dataesr/scientific-paragraphs-categorization huggingface dataset:
, 2014). Our results are consistent with these previous observations, as acetate incorporation at advanced stages of Fe biomineralization can be attributed to metabolic activity of non-mineralized and FIGURE 6 | 13 C 14 N/ 12 C 14 N as a function of 16 O/CN determined by NanoSIMS in single mineralized (red) and non-mineralized (black) cells grown for 4 days (t min = 4 days) in biomineralization medium (Lp-, Mt-, FeP-, Gt-media) then transferred for 4 h, 1 day, or 4 days in labeled medium. Errors on y-axis values were calculated as (1/ 13 C 14 N + 1/ 12 C 14 N) 1/2 , and correspond to negligible values; the representation of data (circles) is larger than and encompasses the error bars. The barycenter of each group of points (mineralized vs. non-mineralized subpopulations) is displayed as (red vs.
Acknowledgments This study was funded by a  CNRS-INSU  grant (program INTERRVIE) to JM. The  National NanoSIMS  facility at the MNHN was established by funds from the  CNRS, Région Ile de France, Ministère délégué à l'Enseignement supérieur et à la Recherche , and the  MNHN. The  Scanning Electron Microscope (SEM)  facility of the  Institut de Minéralogie, Physique des Matériaux et Cosmochimie  is supported by  Région Ile de France  grant  SESAME 2006 N • I-07-593/R ,  INSU-CNRS, INP-CNRS, University Pierre et Marie Curie -Paris 6 , and by the  French National Research Agency (ANR)  grant no. ANR-07-BLAN-0124-01.
Patients and methods Study population. The Bonne Pratiques de Chimiothérapie (BPC ® ) software, which is a computer software for chemotherapy prescription from the medical office to the centralized pharmaceutical unit in charge of antineoplastic drug preparations, has been routinely used since 2001. The BPC ® software prospectively registers the type of disease, the physician in charge, the date of treatment cycles, the type of regimen, the possible dose adjustments, the cause of interruption and the treatment delay. Through this database, all consecutive patients with metastatic prostate cancer treated by carboplatin (AUC=5) and etoposide (100 mg/m² intravenous infusion on days 1-3 every 3 weeks, or 75 mg orally administered daily for 10 days every 4 weeks) in the Federative Regional Cancer Institute of Franche-Comté were identified.
The Doubs Cancer Registry provided information on patient outcomes, patient and tumor characteristics and survival data. To complete the database, a retrospective search through the medical charts was conducted to collect information on the site of metastatic lesions, performance status (PS), lines of anticancer treatment, adverse events, treatment response and date of progression. The biological status was assessed after each cycle and tumor response was assessed at 3 and 6 months after treatment initiation. This database has been approved by the National Commission on Informatics and Liberties (no. 2012-412 of 22/11/2012). The protocol was approved by the Central Ethics Committee (Comité de Protection des Personnes Est-II). Statistical analysis. The primary objective was the assessment of the efficacy of the carboplatin-etoposide regimen in terms of OS.
Image Processing All image processing were performed using CellAnimation  [15] , Fiji  [16]  and custom apps developed in MATLAB (Mathworks, MA) and Python. Maximum intensity projection (MIP) of Z-stacks was performed to visualize all foci and nuclei within one single 2D image. We used the trainable Weka segmentation plugin in Fiji to develop a classifier which assigned pixels to either foreground or background pixels. To segment nuclei clusters into individual nuclei we used a custom convexity restricted watershed. This was done by combining a standard distance watershed with an algorithm which excluded shapes having only convex angles from segmentation  [17]. This was based on the observation that single nuclei are convex shapes while nuclei conglomerates exhibit concave angles. To eliminate non-significant concavities from shape contours we used a Douglas-Peucker line simplification algorithm  [18].
This led to very accurate identification of individual cells (Fig  1C ). Segmented cells were then automatically tracked using a custom pipeline in CellAnimation (Fig  1D ). The pipeline detects mitotic events and assigns ancestry information. For these movies cells up to four generations of cells were detected (Fig 1E  and 1F ). For each time-lapse series the software generates two csv files. The tracking file lists the track ID and shape features (centroid position, area, perimeter, etc. ) of every nucleus in the movie. The ancestry file lists the detected parent ID, start time and split time for every cell. In addition to the csv files, a set of images is produced which overlays the track IDs and cell generation on the original images. These images can be used for manual validation of the automatic tracking.
Data Processing Cell and foci numerical features extracted from the time-lapse movies were processed using R (Team 2006) and RStudio (RStudio, MA). Foci classes were assigned based on their total area and mean fluorescence intensity. We used a Gaussian mixture model applied to a random subsample of 10,000 data points to determine the classes. To test the stability of the classes we applied the Gaussian mixture algorithm 10 times to different random subsets of 10,000 points each with a maximum of five clusters allowed. The algorithm consistently selected four classes as the optimum number of classes for the data with class boundaries similar between runs. To determine the conversion rates between different foci classes we used linear programming techniques. In addition to the four classes determined automatically we added a class 0 to account for protein which is not part of a focus (total intensity of protein not in foci).
Cell proliferation assays Cell proliferation analysis was conducted using Click-iT EdU Alexa Fluor 647 Flow Cytometry Assay Kit (Life Technology). Briefly, EdU was added into cell-culture medium to a final concentration of 10 mmol/l one hour before the endpoint of the experiments. Cells were collected after trypsin treatment, washed once with 2 ml of 1% BSA in PBS, fixed using Click-iT fixative, and incubated for 15 min in saponin-based permeabilization solution. Cells were then treated with Click-iT reaction cocktail, according to manufacturer's instruction, for 30 min before flow cytometry analysis. DAPI (1 mM) (FxCycle Violet Stain; Life Technologies) was added directly before FACS analysis. Data were acquired on an LSRFortessa (BD Biosciences) and analyzed with FACS Diva software (BD).
Tamoxifen treatment to achieve efficient activation of recombinase CRE and excision of SV40LT Our previous data obtained with EndoC-bH2 indicate that constitutive CRE expression results in excision of SV40LT  [10]. Under such conditions, 21 days after transduction with CRE-expressing lentiviral vector, proliferation was massively reduced and insulin content increased. To follow excision efficacy in EndoC-bH3 cells that express CRE-ERT2, we used 3 readouts: SV40LT expression, incorporation of EdU for proliferation assessment and insulin content measurement. Both the concentration of TAM and the duration of treatment were investigated. Excision efficacy was monitored 21 days after TAM addition using increasing doses from 1 to 10 mM. TAM was maintained in the medium for 7 or 21 days (Figure  2A ).
ACKNOWLEDGMENTS We thank  Marine Giry  from the  Genotyping & Sequencing  platform of the  Institut du Cerveau et de la Moelle (ICM)  for technical assistance in performing CGH array and the iVector platform of the ICM for technical assistance in lentiviral vector production. This work was supported by grants from the  7th Framework Program  of the  European Union  under grant agreements no. 241883  (BetaCellTherapy), from the  Innovative Medicines Initiative Joint Undertaking  under grant agreement no. 155005  (IMIDIA), resources of which are composed of financial contribution from the  European Union 's  Seventh Framework Programme  ( FP7/2007-2013 ) and EFPIA companies' in kind contribution e for this specific work with additional financial contribution from  Sanofi  as part of their in kind contribution.
R. S. 's laboratory belongs to the  Laboratoire d'Excellence consortium Revive  and to the  Departement Hospitalo-Universitaire (DHU) Autoimmune and Hormonal diseases  and is supported by the  Foundation Bettencourt Schueller. P. R. 's laboratory is supported by the  Institut Hospitalo-Universitaire de Neurosciences Translationnelles de Paris ,  IHU-A-ICM, Investissements d'Avenir   ANR-10-IAIHU-06. Work in the Solimena group is supported in part with funds from the  German Ministry of Education and Research  to the  German Center for Diabetes Research  (DZD e. V. ).
Results The event yields after all selections are listed in Table  3  along with their combined statistical and systematic uncertainties. The number of signal events from the HW process is also listed for B(t → H + b) = 10%. The signal event yield is obtained using the SM tt cross section. The total number of expected background events matches well the number of observed data events within uncertainties. The dijet mass distribution after all selections is shown in Fig. 5. The dotted line represents the expected distribution of signal and background events for B(t → H + b) = 10%. Again, the data are in agreement with the SM background expectation. An upper limit is obtained on B(t → H + b) as discussed later in this Section. Assuming that any excess or deficit of events in data, when compared with the expected background contribution, is due to the t → H + b, H + → cs decay, the difference ∆N between the observed number of data events and the predicted background contribution is given as a func-tion of x = B(t → H + b) via the following relation: ∆N = N BSM tt -N SM tt = 2x(1 -x)N HW + [(1 -x) 2 -1]N SM tt.
RNA extraction and real-time quantitative PCR Total RNA was extracted from hepatocytes using a commercial kit (Qiagen) following the manufacturer's recommendations. The amount of isolated RNA was estimated by ribogreen fluorescence and its purity was assessed by the absorbance ratio 260/280 nm. Total RNA (1 μg) was reverse-transcribed and real-time quantified using SYBR Green I Master and the appropriate primers (Additional file 2: Table  S2 ) in a LightCycler 480 instrument. In parallel, the mRNA concentration of human housekeeping βactin was always analysed as an internal normalization control. The real-time monitoring of the polymerase chain reaction (PCR) and the precise quantification of the products in the exponential phase of the amplification were performed with the LightCycler Relative Quantification Analysis software (Roche Applied Sciences) in accordance with the manufacturer's recommendations.
5c ). Thus, the VAL9-HEP display sufficient detoxifying enzyme activity required to rescue the animals. Transplanted mice were sacrificed at three time points (2, 4 and 8 weeks) after transplantation. To verify that the transplanted hepatocytes homed towards the liver without migrating to other organs, we analysed the transplanted cell distribution in other organs such as the spleen and lungs 8 weeks after transplantation. No human cells were detected in any of the analysed organs as assessed by immunohistochemistry (IHC) against GFP (data not shown). IHC revealed that the liver displayed a normal histology with no sign of tumours (data not shown). The spleen, lung and kidneys were also normal. No signs of adenocarcinomas were visible in the peritoneum (data not shown).
To this end, well-defined methods should be established to reduce the tumourigenicity of transplanted cells and a strict elimination of undifferentiated hESCs from transplanted cells  [55, 56]. In our VAL9-HEP engrafted mice, we investigated the appearance of tumours at the time of sacrifice. No sign of tumour formation was evident in grafted livers or in other major organs. However, additional long-term studies are required to confirm the ultimate safety of VAL9-HEP. We demonstrate in this study, for the first time, that engrafted human VAL9-HEP are able to rescue mice with ALF. This was evaluated by the significant decrease in AST and ALT and by the rescue of transplanted animals. The data suggest that the VAL9-HEP expressed sufficient levels of detoxification enzymes at the time of transplantation.
Acknowledgements This work was supported by the  European Commission 's  Seventh Framework Programme   FP7-HEALTH. 2011. 1. 4. 2  under grant agreement No. 278152  "InnovaLiv", and from  French National Research agency (ANR ,  2010-RFCS-004  « Liv-iPS »). LT was a recipient of a Sara Borrell Contract from the  "Instituto de Salud Carlos III" of the Spanish Ministry of Economy and Competitiveness. JC has a fellowship from the  French Ministry of Research. ZH and MA were supported by the  InnovaLiv grant.
Acknowledgements We would like to thank  O. Kepka  and  O. Lebedev  for valuable discussions. SF acknowledges the  Brazilian Ministry of Science, Technology and Innovation  for financial support, and the  Institute of Theoretical Physics of Sao Paulo  ( ICTP/SAIFR ) for hospitality. GG would like to thank the  Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)  for financial support.
Values are expressed as mean ± SEM. Triangles in (A) represent differences between firsts (black) and second (white) fEPSPs, P < 0. 05. Differences between ratios, * P < 0. 05; * * P < 0. 01. Student t-test. Recordings were carried out for 5 min. The power spectrum of hippocampal LFP activity was calculated with the help of the MatLab 7. 4. 0 software (MathWorks, Natick, MA, USA), using the fast Fourier transform with a Hanning window, expressed as relative power and averaged across each recording session  (Madroñal et al. , 2009).
Data Collection and Analysis Local field potentials, fEPSPs, and 1-volt rectangular pulses corresponding to kainate injections and brain stimulations were stored digitally on a computer through an analog/digital converter (CED 1401 Plus, Cambridge, England). Data were analyzed off-line: for LFP with the MatLab 7. 4. 0 software, and for fEPSP recordings with the Spike 2 (CED) program. Five successive fEPSPs were averaged, and the mean value of the amplitude (in mV) was determined. Computed results were processed for statistical analysis using IBM SPSS Statistics 18. 0 (IBM, New York, NY, USA) or Sigma Plot 11. 0 (Systat Software, Germany). The statistical significance of differences between groups was inferred by one-way ANOVA and ANOVA for repeated measures (data by groups), with a contrast analysis (Dunnett's posttest) for a further study of significant differences, or the Student t-test.
ACKNOWLEDGMENTS The authors thank  María Sánchez-Enciso  and  Natàlia Plana  for technical assistance,  Isabel Sáez  for critical review, and  Tanya Yates  and  Roger Churchill  for correcting the English version of the manuscript. This work was supported by grants from the  Spanish MINECO  (grant numbers  BFU2014-56692-R  and  BFU2011-30554 ) to AG, JD-G, and JG, from the  Junta de Andalucía  ( BIO122 ,  CVI 2487 , and  P07-CVI-02686 ) to AG and JD-G, and from the  CIBER de Diabetes y Enfermedades Metabólicas Asociadas (ISCIII, MINECO) , the  Human Frontiers Science Program  ( RGP0027/2011 ), and the  Fundación Ramón Areces  ( CIVP16A1862 ) to JG.
Cardiovascular magnetic resonance derivation cohort The CMR derivation cohort consisted of stable patients with mild-to-severe AS. Patients were recruited from the outpatient clinics at the Edinburgh Heart Centre from March 2012 (clinicalTrials. gov identifier NCT01755936). Patients who had other significant valvular heart disease (≥ moderate), contraindications to CMR or cardiomyopathies (acquired or inherited) were excluded. As this study aimed to identify variables of midwall myocardial fibrosis due to AS, we excluded patients with previous myocardial infarction based on clinical history and confirmed on CMR. Blood samples were taken at the time of CMR and clinical assessment.
External outcome cohort The external outcome cohort comprised of asymptomatic patients with at least mild AS from the COFRASA and GENERAC studies (clinicalTrials. gov numbers NCT00338676 and NCT00647088, respectively). These patients were prospectively recruited since November 2006. Exclusion criteria were AS due to rheumatic valvular disease or radiotherapy, previous infective endocarditis, other significant valvular diseases (≥moderate), and severe respiratory or renal insufficiency.
Statistical analysis Baseline characteristics were reported as percentages for categorical variables, mean + standard deviation or median (inter-quartile range) for continuous variables as appropriate. The distribution of all continuous variables was tested for normality using the Shapiro-Wilk test. Statistical analyses were performed using SPSS version 20 (IBM Corp. , Armonk, NY, USA) and GraphPad Prism version 5. 0 (GraphPad Software, San Diego, CA, USA). Statistical significance was taken as a two-sided P , 0. 05.
Acknowledgements The  Wellcome Trust Clinical Research Facility  and the  Clinical Research Imaging Centre, Edinburgh  assisted in the conduct of the study. Mary Stoddard  and  Edwin Carter  assisted with the analysis of high-sensitivity plasma cardiac troponin I concentrations and  Abbott Laboratories  for providing the assay reagents. Le Thu Thao wrote the program for the online clinical calculator and  Leif Roschier  designed the nomogram using PyNomo. We thank the  Department of Biochemistry of Bichat Hospital, Paris  ( Dr Monique Dehoux ) and the technician of the  Department of Biochemistry of Tenon Hospital, Paris  ( Marie Christine Ricon et Alicia Poniard ).
Funding A. S. V. S. , N. L. M. , D. E. N. , and M. R. D. are supported by the  British Heart Foundation  ( CH/09/002 ,  FS/10/024 ,  FS/10/26 , and  FS/14/78/ 31020 ). D. E. N. holds a  Wellcome Trust Senior Investigator Award  ( WT103782AIA ). C. W. L. C. is supported by the  National Research Foundation-Ministry of Health, Singapore. The  Wellcome Trust Clinical Research Facility  and the  Clinical Research Imaging Centre  are supported by the  NHS Research Scotland  through  NHS Lothian. The COFRASA (clinicalTrials. govnumber  NCT 00338676 ) and GENERAC (clinicalTrials. govnumber  NCT00647088 ) studies are supported by grants from the  Assistance Publique -Hopitaux de Paris  (PHRC National 2005 and 2010 and PHRC regional 2007). Funding to pay the Open Access publication charges for this article was provided by  British Heart Foundation.
Statistical analysis Median and interquartile (IQR) ranges were calculated. Diagnostic values of each test (sensitivity, specificity, positive and negative predictive value, likelihood ratio for positive and negative tests) were calculated as recommended  [16]. For continuous variables, the Mann-Whitney U test was used. For categorical variables, Chi square was used. P values were considered significant if p0. 05. The Kruskal-Wallis test was carried out to calculate the differences of IFN-γ and TST levels between the groups. The comparison between the QFT-GIT and TST was made by using Mc Nemar Chi square tests, treating the data as paired. Agreement between the two tests was estimated using unweighted Cohen's kappa (ĸ) statistics with agreement considered ''slight" for k 0. 20, ''fair" for 0.
4 evomilnacipran is an SNRI, and its antidepressant action is thought to be related to potentiation of norepinephrine and serotonin in the central nervous system through inhibition of reuptake at serotonin and norepinephrine transporters. 5 Levomilnacipran has a greater potency in vitro for norepinephrine reuptake inhibition than for serotonin reuptake inhibition without directly affecting the uptake of dopamine or other neurotransmitters in vitro. 6 An extendedrelease formulation of levomilnacipran (FETZIMA ® ) received US Food and Drug Administration (FDA) approval in July 2013 for the treatment of major depressive disorder in adults, with a recommended dose range of 40-120 mg once daily. 5 DA approval was based on the results of three phase III studies (ClinicalTrials. gov ] [12]  This report presents the disposition and metabolic profile of [ 14 C]-levomilnacipran in humans, monkeys, and rats, and describes the in vitro binding of [ 14 C]-levomilnacipran to human plasma proteins.
Nine men were enrolled in the study; PK analysis and mass balance were performed on data from four men who did not vomit after oral administration of study drug. Calculations of blood-to-plasma ratio of [ 14 C]-radioactivity were performed on data from all nine men. Blood, urine, and feces samples for mass balance and PK analyses were collected from Day 1 to Day 6. Blood samples were collected by venipuncture or drawn from a catheter in the forearm into polyethylene tubes containing lithium heparinate as anticoagulant. Samples for radioactivity measurement and for levomilnacipran and N-desethyl levomilnacipran assay were collected at the following times: pre-dose and then 1 hour, 2 hours, 2. 5 hours, 3 hours, 3. 5 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours post-dose.
Then, the sample was centrifuged at 2500× g for 5 minutes at 4°C. The organic phase was transferred to another conical polypropylene tube, and 0. 1 mL of 0. 5% formic acid solution was added. The sample was centrifuged at 2500× g for 5 minutes at 4°C. After centrifugation, the organic phase was discarded, and the excess of ethyl acetate was evaporated by a slight nitrogen stream for 2 minutes. The extract was then transferred to an injection vial for analysis. The analytical system used was the Acquity™ sample and binary solvent manager combined with Quattro Premier XE mass spectrometer and Waters MassLynx ® software (version 4. 1). Reverse-phase chromatography was applied before electrospray ionization in positive mode and tandem mass spectrometry detection. Chromatography was performed on a Synergi Polar-RP 100A column (50 mm ×2.
3 nCi/g (bottom range), 7,999 nCi/g (middle range), and 17,675 nCi/g (top range). Calibration line and quality control standard values were obtained by combusting known weights of radioactive solutions used in preparation of the standards. Samples were combusted in a Packard Model 307 automatic sample oxidizer (PerkinElmer LAS (UK) Ltd) before liquid scintillation counting. Quantitative wholebody phosphor imaging was carried out using a Fuji model FLA5000 phosphor imager system (Raytek Scientific Ltd, Sheffield, UK). Aida™ software (v3. 27) was used to calibrate individual scans and to quantify levels of radioactivity. Freeze-dried sections were placed against a phosphor screen (Raytek Scientific Ltd) for an exposure period of 18 hours. Following exposure, the phosphor screen was scanned by a laser beam, and the latent image was captured and stored in an electronic data file.
Data analysis PKs and mass balance Plasma PK parameters (maximum plasma drug concentration [C max ], time of maximum plasma drug concentration [T max ], area under the plasma concentration-versus-time curve from time 0 to the last observed plasma concentration [AUC last ] and from time 0 to infinity [AUC inf ], and terminal elimination half-life [T 1/2 ]) of levomilnacipran and N-desethyl levomilnacipran were derived from a non-compartmental analysis using WinNonlin ® (version 5. 2) for human data or Kinetica™ (version 4. 2, InnaPhase Corporation) for animal data. Descriptive statistics of percentage of the dose excreted in urine and feces were reported. The mass balance (corresponding to the percentage of [ 14 C]-levomilnacipran excreted in urine and feces) was calculated after measuring the radioactivity recovered in urine and feces samples.