found to be above 10-14 generally. QSAR modelling using the Dermwin programme within the US EPA's EpiSuite software (US EPA, 2016) suggests that these substances with Cn ≥ 10 have log Kow values greater than 8.
RNA isolation and RT-qPCR The isolation of RNA from HepaRG and HepG2 cells, reverse transcription, and qPCR analyses were performed as described previously  (Attignon et al. , 2017). The oligonucleotide sequences (Table  1 ) were designed using the OLIGO Explorer software or were found in the literature and were purchased from Eurogentec (France). The relative amounts of mRNA were estimated by the delta-delta Ct method  (Livak and Schmittgen, 2001)  using RPL13A as the reference gene. The variance from the replicate Ct values was carried through to the final calculation of relative quantities using standard propagation of error methods.
Acknowledgments This study was supported by funds from the  FRA (Fondation pour la Recherche en Alcoologie ,  n°2016/02  and  2017/03 ), the  Commission of the European Union 's  Seventh Program  for research, technological development and demonstration under the grant agreement n°603946 (Health and Environment-wide Associations via Large Population Surveys (HEALS) including a post-doctoral fellowship (E. D. )) and by funds from the  Institut National de la Santé et de la Recherche Médicale (INSERM)  and the  University Paris Descartes. E. A. and A. L. received doctoral fellowships from the  MESR (Ministère de l'Enseignement Supérieur et de la Recherche ). The  CYP2E1  ("cognac" rabbit) primary antibody was a kind gift from  Dr. I. De Waziers ,  INSERM UMR 1147. We thank  Dr. L. Aggerbeck  and  Pr.
Another variation is the closed loop model. In this model, the gut remains in the animal and each extremity of the part of interest is ligatured. The drug is then injected in the isolated part. At the end of the experiment, drug concentration is measured inside the gut and the absorption rate is deducted from the initial concentration. It presents several advantages over the previous method, such as the exploration of the effects of inhibitors or drug interactions, and can be used to study drugs that are poorly permeable. Because the variation in the quantity is extremely insignificant, this method requires an analytical method with a very low limit of quantification. Although the permeability of passively absorbed drugs correlates well with human data [31], this is not as clear for drugs absorbed by active transport.
Acknowledgements Our research was supported by the  Centre National de la Recherche Scientifique CNRS, University of Rouen, INSA Rouen , and  Labex SynOrg  ( ANR-11-LABX-0029 ). H. C. thanks the  French "Ministère de la Recherche et de l'Enseignement Supérieur"  for a doctoral fellowship. H. G. thanks  Normandy University  for a postdoctoral grant. The  French Fluorine Network (GIS Fluor)  is also acknowledged.
In a 6-week observational study of 30 patients with evaporative DED, EvoTears ® significantly improved corneal staining, Schirmer scores, TBUT and OSDI scores from baseline  [101]. During this study, three patients experienced mild-to-moderate hypersensitivity to EvoTears ® and stopped treatment, after which they recovered fully  [101]. Two further observational studies are currently recruiting (NovaTears ® ; www. clinicaltrials. gov). In patients with a mixed aetiology of MGD and aqueousdeficient DED, artificial tears address problems common to both conditions; through mechanisms such as reduction of hyperosmolarity, reduced friction on blinking, spreading of the TFLL and dilution of inflammatory cytokines in the tears, artificial tears may reduce proinflammatory stimuli  [80].
Surgical options Surgical options for MGD generally involve treating the complications of MGD, such as conjunctivochalasis, entropion, ectropion and horizontal eyelid laxity, rather than the primary disease  [80]. Intraductal meibomian gland probing removes meibomian gland secretions by mechanically opening and dilating the meibomian gland orifice and duct  [119]. This technique is still controversial but was shown to be effective in relieving the symptoms of obstructive MGD, with 95% of patients experiencing postprocedure relief and 100% of patients experiencing relief 4 weeks following the procedure. Participants are currently being recruited for a randomized, double-blind trial (NCT02256969) investigating the efficacy of intraductal meibomian gland probing compared with a sham procedure in patients with refractory MGD  [120].
COMMUNICATION Here we present the discovery of eight new albicidins from Xanthomonas through a non-targeted LC-MS/MS approach combined with spectral networking using Global Natural Product Social Molecular Networking (GNPS), a recently introduced platform for MS/MS data analysis. [10] The mass spectrometric structure elucidation was followed by a subsequent total synthesis and an antibacterial profiling of the synthetic derivatives. For the mass spectrometric analysis of culture extracts from X. albilineans, we implemented a bioactivity-guided pre-purification by solid phase extraction (SPE) and semi-preparative HPLC. The HPLC fractions with antibacterial activity were subsequently submitted to LC-MS/MS analysis. The application of this workflow (cf. supporting information, SI) rendered a series of new albicidin derivatives of which structures were deduced based on exact mass and MS/MS fragmentation patterns.
Antibacterial activity was observed from HPLC-fractions (SI) at retention times of 6. 6-7. 6 min with the biggest inhibition zone at 7. 4 min (retention time of albicidin). A shoulder in the bioactivity chromatogram at 6. 8 min indicated further bioactive compounds. Hence, these fractions were submitted to non-targeted LC-MS/MS. With approximately 2,000 MS/MS spectra per fraction, we generated >20,000 spectra in total. To facilitate the MS/MS data analysis, we performed spectral networking using GNPS. [10] Hence, identical MS/MS spectra are combined and consensus spectra are compared to each other as well as to a spectral library. Consensus spectra are then visualized as nodes, which are connected to other nodes depending on their spectral.
Heretofore, OleT JE is the only one to predominantly catalyze the decarboxylation of long-chain fatty acids generating 1-alkenes as the major products and α-and β-hydroxy fatty acids as the side products (Scheme 1)  [13, 16, 22]. It would be of great interest and importance to explore more P450 fatty acid decarboxylases and expand the enzyme inventory for future broader biotechnological applications. In an attempt to screen for biocatalysts capable of converting medium-chain C 12 fatty acid (lauric acid) to 1-undecene for potential applications in biofuels and biolubricants, two new P450 sequences, CYP-Aa162 (CYP152A8, GenBank Accession Number: WP_008340313) from Alicyclobacillus acidocaldarius LAA1 and CYP-Sm46 (CYP152L2, GenBank Accession Number: EKU50422) from Staphylococcus massiliensis S46, were identified apart from OleT JE and P450 BSβ.
We found that this sequence has an extra long (~29 amino acids) N terminus with no functional annotations when compared with most other CYP152 members including those cytochrome P450 family proteins from other Staphylococcus species (Additional file 1: Figure  S1 ). Analyses of the CYP-Sm46 protein sequence using several protein prediction tools such as Phobius, TMHMM 2. 0, and SignalP 4. 1  [39] [40] [41]  also showed no positive return of either a signal peptide or transmembrane helices within the N-terminal region of 60 amino acids. A further BLAST search revealed a recently added (17-Jan-2015) 'truncated' entry of CYP-Sm46 (GenBank Accession Number: WP_039990689), hereafter called CYP-Sm46Δ29, which decodes from an alternative start codon (GUG) and therefore has the 29 N-terminal amino acids removed.
Site-directed mutagenesis of CYP-Aa162 and P450 BSβ fatty acid hydroxylases The active-site sequence alignment of CYP-Aa162 and CYP-Sm46Δ29 with those of P450 BSβ and OleT JE revealed two major residue differences (Additional file 1: Figure  S8 ): the histidine and isoleucine residues in the FFA decarboxylases of OleT JE (H85 and I170) and CYP-Sm46Δ29 (H86 and I171) are replaced by a glutamine and a valine in CYP-Aa162 (Q85 and V170) and P450 BSβ (Q85 and V170), respectively. According to the crystal structure of OleT JE (PDB: 4L40)  [18] , H85 and I170 are positioned at the two sides of the substrate carboxyl group with the distance of 5. 1 and 3. 4 Å, respectively. Previously, Rude et al. [13]  reported an improved decarboxylation activity (~50%) of P450 BSβ Q85H variant towards palmitic acid (C 16 ), suggesting an important role of this histidine residue in regulating the decarboxylation chemoselectivity of OleT JE.