dataesr/scientific-paragraphs-categorization huggingface dataset:
gov identifier NCT01835938 and NCT01292824). Moreover, a significant number of compounds tested in this study are already FDA-approved for treatment of chronic HCV infection: telaprevir, boceprevir, sofosbuvir and simeprevir. Erlotinib and dasatinib have been approved for cancer treatment exhibiting a good safety profile. 54 It will thus be interesting to investigate the synergistic effect of these drugs in patients with chronic hepatitis C. Taken into account the efficacy, safety, pharmacokinetics, stage of development combined with the synergy data of the various compounds (figures 1-7), our data suggest that combinations of simeprevir  34  or sofosbuvir  40  with erlotinib could be a starting point to assess synergy in randomised clinical trials. Combining sofosbuvir and anti-CLDN1 or anti-SR-BI mAb might be promising for prevention of liver graft infection following the clinical development of the monoclonal antibodies.
Acknowledgements We thank  Dr R Bartenschlager  ( University of Heidelberg, Germany ) for providing plasmids for production of HCVcc,  Dr FV Chisari  ( The Scripps Research Institute, La Jolla, CA ) for the gift of Huh7. 5. 1 cells,  Dr CM Rice  ( Rockefeller University, New York, NY ),  Dr JA McKeating  ( University of Birmingham, UK ),  Dr D Samuel  (Inserm  U785 ,  Paul Brousse Hospital, Villejuif, France ),  Dr JM Pawlotsky  (Inserm  U955 ,  Henri Mondor Hospital, Créteil, France ),  Dr T Berg  ( University Hospital, Leipzig, Germany ),  Dr RT Chung  ( Massachusetts General Hospital, Boston ) and  Dr M Dandri  ( University Medical Center, Hamburg, Germany ) for helpful discussions. We thank  L Heydmann ,  S Durand ,  T Wu  and  N Brignon  ( Inserm U1110 ) for excellent technical assistance.
Funding This work was supported by  Inserm ,  University of Strasbourg , the  European Union  ( ERC-2008-AdG-233130-HEPCENT ,  INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009 and 2012 ,  EU FP7 HepaMab) ,  ANRS  ( 2011/132 ,  2012/239 ,  2012/318 ,  2013/108 ),  Laboratoire d'excellence LabEx HEPSYS (Investissement d'Avenir ;  ANR-10-LAB-28 ), the  Institut Hospitalo-Universitaire Mix-Surg  and the  Direction Générale de l'Offre de Soins  ( A12027MS ). This work has been published under the framework of the LABEX  ANR-10-LABX-0028_HEPSYS  and benefits from a funding from the state managed by the  French National Research Agency  as part of the investments for the future programme. The group in Leuven was funded by a grant from the  Fund for Scientific Research (FWO)  ( G. 0728. 09N )and KULeuven  GOA 10/014.
EpiTYPER assay for quantitative DNA methylation analysis The EpiTYPER assay (Sequenom) was used to quantitatively analyze the DNA methylation state of PARP-1 and TET1 CGIs. 1 μg of DNA was bisulfiteconverted using the EZ-96 DNA Methylation Kit (Zymo Research) with the following modifications: incubation in CT buffer was performed for 21 cycles of 15 min at 55°C and 30 sec at 95°C and elution of bisulfite-treated DNA was performed in 100 μl of water. PCR was performed on 10 ng of bisulfite-treated DNA using specific primers (reported in Supplementary Methods). The two TET1 amplicons mapped in regions chr10:70,320,085-70,320,271 and chr10:70,320,251-70,320,466 respectively, while PARP-1 amplicon mapped in chr1:226,595,508-226,596,006 region. After data cleaning, it was possible to measure the methylation state of 27 and 31 CpGs in TET1 and PARP-1 CGIs respectively.
Data Analysis The two sunspots studied here are simple round sunspots; one is identified in the active region (AR) NOAA 11084 (southern hemisphere) and the other one in AR NOAA 11092 (northern hemisphere). Both spots conform to the hemispheric pattern of chirality  (Balasubramaniam et al. 2004 ). These two spots were chosen for our study because (1) they are regular, of round shape with a nearly uniform twist in the azimuthal direction in chromospheric and coronal images; (2) they are isolated and not surrounded by other strong polarities, and therefore of minimal complexity; and (3) they are not involved in flaring activity in the range of times selected for the present analysis. The contextual pictures (chromospheric, coronal, photospheric continuum, and longitudinal magnetogram) of the two sunspots are displayed in Figure  1.
The data are called Hinode level 2 data sets at HAO/CSAC. We estimate the background (quiet-Sun region in the field of view shown in Figure  1 ) noise in the longitudinal and horizontal component of the magnetic field in these maps to be ≈50 G and ≈120 G, respectively, at 1σ level. The 180 • azimuth ambiguity of the observed magnetic field is easily solved with the acute angle method  (Metcalf et al. 2006)  as the two sunspots studied here are simple round sunspots. In this method the azimuth solution making acute angle with respect to the potential field azimuth direction is taken as the correct solution. It is known that, except for the highly sheared PILs of complex active regions, the acute-angle method works very well. For a review of azimuth ambiguity resolution algorithms see  (Metcalf et al.
Linear Force-free Field Modeling We model the twisted coronal and chromospheric magnetic structures in both ARs assuming the LFFF approximation. To compare the models with observations, we use SDO/AIA data taken in the 171 Å and 304 Å wavelength bands (henceforth AIA 171 and AIA 304). The magnetic field models are obtained using a fast Fourier transform (FFT) method described by  Alissandrakis (1981) , developed by  Démoulin et al. (1997) , and used in a number of studies (see, e. g. ,  López Fuentes et al. 2006). As boundary conditions for the model we use longitudinal magnetograms from SDO/HMI corresponding to the closest time to the AIA observations. The above procedure consists of the extrapolation of the observed photospheric field into the corona following the LFFF equation: ∇ × B = αB.
The authors thank the Hinode SOT, HAO/CSAC, and SDO teams for providing the data sets online. M. L. F. acknowledges financial support from Argentinean grants PICT 2007-1790 (ANPCyT),  UBACyT 20020100100733, and PIP 2009-100766 (CONICET). M. L. F. is a member of the Carrera del Investigador Cientifico (CONICET).
PRELIMINARY EXPERIMENTS We experimented with CPBPV FP on two cases of floatingpoint arithmetic pitfalls: programs with cancellation and absorption phenomena. 5  All experiments were done on an Intel Core 2 Duo at 2. 8 GHz with 4 GB of memory running 64-bit Linux. We assume 1 DSA stands for Dynamic Single Assignment. In DSA-like form, all variables are assigned exactly once in each execution path. 2 k is usually incremented until a counterexample is found or until the number of time units is large enough for the application. 3 2B-consistency  [11]  states a local property on the bounds of the domains of a variable at a single constraint level. Informally, the domain of variable x is 2B-consistent if, for any constraint c, there exists at least one value in the domains of all other variables such that c holds when x is set to the upper or lower bound of its domain.
4 3B-consistency  [11]  checks whether 2B-Consistency can be enforced when the domain of a variable is reduced to the value of one of its bounds in the whole system. 5 Absorption in an addition occurs when adding two numbers of very different order of magnitude, and the result is the value of the biggest number, i. e. , when x + y with y = 0 yields x. Cancellation occurs in s -a when s is so close to a that the subtraction cancels most of the significant digits of s and a. C programs handling IEEE 754 floating-point arithmetic, intended to be compiled with GCC without any optimization option and run on an x86 64 architecture managed by a 64-bit Linux operating system. Rounding mode was set to the nearest, i. e. , where ties round to the nearest even digit in the required position. We first describe the programs, and then we compare the performance with existing tools.
Program slope This program approximates the derivative of a function at a given point x0 by computing the slope of a nearby secant line with a finite difference quotient: f ′ (x0) ≈ f (x0 + h) -f (x0 -h) 2h Over the real numbers, the smaller h is, the more accurate the formula is. The program slope in Fig. 4  implements this formula with the square function f (x) = x 2. For function f (x) = x 2 the derivative is given by f ′ (x) = 2x which yields exactly 26 for x = 13. Over the floats, Fluctuat and rAiCp approximates the return value of the slope program to the interval [0, 25943] when h ∈ [10 -6 , 10 -3 ] and x0 = 13. CPBPV FP found test cases for the different suspicious intervals with ǫ = 1: • h = 7. 934571 • 10 -6 and res = 24. 999998 when res is restricted to interval [0, 25] • h = 2.
Nuclei were stained with Hoechst (0. 5 µg/mL, Life Technologies). Omission of the primary antibody was used as control and no immunostaining was observed. Sections were mounted using Prolong Gold Antifading reagent on Superfrost glass slides (Life Technologies). Images were taken and processed using a confocal microscope (LSM 700) and Zen software (Zeiss, Jena, Germany).
MMPs AND TIMPs CONTENT IN THE HIPPOCAMPUS OF 5xFAD AND WT MICE ACROSS AGE MMP levels from hippocampal soluble and membrane-enriched fractions were analyzed by WB. In the soluble fraction, MMP-2 levels did not change with age in WT mice, whereas MMP-9 exhibited a significant decrease (35%) between 2 and 4-6 months (Figure  2A ). In 5xFAD mice, the levels of both MMPs increased significantly at 4 months of age compared to 2 months. For MMP-9, this increase was also significant when compared to 6 months. Moreover, we found that MMP-2 and MMP-9 levels were increased in 5xFAD compared to WT only at 4 months by a 30% and 67%, respectively. We observed no changes in MMP-2 and MMP-9 levels between genotypes at 2 or 6 months. An additional faint band (∼90 kDa) compatible with the expected size of the active form of MMP-9 was also detected (Figure  2A ), but no significant differences were found across genotypes (data not shown).
ACKNOWLEDGMENTS This work was supported by funding from the  CNRS  and  Aix-Marseille Université , and by grants from the  French National Agency for Research (ANR)  to  Santiago Rivera  and  Michel Khrestchatisky  (TIMPAD, PREVENTAD) within the frame of the  French "Fondation Plan Alzheimer ". The work was also supported by LECMA grants to  Santiago Rivera ,  Michel Khrestchatisky  and  Frédéric Checler  and by grants to  Santiago Rivera  and  Michel Khrestchatisky  from " Fonds Européen de Développement Régional »FEDER  in PACA, by " Fondation pour la Recherche Médicale " and by the  "Conseil Général des Alpes Maritimes " to  Frédéric Checler. This work was also supported through the  LABEX (excellence laboratory, program  investment for the future)  DISTALZ (Development of Innovative Strategies  for a Transdisciplinary Approach to ALZheimer's disease).
1987). Spirometry was assessed in the standing position with a noseclip using a 10-L water-filled survey-recording spirometer and an Eagle II minicomputer (Warren E. Collins, Braintree, MA, USA). Values were adjusted by body temperature and pressure. A minimum of three acceptable spirograms was obtained, of which at least two were reproducible within 5% for both FVC and FEV 1. Each technician underwent training before taking measurements for this study. Methacholine challenge tests were conducted between 1984 and 2000 using procedures adapted from  Chatham et al. (1982). We used data from the most recent test available for each subject at that visit. Participants with ischemic heart disease or baseline FEV 1 < 60% of the predicted value were excluded, and some elected not to participate. Methacholine inhalations were adminis tered at incremental doses corresponding to 0, 0.
Primers and conditions were previously described  (Lepeule et al. 2012 ). These genes were selected because they are expressed in leukocytes (AceView 2013) and are related to cardiorespiratory health, inflammation, and oxidative stress mechanisms  (Lepeule et al. 2012; Poole et al. 2011; Sin and Man 2008). The promoter regions were located using Genomatix Software (Genomatix Software Inc. , Ann Arbor, MI, USA) (see Supplemental Material, Table  S1 ). For each gene, we measured 1-5 CpG sites (positions) located within or outside of CpG islands. DNA methylation analysis was repeated on each sample, and results were averaged to reduce assay variability. We used non-CpG cytosine residues as built-in controls to verify bisulfite conversion. The degree of methylation was expressed for each DNA locus as percent methylated cytosines over the sum of methylated and unmethylated cytosines.
The median distance of the participant homes was 20. 8 km to the BC and PM 2. 5 monitoring site, and 20. 2, 22. 3, and 21. 4 km, respectively, for the CO, O 3 , and NO 2 monitors. We obtained temperature and relative humidity data from the National Weather Service Station at Logan Airport (Boston, MA, USA), located aproximately 12 km from the examination site. Daily averages were calculated when at least 75% of the hourly values for a given day were available. For each pollutant concentration, we considered a range of short-term and subchronic exposure windows preceding each subject's examination, including: 4 hr, 24 hr (lag 0), previous day (lag 1), and 3, 7, 14, and 28-day moving averages. Because all visits were scheduled for the morning, exposure windows were calculated from 0800 hours the day of the visit.
DNA methylation marks are established mainly during early life, and although thought to be a fairly stable measure, DNA methylation has been associated with aging  (Madrigano et al. 2012). In our data, almost all associations between air pollutants and lung function remained after adjustment for DNA methylation, which suggests that pulmonary effects of air pollutants were not mediated by methylation. We checked the locations at which we measured DNA methylation on UCSC Genome Build hg19 (http://genome. ucsc. edu/ cgi-bin/ hgGateway). We specifically designed the assays to exclude SNPs (single-nucleotide polymorphisms) from the CpG sites analyzed and the sequences hybridized by the polymerase chain reaction and pyrosequencing primers. However, because dense genotyping data are not available for this study, we cannot exclude effects from SNPs nearby or remotely located relative to the sequence analyzed.
Therefore it is unlikely that any exposure measurement error would bias the effect away from the null, and this might explain the lack of statistical significance of our PM 2. 5 -related results. Second, study results were observed in a cohort of elderly men, which may limit the generalizability of our results to similar populations. Third, for the sake of feasibility, we dichotomized DNA methylation at each CpG site to examine interactions with pollutants concentration. Interactions were analyzed for multiple CpG sites, pollutants, and outcomes, and require caution regarding potential false-positive findings. Finally, although we adjusted for the percentage of white blood volume 122 | number 6 | June 2014 • Environmental Health Perspectives cell types, we did not have data available for lymphocyte subsets.
Matrix assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) are the two main ionization techniques that are applied in apoplastic proteome studies while ion separation and detection uses mainly time-of-flight (TOF) or quadrupole mass analyzer. Tandem MS (MS/MS) is now commonly used to improve the sensitivity and accuracy of peptides/proteins identification and the different techniques are very often combined (like MALDI-TOF/MS or ESI-MS/MS, Tables  1, 2 ). The identification of proteins present in the apoplast in a given plant-pathogen interaction implies an access to a proteome and/or a genome database of the two organisms, which is not always the case. Alexandersson et al. (2013)  suggest the use of a combined plant-pathogen protein database extended with a random sequence database to avoid false positive hits from host peptides when matching pathogen peptides.
LEADERLESS SECRETION PROTEINS Plant proteins are secreted to the apoplast mainly via the classical ER-Golgi route. SignalP or TargetP software is widely used to predict signal peptides from the sequences  (Emanuelsson et al. , 2007; Petersen et al. , 2011)  and to identify proteins that are secreted through the classical ER-Golgi. However, there is increasing evidence that a subset of apoplastic proteins is likely to be secreted by non-classical pathways. Non-classical or leaderless secretion is common to all eukaryotes, including plants. Computational analysis using different algorithms have been developed to assist in the identification of unexpected secreted proteins. SecretomeP allows secretion prediction based on sequence features conserved or frequently observed in secreted bacterial and mammalian proteins  (Bendtsen et al.
, 2004). Cheng et al. (2009)  found that 60% of the Leaderless Secreted Proteins (LSPs) identified in the Arabidopsis secretome were predicted to be secreted with SecretomeP. Among these predicted LSPs actually found in the apoplast, we can mention calmodulin, jacalin, or superoxide dismutase. Although no identified plant superoxide dismutase has a signal peptide, extracellular superoxide dismutase activity in stressed or pathogen-infected plants has been previously reported  (Hernández et al. , 2001; Karpinska et al. , 2001). In the same way, calmodulin is known to be an intracellular calcium sensor, but it has recently been suggested that calmodulin could serve as a dual messenger with roles either inside or outside the cell depending on stress factors  (Cui et al. , 2005). However, it should be noted that SecretomeP software may not be well-adapted to plant proteins since it has been designed for mammalian proteins.
In addition, only a small proportion of the LSPs identified in apoplastic proteome studies gave a score above threshold  (Cheng et al. , 2009; Fernandez et al. , 2012). The difficulties in preserving membrane integrity and extracting non-contaminated apoplastic fluids combined with the limitations of the bioinformatics programs in predicting sub-cellular localization have to be taken into account to understand the contrasting variations of LSPs content between experiments. New computational tools such as software or databases are emerging and should help to predict more precisely and with greater certainty the proteins produced through alternative secretion pathways. LocTree3 is a new software program that predicts protein subcellular localization through a consistent new framework with a high prediction success especially for secreted proteins (https://rostlab.
org/services/loctree3) (Goldberg et al. , 2012). The comparative platform OrysPSSP is composed of a core "small secreted protein" (SSP) database and a dynamic web interface that integrates a variety of user tools and resources and allows the screening of SSP on the genome scale and across the phylogeny of plant species (http://www. genoportal. org/PSSP/index. do) (Pan et al. , 2013). The existence of these alternative secretory routes could be explained by the need of rapid and effective regulation of secretion to provide a selective advantage to the plant cell. There is growing evidence of complex and highly coordinated spatiotemporal protein secretion in plants. Kaffarnik et al. (2009)  showed that most of the proteins induced in Arabidopsis by the virulent Pseudomonas syringae DC3000 or the avirulent AvrRpm1 strains had no secretion signals as compared to non-pathogenic HrpA strains.
DUF26 genes were previously found to be up-regulated upon pathogen infection, JA treatment  (Kim et al. , 2003 (Kim et al. , , 2004b) )  and wounding  (Shen et al. , 2003). Recent studies have identified DUF26 proteins regulated upon pathogen infection or elicitor treatment  (Kim et al. , 2009 (Kim et al. , , 2013;; Zhou et al. , 2011; Shenton et al. , 2012). Several lines of evidence support the fact that these proteins could be involved in the perception of the pathogen or the transduction of the signal after perception. The proteins containing DUF26 domains, which are usually found in serine/threonine kinases, are annotated as small secretory proteins and are associated with plant receptor protein kinase domains in databases. These proteins accumulate earlier in incompatible rice/Magnaporthe grisae interactions than in compatible ones  (Kim et al.
The purpose of this study is to estimate how variations in the plasma density can affect diffusion rates resulting from wave-energetic particle interactions and consequently the energetic electron population. In Sect. 2 we use CRRES measurements to study the distribution of electron plasma densities for selected L * values, magnetic local times (MLT) and magnetic activities. In Sects. 3 and 4 we determine pitch angle and energy diffusion rates due to wave-particle interactions with chorus and plasmaspheric hiss respectively, for extreme values of the plasma density determined from the CRRES measurements using the WAPI code and typical wave characteristics. WAPI, developed at ONERA, is based on quasi linear theory as described in  Glauert and Horne (2005)  for the PADIE (Pitch Angle Diffusion of Ions and Electrons) code, and calculates fully relativistic quasilinear pitch-angle and energy diffusion coefficients for resonant wave-particle interactions in magnetized plasma.
The plasma density was derived from measurements of the wave electric field in the frequency range 100 Hz-400 kHz by the Plasma Wave Experiment (PWE)  (Anderson et al. , 1992). In the plasmasphere the plasma density was determined from emissions at the upper hybrid frequency. Further out, in the trough region, where the upper hybrid line is usually not well defined, the plasma density was estimated from the lower frequency limit of the electromagnetic continuum radiation, which is taken to be a plasma wave cutoff at the plasma frequency  (Gurnett and Shaw, 1973). Plasma densities derived from the CRRES PWE data have already been studied by  Sheeley et al. (2001)  and used to define a model of electron plasma density between L = 3 and L = 7. In this study, the goal is not to define a new model but rather to assess how variations in the plasma density can affect diffusion rates from wave-particle interactions and the resulting electron distribution in the radiation belts.
At this L * value the densities given by the GCPM, Sheeley model and Carpenter model are very different. From the Carpenter model, for quiet and moderate activity, the electron density is high (inside plasmasphere) and corresponds to the 98th percentile of CRRES data while for active conditions the electron density is lower (outside plasmasphere) and corresponds to the 40th percentile at midnight and to the 60th percentile at noon. From GCPM, for quiet conditions the electron density corresponds to the 95th and 60th percentiles for noon and midnight respectively, for moderate conditions the density corresponds to the 95th and 15th percentiles for noon and midnight and finally for active conditions the electron density is lower than the minimum value measured by CRRES for noon and corresponds to the 1st percentile for midnight.
Effect of density dynamics on particle interaction with chorus waves To examine the effects of extreme densities, to see what might happen during extreme events, pitch angle and energy diffusion rates have been calculated using the ONERA WAPI code and typical chorus wave parameters. The WAPI code, developed at ONERA, computes pitch angle and energy diffusion coefficients due to wave-particle interaction for all energies and all location in space. WAPI is valid in the case of interactions of electrons and protons with "whistler" and EMIC waves, in a cold magnetized plasma, whatever the plasma density, the propagation angle and the number of resonances. WAPI uses the quasi-linear theory defined by  Kennel et al. (1966) , and the diffusion coefficients definition described by  Lyons (1974a, b)  and  Albert (1999 Albert ( , 2005)).