dataesr/scientific-paragraphs-categorization huggingface dataset:
Fura-2AM-loaded cells were treated with 2 μM thapsigargin in HBBSS without CaCl 2 (0Ca 2+ ) to trigger calcium efflux from the RE. To test SOCE, calcium was reintroduced in the medium by using classical HBBSS (+Ca 2+ ). During the acquisition, cells were irradiated alternately with 340 and 380 nm light, and fluorescence from the trapped dye was measured at 510 nm. The ratio of fluorescence intensities recorded after excitation at 340 nm (F340) and at 380 nm (F380) was used to estimate intracellular calcium concentrations ([Ca 2+ ] i ) and was acquired every 5 seconds with a digital CMOS camera (Hamamatsu, ORCA-Flash2. 8 C11440-10C). The monochromator and the photometers allow emission and detection of fluorescence from ~12 cells in the field of view. Data analysis was performed using MM fluor software (Universal Imaging Corporation).
Mcl-1 expression was monitored by western blot; (C) Cells were treated with increasing dose of CAI for 48h for IGROV1-R10 and 72h for OVCAR3 and SKOV3. The effect of CAI treatment on the activation of the PI3K/Akt/mTOR pathway was analyzed by studying the protein expression of P-Akt (Ser473 and Thr308) and total Akt, P-mTORC1 (Ser2448) and P-mTORC2 (Ser2448), P-p70S6K (Thr389) and total p70S6K and P-4E-BP1 (Thr70) and total 4E-BP1 by western blot analysis. Protein levels (standardized based on actin) were determined by densitometry scanning with Image J software to generate the values shown in the bar graphs. Results are expressed as mean ± SEM. Statistical differences were analyzed with a Student t-test: * p< 0. 05, ** p< 0. 01, *** p< 0. 001 (n=3).
ACKNOWLEDGMENTS The research was supported by the  Ligue Contre le Cancer (Comité départemental de l'Orne). Marie-Laure Bonnefond  and  Romane Florent  were funded by a grant from  Normandy Regional Council  and  Marie-Laure Bonnefond  was also funded by  Accord Healthcare Inc. We thank  Marilyne Guillamin  ( Flow Cytometry Core Facility , SF 4206 ICORE of  University of Caen Normandy ) for technical assistance. We thank  Dr Nicolas Vigneron  ( INSERM U1086 ,  ANTICIPE ) for his advice about statistical data,  Dr Marie Villedieu  ( INSERM U1086 ,  ANTICIPE ) for her careful reading and  M. Ray Cooke  for English editing.
Funding The  French National Research Agency  through the national " Investissements d' avenir" program  ( ANR-10-LABX-21 ,  LABEX RESSOURCES21 ) and through the  ANR-14-CE04-0005  Project " Agromine " is acknowledged for funding support to  G. Echevarria  and A. van der Ent. A. van der Ent is the recipient of a  Discovery Early Career Researcher Award  ( DE160100429 ) from the  Australian Research Council.
Neutron reflectometry measurements NR measurements were carried out using the FIGARO instrument at the Institut Laue-Langevin (ILL)  (Campbell et al. , 2011). Data were recorded using neutrons with wavelengths of 2-30 Å at incident angles of 0. 62°and 3. 8°. Data from three samples were recorded to illustrate the effect of replacing the h-cholesterol by d-cholesterol. A mixture of 1:4 cholesterol to dipalmitoylphosphatidylcholine (DPPC) by mole was prepared in each case as a chloroform solution. After spreading and compression to a surface pressure of 25 mN m -1 , the reflectivity was measured, which was normalized with respect to a measurement of pure D 2 O. Three neutron contrasts were studied (i) h-cholesterol with d 62 -DPPC on null reflecting water (NRW), (ii) h-cholesterol with d 62 -DPPC on D 2 O and (iii) d-cholesterol with h-DPPC on NRW, where NRW is a mixture of 8.
Sterol analysisdeuterated versus non-deuterated samples Samples of the unlabelled (control) and perdeuterated cholesterol producing P. pastoris cell paste from flask cultures were analysed by gas chromatography-mass spectrometry (GC-MS) for their sterol composition as described above. Deuterated sterols show a shorter retention time (between 0. 6 and 0. 9 min) by comparison with their non-labelled analogues, in accordance with the published data on perdeuterated ergosterol produced in P. pastoris. Fig. 1  shows the gas chromatogram for the sterols produced by the strain (i. e. cholesterol, 7-dehydroxycholesterol (7-DHC) and zymosterol) under both non-deuterated (Fig. 1(a) ), and deuterated (Fig. 1(b )) conditions. Tables  1a  and 1b  show the sterol compositions of both unlabelled and perdeuterated cholesterol-producing P.
Evaluation of the potential of perdeuterated cholesterol in neutron reflectivity studies The observed reflectivity data are shown in Fig. 5. Fits to these data were carried out using the Motofit software in Igor Pro  (Nelson, 2010). The fitted thickness was 14. 7 Å for the tail region, and 10. 0 Å for the head region in all cases. Three different contrasts are shown in Fig  5:  (i) perdeuterated cholesterol (d-cholesterol) and hydrogenated DPPC (h-DPPC) on null-reflecting water (NRW) (blue curve), (ii) unlabelled cholesterol (h-cholesterol) and d 62 -DPPC on NRW (green curve), (iii) hcholesterol and d 62 -DPPC on D 2 O (red curve). Contrast (i) allows the surface excess of cholesterol to be determined; contrast (ii) allows the surface excess of DPPC chains to be determined, and contrast (iii) allows the hydration of the head group layer to be determined.
Acknowledgements V. T. F. acknowledges support from the  EPSRC  under grant numbers  GR/R99393/01  and  EP/C015452/1  which funded the creation of the  Deuteration Laboratory (D-Lab) in the Life Sciences group  of the ILL. This work used the platforms of the  Grenoble Instruct-ERIC Centre (ISBG ;  UMS 3518 CNRS-CEA-UGA-EMBL ) with support from  FRISBI  ( ANR-10-INSB-05-02 ) and  GRAL  ( ANR-10-LABX-49-01 ) within the  Grenoble Partnership for Structural Biology  (PSB). G. A. S. acknowledges the support of this work by the  Federal Ministry of Science, Research and Economy (BMWFW) , the  Federal Ministry of Traffic, Innovation and Technology (bmvit) , the  Styrian Business Promotion Agency SFG , the  Standortagentur Tirol , the  Government of Lower Austria and Business Agency Vienna  through the  COMET-Funding Program  managed by the  Austrian Research Promotion Agency FFG.
Circular Dichroism Spectroscopy Circular dichroism (CD) spectra recorded at room temperature from 190 to 260 nm on a CD6 dichrograph (Jobin-Yvon, Longjumeau, FRA), using quartz cells with a 0. 05 cm path length. For each spectrum, 5 scans were accumulated and then averaged. The baseline was obtained by recording a spectrum of the neat solution, and it was subtracted from the peptide spectrum. Ellipticity was reported as mean residue molar ellipticity in deg•cm 2 •dmol -1. Crystalline CsA and also microspheres formulations equivalent to 0. 4 mg/mL of CsA was dissolved in diluted acetonitrile with water (55% w/w), and analyzed for secondary structure where the CD spectra were accumulated three times for data collection. Each data point was carried out in triplicate.
Statistical Analysis Pharmacokinetic analysis of plasma concentration results was performed using model independent methods. The area under the curve of the plasma concentration-time (AUC) and the cumulative AUC were assessed by the WinNonlin program (version 5. 2 Pharsight Corp. , Mountain View, CA), using the non-compartment method. Maximum whole blood concentration (C max ) and time to reach maximum whole blood concentration (T max ) were directly obtained from the plotted data. The relative oral bioavailability for the SASD/CsA formulation was determined by the ratio of AUC SASD/ AUC Neoral® , and was expressed as a percentage.
Literature Search and Inclusion Criteria We conducted a systematic literature search via the PubMed and Cochrane platforms on September 1st, 2017, on all articles published and indexed up to this point. To identify relevant articles on original research, we associated terms referring to the use of cannabis or cannabis-related psychoactive substances, animal models, and vascular reactivity or stroke according to a predefined search algorithm (see below). All experimental studies on animals were eligible. We did not place any restrictions on the design of the study to be included, as long as it was conducted on an animal model. Personal databases of the authors were screened for relevant articles, as were bibliography lists of relevant reviews, which were then manually added.
Literature Search Our systematic literature search revealed 380 publications on PubMed. To these, 20 articles were added manually from personal databases (J. S. R. and V. W. ). After screening of titles and abstracts, 19 articles were added from cross-references and in total 62 articles remained for full-text assessment. Of these, 11 articles were excluded with reason, leaving included 51 articles for qualitative synthesis (see Figure  S1  in Supplementary Material).
Animal Models in Cardiovascular Research on cannabinoids-a Possible Outlook The importance of the choice of a model system was underlined by O'Sullivan et al. in the recent review and meta-analysis by  Sultan et al. (2018). They systematically searched for publications on the haemodynamic effects of THC in humans and in vivo animal models and extracted data on the doses, changes in blood pressure, heart rate, and blood flow, experimental conditions and each model used. In humans heart rate was monitored. Overall, blood pressure, heart rate, and blood flow changes were heterogenous and depended on the species, consciousness level, anaesthetic agent, and administration mode. This seems to be in line with our observations regarding cannbinoids' effects on vasculature in vivo and in vitro. The authors underline the need for further investigations of THC's haemodynamic effects in humans.
5418 Å) radiation and a high efficiency one dimensional detector (Lynx Eye type, Bruker, Karlsruhe, Germany), operated in integration mode, were used,. The data were collected from the 2θ range 20 • -70 • , with a step of 0. 02 • and 34 s measuring time per step. The crystallite size (D) of the prepared HAp was calculated by the Scherrer's equation: D = Kλ/βcosθ where, K is a dimensionless shape factor, with a value close to unity, λ is the wavelength of Cu-Kα radiations (λ = 1. 5405 Å), β is full width at half maxima of the most intense peak (211) and θ is the Bragg angle (in degrees). The morphology of the newly developed materials was investigated by scanning electron microscopy (SEM), using a HITACHI S4500 microscope (Tokyo, Japan) equipped with an energy dispersive X-ray attachment (EDAX) (Tokyo, Japan).
The compounds were identified using the using NIST and Wiley Registry 8 Edition mass database, n-alkalene (C9-C22) hydrocarbon series (Nile, Italy), and by comparing the mass spectra with MS literature  [92] [93] [94]. The results of compound content were presented as relative area percent (%). The surface percentages obtained from the determination of standard chromatogram were used for the quantitative analysis. Qualitative analysis of antimicrobial activity. The antibacterial assays were performed using one reference bacterial strain: E. coli ATCC 25922, and three clinical isolates from the collection of microorganisms in the Microbiology Department (Faculty of Biology, University of Bucharest): E. coli ESBL 4493 (an extended spectrum beta-lactamase producing strain), S. aureus 1426, methicillin-resistant S.
The research was conducted in the following databases: PubMed, Scopus, BIREME, Scielo, Open Grey, and Science Direct. Based on the inclusion criteria, 30 articles were selected and discussed in this review. The studies listed revealed a potential activity of EOs and their compounds for the treatment of inflammatory diseases, especially in chronic inflammatory conditions, with the main mechanism involving reduction of reactive oxygen and nitrogen species associated with an elevation of antioxidant enzymes as well as the reduction of the nuclear factor kappa B (NF-κB), reducing the expression of proinflammatory cytokines. Thus, this review suggests that EOs and their major compounds are promising tools for the treatment of chronic inflammation.
Material and Methods 2. 1. Search Strategy. In this review, the specialized databases PubMed, Science Direct, Scopus, Open Grey, Scielo, and BIREME were used for literature search in March and April 2018, using different combinations of the following keywords: essential oils, volatile oils, antioxidants, and inflammation. We did not contact investigators, and we have not attempted to identify unpublished data until the date of the search.
Data Extraction. Data were collected and examined by one reviewer using standardized forms and were checked by a second reviewer. The information extracted from the articles included EOs or their major compounds, cell lines (in vitro studies), animal models (in vivo studies), doses or concentrations, routes of administration, biochemical assays, and molecular mechanisms investigated. 2. 4. Methodological Quality Assessment. The risk of bias and quality of preclinical in vivo studies were performed using an adapted checklist  [21] [22] [23]. This investigation allowed assessing the methodological quality of the included studies concerning mainly the randomization of the treatment allocation, blinded drug administration, blinded outcome assessment, and outcome measurements.
Results and Discussion 3. 1. Study Selection. The primary search identified 429 articles (200 from Scopus, 18 from Science Direct, 32 from BIREME, and 179 from PubMed). However, 146 manuscripts were indexed in two or more databases and considered only once, resulting in 283 original articles. After an initial screening of titles and abstracts, 192 articles were excluded because they did not meet the inclusion criteria or presented completely different themes from the proposal of this review. After an initial screening of titles and abstracts and a full-text analysis, 27 articles were considered potentially relevant. In addition, 3 articles were included after manual search for data extraction, totalizing 30 final articles included in this systematic review. A flowchart illustrating the progressive study selection and numbers at each stage is shown in Figure  1.
Conversely, it could be observed that more extended release rates might be obtained for test hydrogels (the drug remained in the body for 36 hours) equated to the reference tablets (the drug remained in the body for 12 hours). Various pharmacokinetic considerations (based on the plasma level time curve) are accessible. The treatment effect was analyzed using a two-tailed t-test (SPSS 12. 0) for comparing the results of test hydrogels with reference tablets. Mean half-life (t 1/2 ) of QTP-F test hydrogels and reference tablets were originated to be 11. 03 ± 0. 12 to 6. 42 ± 0. 19 h (p <. 01), respectively. Mean C max was found to be as17. 98 ± 0. 93 and 17. 24 ± 1. 08 mg/ml (p <. 05), Mean T max for test hydrogels and reference tablets were found to be 2. 20 ± 1. 32 and 7. 99 ± 0. 02 hours (p <.
Finally, we added the toll-like receptor 4 (TLR4) as it is a specific receptor for lipopolysaccharide known as a signal for microglia activation and as microglia is the only central nervous system glial cells that express TLR4  [44]. PCR data were exported and analyzed in an informatics tool (Gene Expression Analysis Software Environment) developed at the Neuro-Centre Magendie. For the determination of the reference gene, the Genorm method was used  [45]. Relative expression analysis was corrected for PCR efficiency and normalized against two reference genes: peptidypropyl isomerase A and succinate dehydrogenase complex subunit A genes for microdissected thalamic nuclei at day 14 and valosin-containing protein and β actin genes for microdissected thalamic nuclei at day 28. The relative level of expression was calculated using the comparative (2 -ΔΔCT ) method  [46] , and naïve animals were arbitrarily set at 1.
After washing, membranes were incubated with a horseradish peroxidase-conjugated secondary antibody (goat anti-rabbit 1/2000; catalog n°7074; Cell Signaling; AB_ 2099233). Immunoreactive bands were visualized using enhanced chemiluminescence (Western Lightning ECL plus, PerkinElmer, France) and detected using the Biorad Chemidoc Touch imaging system. Between antibodies, membranes were stripped with a solution containing β-mercaptoethanol and re-blocked with fat-free milk. Quantitative analysis was performed by densitometry with ImageJ software (NIH, Bethesda, MA) and normalized with the loading control beta-actin.
Imaging and analysis of stained sections Quickly after histochemistry or the immunofluorescence treatment, stained sections were examined with a Leica DMI6000 spinning disk microscope (Leica Microsystems, Wetzlar, Germany) and digital images were captured with a HQ2 CCD camera (Photometrics, Tucson, USA) under a × 20 objective (HC PL APO CS, 0. 7 NA, Leica Microsystems, Wetzlar, Germany). The diode lasers used were at 408 nm (for DAPI), 491 nm (for Alexa 488), and 561 nm (for cyanine 3). The technique of scan slide was used in order to visualize and reconstruct all areas of interest. The mosaics were done with a motorized stage Scan IM (Märzhäuser, Wetzlar, Germany). This system was controlled by MetaMorph software (Molecular Devices, Sunnyvale, USA). Parameters were determined at the beginning of the acquisition and were maintained for all acquisitions of the same experiment.
Statistical analysis All data were analyzed using a scientific graphing and data analysis software GraphPad Prism 5 (GraphPad Software). When the KS normality test failed, a Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks was performed followed by an all pairwise multiple comparison procedures (Dunn's method). When the KS normality test passed, one-way ANOVA followed by Tukey's post hoc test was used. Linear relationships were assessed using Pearson's correlation test. A p level of 0. 05 was set as the level of statistical significance. As naïve animals were arbitrarily set at 1 in the figures of PCR results, all other data (behavior and immunohistochemistry) were also presented as percentage of naïve. All data are expressed as mean ± SEM.
Acknowledgements The microscopy was done in the Bordeaux Imaging Center a service unit of the  CNRS-INSERM and Bordeaux University , member of the national infrastructure  France BioImaging. The help of  Christel Poujol ,  Sébastien Marais , and  Fabrice Cordelières  is acknowledged. The Western blot analysis was done in the  Biochemistry and Biophysics Platform of the Bordeaux Neurocampus at the Bordeaux University  funded by the  LABEX BRAIN  ( ANR-10-LABX-43 ) with the help of  Yann Rufin. We are grateful to  Aurelie Amadio  and  Dr. Philippe Zizarri  for their technical help and to  Françis Renaudon  for his advice concerning Adobe Illustrator.
Funding This work was supported by a doctoral fellowship from  Ministère de la recherche et de la technologie  and from INSERM as well as a grant from  Neurocampus  to L. B. This project was supported by  INSERM ,  Université de Bordeaux ,  LABEX BRAIN ANR-10-LABX-43 , and  Fondation pour la Recherche Médicale (Equipe FRM ).
Evaluation of Drug Encapsulation Quantitative analysis was performed using a Shimadzu high pressure liquid chromatography (HPLC, Shimadzu Scientific Instruments, Tokyo, Japan) prominence system consisting of a degasser (DGU-20A5, Tokyo, Japan), a liquid chromatograph (LC-20 AD, Shimadzu Scientific Instruments, Tokyo, Japan), an auto sampler (SIL-20AC, Shimadzu Scientific Instruments, Tokyo, Japan), a UV/Vis detector (SPD-20A, Shimadzu Scientific Instruments, Tokyo, Japan) and a column oven (Athena C18, Shimadzu Scientific Instruments, Tokyo, Japan). A modified previously validated method was used for the analysis  [13]. In detail, a CNW Technology Athena C18, (250 mm × 4. 6 mm and 5 µm internal diameter) at column temperature of 40 • C chromatographic work station (CSW)was used for regression analysis and data acquisition.
[9]. Their identifications were based on their relative mobilities compared to structurally well-characterized external standards. Lipid quantification were performed based on fluorometric analysis of TLC to be converted to a percentage, with untreated samples normalized to 100%. Interestingly we observed a decrease of the PDIM B and triacylglycerol (TAG) and a slight decrease of PDIM A in aloe emodin-treated M. tuberculosis (Fig. 1 ) and no variation in mycolic acid methyl esters (MAMES) (data not shown). As vancomycin can target mycobacteria lacking PDIM A and PDIM B lipids in their cell wall  [6] , it is tempting to assume that the weak synergy observed by the combination of aloe emodin with vancomycin result from the PDIM B reduction attenuated by a mild impact on PDIM A. Considering that vancomycin combined with cerulenin is efficient on most MDR and XDR strains  [6] , we tested aloe emodin (3 lg/mL) and vancomycin (10 lg/mL), both separate and combined on a set of MDR and pre-XDR clinical isolates using the MGIT960/TBeXIST system.
These GSH-PEG liposomes (G-technology) have also demonstrated brain targeting as well as therapeutic efficacy in murine models of brain cancer (2B3-101; drug: doxorubicin  [143, 144] ) and neuroinflammation (2B3-201; drug: methylprednisolone  [145] ). As an example, the major results obtained with 2B3-101 in cells and animals are presented in Figure  5. The 2B3-201 product has recently completed a phase I trial in healthy volunteers  [146] , while the 2B3-101 product has completed a phase I/IIa trial in patients with various forms of brain cancer (ClinicalTrials. gov Identifier: NCT01386580  [147, 148] ) and is currently being tested in a phase II trial in patients with breast cancer and leptomeningeal metastases (ClinicalTrials. gov Identifier: NCT01818713). GSH-coating is also under investigation to obtain the brain delivery of drugs encapsulated into NPs.
Background. Oral fosfomycin is indicated for uncomplicated urinary tract infections with activity against MDR-uropathogens. Despite off-label use of giving three doses every 2-3 days, limited supporting data are available. We performed pharmacodynamic profiling using a dynamic bladder infection in vitro model to assess adequacy of repeat doses of fosfomycin. Methods. A bladder infection in vitro model simulating urinary fosfomycin concentrations after 3 g (equiv. ) oral doses was used with Mueller-Hinton broth  (MHB)  with 25 mg/L glucose-6-phosphate. Fosfomycin exposures were validated by LC-MS/ MS measurements. Pharmacodynamic response of 16 clinical Enterobacteriaceae isolates were examined (eight E. coli, four E. cloacae, four K. pneumoniae; agar dilution MIC 0. 25-64 mg/L) following three doses of fosfomycin given every 72, 48 or 24 hours, compared with single dose therapy.
We examined the PK/PD relationship between KBP-7072 drug exposures and treatment effect using a neutropenic murine pneumonia model against a diverse group of SA and SPN. Methods. Five SAs (three MRSAs) and six SPNs (three PCNs NS, two Tet R ) strains were used. MICs were determined by CLSI Methods. Plasma and ELF PK was determined after SC dosing (range 1-256 mg/kg). Lung burden was assessed by CFU counts at the beginning and end of therapy (24 hours). Infected mice were treated with KBP-7072 by SC route: SA dose range 0. 25-64 mg/kg/6 hours, SPN dose range 0. 06-16 mg/kg/6 hours. The Emax Hill equation was used to model the dose-response data to the PK/PD index AUC/MIC. The magnitude of the PK/PD index (plasma free and ELF total concentrations) associated with net stasis, 1-and 2-log kill were determined in the pneumonia model for all strains.
Acknowledgments This compassionate use/cohort ATU program was supported by  Santen SAS, Evry, France. The authors thank  Chameleon Communications International Ltd. , London, UK , for medical writing, and  BioScience Communications, New York, NY, USA , for medical writing and copyediting, which was funded by  Santen SAS. Neither honoraria nor payments were made for authorship. Selected data in this manuscript have been presented in abstract/poster format at the  Association for Research in Vision and Ophthalmology meeting , April 30-May 4, 2016, Seattle, WA,  USA , and the  Tear Film and Ocular Surface Society  meeting, September 7-10, 2016, Montpellier, France.