dataesr/scientific-paragraphs-categorization huggingface dataset:
Collagen deposition The presence of collagen deposition was demonstrated by specific Syrius Red stainings, briefly, the sections were deparaffinized (3 toluene baths, 5 min) and then rehydrated by three successive baths of ethanol (100°, 95° and 50°, 5 min) and a water bath (5 min). Sections were incubated 30 min in a solution of Sirius Red (0. 1% F3B saturated picric acid) before being rinsed with water 5 min. The slides were observed under an optical microscope (Eclipse E400, Nikon) at a magnification ×2. Photographs (Microfire, Optronics) were analyzed using the 3. 0 software MorphoExpert to allow quantification of the surface measured by the collagen relative to the total area of tissue fibrosis.
Statistical analysis Since values for behavior were not normally distributed, they were subjected to nonparametric statistical analysis. To assess whether the withdrawal responses changed over time, Friedman's test was used. When Friedman's test was found significant (P < 0. 05), pairwise comparisons were made using Wilcoxon's signed rank test. Time point comparisons between groups were made using a nonparametric Kruskal-Wallis. When Kruskal-Wallis test was significant (P < 0. 05), pairwise comparisons were made using Mann-Whitney U test. The c-Fos results were expressed as mean ± SEM of the number of positive nuclei/section. Statistical analyses were performed using GraphPad Prism software (Graph-Pad, San Diego, CA, USA). One-way ANOVA were followed by post-hoc multiple comparisons using Bonferroni's test.
Fracture pain is blunted in the absence of kinin receptors Baseline values for pain behavior parameters were not significantly different between groups before fracture induction (Fig. 1 ). Similarly, no behavioral modification occurred in the non-fractured tibia mice (data not shown). After fracture, behavioral pain measurements were significantly but differently reduced both in B1KO and B2KO mice when compared to WT mice (Fig. 1 ). Maximal pain was observed in WT animals. In B1KO mice, both mechanical and thermal sensitivity were significantly and persistently reduced from 2 h up to 7 days post fracture. In B2KO mice no difference was observed in mechanical sensitivity whereas thermal sensitivity was reduced to a similar level as that observed in B1KO. The subjective pain scale was significantly lower both in B1KO and B2KO mice when compared to WT mice from 2 h to 5 days.
B1 receptor antagonists were given either as gavage using SSR240612 (10 mg/kg body weight) or as a single subcutaneous injection of R954 (10 mg/kg body weight). Behaviors were recorded for 8 h and then once the subsequent day 24 h after drug administration. Each bar represents mean ± SEM of 6 mice per group. B: baseline. Data were subjected to Friedman's test followed by Wilcoxon' signed rank test. *, # and € P < 0. 05 compared with saline-treated WT mice neuronal activation was reduced in B2KO. Considering the time course of this immediate early gene induction, this result suggests that B1R is not involved in the acute generation of fracture pain, possibly because B1R might not be located directly on sensory neurons but on surrounding tissue. Second, inflammation appears to be a prerequisite to ensure B1R induction and subsequent activation, as demonstrated here by RT-PCR and Western Blotting.
WT, B1KO and B2KO were subjected to tibial fracture and received a single injection of K (50 mg/kg body weight) at time 0. Behaviors were recorded during 4 h. Each bar represents mean ± SEM of 6 mice per group. Data were subjected to Friedman's test followed by Wilcoxon signed rank test. *P < 0. 05 compared with fractured untreated WT pain quotation were diminished in KOB2 fractured mice, but mechanical hyperalgesia was not affected. These results are consistent with prior studies that observed BK signaling contributed to heat but not mechanical hyperalgesia in animal pain models  [43] [44] [45] [46]  and in humans  [47]. In the present study, three behavioral tests indicate that acute treatment with either B1 or B2 antagonist reduced post-fracture pain in WT mice. As B1 receptor is not detectable in non-fractured WT mice and appeared specifically expressed in the fracture area, inhibition of B1R may be a potential therapeutic target for reducing fracture pain.
among several heterogenous data sources (such as data from hospitals or claims database) is able to detect early addictovigilance signals and warnings as illustrated with three following examples: cannabis use and acute serious cardiovascular disorders, new synthetic opioids (ocfentanil, carfentanil) and severe opiate overdose or deaths, the diverted use of psychoactive drugs (codeine analgesics or sedative H1 antihistamines called purple drank) by adolescents and young adults. The choice of a broad strategy and the multifaceted system implemented by the French Addictovigilance Network using elements of pharmacology (fundamental, clinical, pharmacoepidemiology) expertise is an innovative method to detect early addictovigilance signals, and to describe its characteristics in order to increase awareness of psychoactive substances by patients, users and health professionals.
Enfin, les bases de données de l'Assurance maladie collectées depuis 2003 dans un vaste « entrepôt numérique », le système national d'information inter-régime de l'Assurance maladie (SNIIRAM) et désormais le système national des données de santé (SNDS) constitue également une mine d'or. Comment ne pas s'y intéresser quand on sait que la résultante en est une des plus grandes bases de données de santé au monde, couvrant 65 millions de personnes et sachant que l'évaluation d'un risque médicamenteux, quel qu'il soit, est indissociable de l'exposition populationnelle au médicament concerné ? D'autant plus que l'accessibilité d'un médicament est un facteur potentiellement impliqué dans les problématiques de détournement et d'abus. Il n'est donc pas étonnant que dès l'ouverture de l'accès à ces bases de données au début des années 2000 dans sa dimension régionale (le SNIIRAM n'étant pas encore dans sa configuration nationale), le réseau francais d'addictovigilance ait développé une collaboration avec l'assurance maladie à l'échelle régionale, afin d'explorer en population générale, les modalités d'utilisation médicaments psychoactifs, les typologies d'usagers et développer des indicateurs de mésusage  [27, 28].
Quelques exemples de signal en addictovigilance Le cannabis et les complications cardiovasculaires graves Le point de départ de ce signal est une étude réalisée au centre hospitalier universitaire de Toulouse, dont l'objectif était d'appliquer au contexte de l'addictovigilance, une approche déjà testée pour augmenter les performances de l'identification des effets indésirables graves entraînant une hospitalisation  [35]. L'hypothèse de ce travail était que compte tenu d'une sous-notification marquée en addictovigilance, les bases de données hospitalières permettraient potentiellement d'identifier les cas et de les caractériser. Ainsi à partir d'une requête sur les bases PMSI utilisant les codes F-11-F19, des dossiers médicaux de patients ainsi identifiés et des analyses toxicologiques, ce premier travail a permis d'identifier sur 3 années, les hospitalisations en lien avec l'usage d'une substance psychoactive à potentiel d'abus  [23].
C'est cette capacité opérationnelle, cette organisation transversale, fluide et cohérente, qu'il faut préserver. Le système n'est sans doute pas parfait mais assurément efficace. Sa stabilité est un atout, un gage de tout premier plan dans une vigilance. Pour autant, le réseau francais d'addictovigilance a constamment proposé et développé des actions et des méthodes d'investigation originales. Le développement de ses outils de pharmacosurveillance à même de capturer des signaux peut être, faibles a priori, mais bien réels en est une preuve, tout comme ses méthodes de repérage dans les bases de données de l'Assurance maladie. Son évolution, rendue nécessaire par une évolution des organisations sanitaires en France, nécessite précaution et équilibre, au risque de désagréger et détricoter plus de 25 ans de savoirfaire.
Methods Medication errors involving oral MTX and reported between 1 st January 2007 and 31 st October 2013 to the French networks of poison control centres (PCCs) or pharmacovigilance centres (PVCs) were analysed. The French network of PCCs comprises 9 centres and the PVCs network is based on 31 centres. Both are located in university hospitals with their own databases. The data system of PCCs depends on the French governmental agency dealing with sanitary safety in food, the environment and at work. The data system of PVCs is located within the French Drug Agency. Although separate centres, PCCs and PVCs regularly communicate, either directly or through their respective agencies. Interestingly, these two sources provided complementary data. For the purpose of this study, each centres were contacted and all agreed to participate.
Due to the retrospective and noninterventional design of this study the approval of the local Ethics Committee was not necessary. Medication errors reported in patients treated with oral MTX were extracted from both databases. Because of the narrow safety margin of prolonged oral MTX treatment with 30 mg per week regarded as the highest tolerable dosage  [11] , our inclusion criteria were intake of more than 2-fold the intended weekly dose (data extracted from the narrative of the reported case) or a weekly cumulative dose ≥ 30 mg. According to the short half-life of MTX  [12] , a follow-up of at least 4 days after the last MTX dose was required in asymptomatic patients. Data were analysed for demographics, indication, prescribed MTX dose, concomitant folic acid intake, clinical complications and medical outcomes.
Results A total of 174 MTX medication errors were retrieved during the 7 years-follow-up by both centres (128 from PCC and 46 from PVC). Of these, 74 (42. 5%) were included after review and agreement by two senior physicians (Anne Marie Patat and Thierry Vial). Causes of exclusion were duplicates between centres in 16 cases, a cumulated dose < 30 mg over one week in 23, isolated medication error in an untreated patient in 9, unconfirmed medication error in 8, unintentional and isolated intake in 5 children, and insufficient data or an unknown outcome in 39. Baseline characteristics of the patients and circumstances of the error are summarized in Table  1. Eleven (14. 9%) patients had a previous moderate or severe alteration of the renal function. Most were treated for rheumatoid arthritis, related rheumatic inflammatory disorders or psoriasis.
8%) died, and the long term outcome was unknown in 7 (11. 5%) patients who had only limited complications that initially improved The 9 deaths occurred within a mean of 23. 4 ± 10. 4 days (range 11-45) after the first occurrence of the medication error. The median age of these patients was 84. 7 ± 6. 6 years (range 71-94) and the mean cumulative dose received was 90. 6 ± 39. 6 mg (range 40-150). The duration of MTX dosing error ranged from only 4 to 16 days. All of them experienced severe haematological disorders (grade 3 in one and grade 4 in 8) and 2 also had serious liver injury. All died from severe sepsis. Of these 9 patients, the medication error occurred in a hospital in 6 cases or in nursing house in 2. The overall rate of death was 12. 2% (CI: 5. 7-21. 8). As the probability of over-reporting the most severe cases to PVC, we separately examined the death rate observed by PCCs which collected data prospectively at the time of toxicological advice and at the time of follow-up.
2% to 24% after MTX dosing errors. In our study, the overall death rate of 12. 2% was exactly within this range. Also important here is that severe cases can occur after only 3 consecutive days of medication error, as reported by others  [6] , and death after a little as a cumulative dose of 40 mg. Eight of the nine deaths were observed in patients who received MTX for more than 6 months before the error, strongly suggesting that the risk of fatalities is higher in these patients. Causes and locations of the errors depend on the countries. Based on reports submitted to the FDA, causes were attributable to the prescribers (37% of cases), the patient (20%), a dispensing error (19%) or a health care professional (17%) in US  [20]. Another nationwide study based on 4 Danish national databases found prescribers, nurses and patients or its relatives as the main persons who made the errors in 40.
Ocular surface staining was then evaluated using a slit lamp under a cobalt blue light (peak of approximately 400 nm). Images were captured by a digital camera using EyeSuite™ software (Koeniz, Switzerland). Corneal fluorescein staining was performed before and every week after the surgery to assess the degree of corneal damage caused by HG and ELG excision. The extent of corneal damage (width and intensity of fluorescein take-up area) was scored according to the following scale: 0, absence of staining; 0. 5, slight punctate staining; 1, diffuse punctate staining; 2, diffuse staining covering less than one third of the cornea; 3, diffuse staining covering more than one third of the cornea; and 4, staining covering more than two thirds of the cornea  [31] [32] [33].
Microscopic analysis and immunostaining quantification Tissue sections were examined using a Zeiss M1 epifluorescence microscope (Axio ImagerM1; Carl Zeiss). The epifluorescence microscope was equipped with a digital camera (Axio Cam HRC; Carl Zeiss) and image acquisition software (Zen; Carl Zeiss). TIFF images were obtained. The microscope was calibrated with samples from the sham mice before acquisitions of those from the DED mice. For the quantitative analysis of GFAP, Iba1, and Piccolo immunoreactivity, TG and TBSC sections were analyzed under epifluorescence microscope using a × 20 objective and the same camera parameters (Axio Vision ImagerM1; Carl Zeiss) as previously described  [35]. Five ipsilateral TBSC and TG sections per animal were used for the DED and sham animals. The same gray threshold level was applied to all sections of the same series.
Statistical analyses The data obtained from sham and DED animals after surgery were compared using the appropriate paired parametric or nonparametric statistical test, as indicated. For statistical analysis, the Kolmogorov-Smirnov test was performed followed by an unpaired t test with Welch's correction or nonparametric t test using Graph-Pad Prism version 7. 00 (GraphPad Software, La Jolla California USA). The difference in nerve fiber impulse activity between control and injured cornea was determined using the Mann-Whitney test or unpaired t test as appropriate. All P values were considered statistically significant when the values were < 0. 05. All results are presented as the mean ± standard error of the mean (SEM).
RT-qPCR analysis was carried out at d21. Levels of cFOS (1. 80 ± 0. 13-fold, P < 0. 01), ATF3 (1. 56 ± 0. 14-fold, P < 0. 01), and GFAP (6. 44 ± 1. 78-fold, P < 0. 05) mRNA, as well as those of iNOS2 (1. 62 ± 0. 14-fold, P < 0. 01) and NOX4 (1. 32 ± 0. 11-fold, P < 0. 05) mRNA, were higher for DED than sham animals (Fig. 9d ). These data clearly highlight that DED induced by excision of the ELG and the HG enhanced neuro-inflammatory responses in the TG.
Database survey (i) Àx þ 1; Ày þ 1; Àz þ 1; (ii) Àx þ 2; y þ 1 2 ; Àz þ 1 2 ; (iii) x þ 1; Ày þ 1 2 ; z À 1 2. Figure 2 A view of the crystal packing of compound (1). The C-HÁ Á ÁO interactions (Table  2 ) involving the major component of the disordered -CF 2 group, are shown as dashed lines. attached to the C(S) atom, the Mn-S-C angle is nearly identical, 106. 26 (  6 ) and ca 105. 64 , respectively (Table  3 ). In contrast, this angle is slightly larger for CECCES and for JEBNOT, ca 108. 8 and 108. 1 , respectively.
search in the Cambridge Structural Database (CSD, V5. 40, update February 2019; Groom et al. , 2016) using a (CO) 5 MnS-C fragment revealed only three hits. These include, [ 2 -1,2-bis(p-fluorophenyl)-ethylene-1,2-dithiolato-S,S 0 ]decacarbonyldi-manganese (CSD refcode CECCES; Lindner et al. , 1983), pentacarbonyl-[(N-pentafluorothio)fluorothioformimido-S]manganese (JEBNOT; Damerius et al. , 1989) and -1,2-dithiooxalatobis(pentacarbonyl)manganese (TOXCMN; Weber & Mattes, 1979). The Mn-S, S-C, Mn-C bond distances and Mn-S-C bond angles are compared to those for compound (1) in.
A search in the Cambridge Structural Database (CSD, V5. 40, update February 2019; Groom et al. , 2016) using a (CO) 5 MnS-C fragment revealed only three hits. These include, [ 2 -1,2-bis(p-fluorophenyl)-ethylene-1,2-dithiolato-S,S 0 ]decacarbonyldi-manganese (CSD refcode CECCES; Lindner et al. , 1983), pentacarbonyl-[(N-pentafluorothio)fluorothioformimido-S]manganese (JEBNOT; Damerius et al. , 1989) and -1,2-dithiooxalatobis(pentacarbonyl)manganese (TOXCMN; Weber & Mattes, 1979). The Mn-S, S-C, Mn-C bond distances and Mn-S-C bond angles are compared to those for compound (1) in.
The mycolactone A/B standard was infused into the electrospray ion source at a concentration of 0. 5 mg/mL in ethanol, with a syringe pump operating at a flow rate of 5 µL/min, together with 250 µL/min water/ACN mixture (40/60), to optimize the ESI conditions (spray voltage, 4500 V; vaporizer temperature, 350 • C; sheath gas pressure, 40 arbitrary units (au); ion sweep gas pressure, 0 AU; auxiliary gas pressure, 15 AU; capillary temperature, 375 • C; tube lens offset, 35 V; skimmer offset, 0 AU) and the selected reaction monitoring (SRM) conditions (collision gas pressure, 1. 8 mTorr; collision energy, 42 V). The nebulisation gas used was nitrogen (N 2 ) and the collision gas was argon (Ar). Data were acquired and processed with Xcalibur software 2. 1 (Thermo Fisher Scientific).
Mycolactone Induces Long-Lasting Dose-Dependent Hypoesthesia Various doses of mycolactone were injected subcutaneously into mouse footpads and hypoesthesia was assessed with Hargreaves plantar test 2, 4, 6, 24, and 48 h after injection (Figure  1A ). Hypoesthesia was measured for doses of 1 to 4 µg mycolactone per footpad. Tissue examination by histological approaches at 2, 24, and 48 h showed that the concentrations of mycolactone inoculated did not induce any tissue damage nor a cellular inflammatory response (Figure  1B ). Putative toxicity after longer time periods was also assessed (72 h, 7 and 15 days) and no side effects of mycolactone were observed (data not shown). Nevertheless, we cannot completely rule out that there might be a risk for potential side effects that we did not noticed.
FUNDING This work was supported by the  region Pays de la Loire  ( Kalmos  project), the  Agence Nationale de Recherche  ( ANR-17-CE18-0001 ), the  Institut Pasteur of Lille  (granted to PB and M-LR), the  Inserm Program ATIP  avenir (granted to LM), the  region Pays de la Loire  ( Kalmos  project) and  Angers University.
2A , Lawsone inhibited keratinocyte proliferation. Furthermore, microarray analysis of HEK cells stimulated with Lawsone pointed to a skewing towards differentiation (Fig. Supplement 2A ). ROC curve analysis of genes of the epidermal differentiation complex (EDC), and family I and II keratins (Table  3 ) revealed a significant enrichment upon Lawsone stimulation (Fig. 2B ). This was mainly due to upregulation of the genes involved in formation of the cornified envelope (Supplementary Dataset File 1). Cornifelin (CNFN), hornerin (HRNR), late cornified envelope 3D (LCE3D), keratin 2 (KRT2) and filaggrin 2 (FLG2) are critical for epidermal differentiation  33, 34. qRTPCR analysis confirmed the induction of these genes in HEK cells upon Lawsone exposure (Fig. 2C ). Thus, Lawsone modulates the expression of genes involved in cornified envelope generation.
Materials and Methods 1,4-naphthoquinone compounds and AhR agonists/antagonist. Lawsone (2-hydroxy-1,4-naphthoquinone), Dioxin (TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin), Phthiocol (Pht, 2-hydroxy-3-methyl-1,4-naphthoquinone) were obtained from Sigma-Aldrich, and CH223191 from Santa Cruz Biotech. All compounds were solubilized in DMSO. Henna was acquired in a conventional shop and dissolved in water. To ensure that the concentration of Lawsone in the Henna preparation was comparable to that of the purified pigment employed in our experiments, we quantified the amount of Lawsone contained in the commercial Henna powder preparation by thin-layer chromatography (TLC). In silico homology modeling. A BLAST search with the sequence of hAhR PASB as a template revealed 58 hits in the Protein Data Bank (PDB) of experimental crystal structures.
Based on sequence alignment, similarities, as well as bound ligands, 7 crystal structures were selected for a multiple sequence alignment and used to build a multiple template-based homology model of hAhR PASB. Apart from X-ray complex of HIF2α/ARNT, previously used as single template  [64] [65] [66]  , we additionally downloaded HIF2α complexed with agonists and antagonists (PDB ID: 3F1O, 4GHI, 4GS9, 4H6J, 5TBM (chainA)), homologous complexes of HIF1α (4ZPR (chain B)) and of Clock/BMAL1 (4F3L) from the PDB and isolated the respective chains. Modeller 9. 17 was used to create the multiple template-based homology model of hAhR. The resulting models were ranked by DOPE scoring. The best scoring model was selected for all subsequent modeling activities. Subsequently, model quality was checked, and the Protein Preparation wizard included in Maestro11v0 software (Schrödinger, LLC, New York, NY, 2018) was used to adjust structural defects using default values.
5. 1 software. GFP imaging was performed using 488-nm laser line. Image sequences were generated every minute using a 20X NA 0. 75/20X Super Fluor objective and 3. 44 µm step size. Bright field images were taken at low-level illumination with a halogen lamp. Where indicated, images were processed with Manual Tracking module (ImageJ software, NIH) on maximum intensity projection. Upon background subtraction for each fluorescence channel, a Gaussian blur filter was applied. Brightness and contrast were set and then multi-channel image sequences were overlaid. Zebrafish cell dynamics analysis. Neutrophils were tracked with the Manual Tracking plugin (ImageJ). The resulting 2D coordinates were analyzed using the Chemotaxis Tool plugin (Ibidi, Germany). (http://ibidi. com/fileadmin/products/software/chemotaxis_tool/IN_XXXXX_CT_Tool_2_0.
Pictures were taken daily until day 6 using a Fujifilm FinePix S5800 camera. Analysis of the data was performed using ImageJ software (https://imagej. nih. gov/ij/). To calculate the size of the wounds the circumference was normalized to the length of an internal control (1 cm of the ruler in the picture) and results were further normalized to day 0. Contact skin irritation model. Skin irritation was induced with 5% sodium dodecyl sulfate (SDS) in conserved water DAC (NRF S. 6) on 4 spots of the volar forearm of 9 subjects using round self-adhesive patches with a diameter of 1. 2 cm (Curatest ® F, Lohmann & Rauscher, Germany). Patches were removed after 24 h and the skin was carefully cleaned with water. Lawsone was applied to the SDS treated sites at concentrations of 0. 5%, 1% and 3% (g/g) in base cream.
Pure base cream served as an intra-individual control. Treatment sites were covered by self-adhesive patches for another 24 h. The extent of skin irritation was assessed by using Moor Full-field Laser Perfusion Imager (FLPI-2, Moor Instruments, Axminster, UK) at time points 2, 3 and 7 days after induction of skin irritation. Microarray hybridization protocol, data preprocessing and analysis. Gene expression microarray studies were carried out as dual-color hybridization of HEK cells from one donor. RNA labeling was performed with the Quick Amp Labeling Kit, two-color (Agilent Technologies). In brief, mRNA was reverse transcribed and amplified using an oligo-dT-T7 promoter primer, T7 RNA Polymerase and Cyanine 3-CTP or Cyanine 5-CTP. After precipitation, purification, and quantification, 300 ng cRNA of both samples were pooled, fragmented and hybridized to custom-commercial whole genome human 8 × 60 k multipack microarrays (Agilent-048908) according to the supplier's protocol (Agilent Technologies).