dataesr/scientific-paragraphs-categorization huggingface dataset:
Data availability The offline forcing data for the Land-Hist experiments and output from the model simulations described in this paper will be distributed through the Earth System Grid Federation (ESGF) with digital object identifiers (DOIs) assigned. The model output required for LS3MIP is listed in the Appendix. Model data distributed via ESGF will be freely accessible through data portals after registration. This infrastructure makes it possible to carry out the experiments in a distributed matter, and to allow later participation of additional modeling groups. Links to all forcings data sets will be made available via the CMIP Panel website 17. Information about accreditation, data infrastructure, metadata structure, citation and acknowledging is provided by  Eyring et al. (2016). -2 s -1 downward T Y X 2 prra rainfall_flux rainfall rate kg m -2 s -1 downward T Y X 2 prsn snowfall_flux snowfall rate kg m -2 s -1 downward T Y X 2 prrc convective_rainfall_flux convective rainfall rate kg m -2 s -1 downward T Y X 2 prsnc convective_snowfall_flux convective snowfall rate kg m -2 s -1 downward T Y X 1 prveg precipitation_flux_onto_canopy precipitation onto canopy kg m -2 s -1 downward T Y X 1 et surface_evapotranspiration total evapotranspiration kg m -2 s -1 upward T Y X 1 ec liquid_water_evaporation_flux_from_canopy interception evaporation kg m -2 s -1 upward T Y X 1 tran Transpiration vegetation transpiration kg m -2 s -1 upward T Y X 1 es liquid_water_evaporation_flux_from_soil bare soil evaporation kg m -2 s -1 upward T Y X 2 eow liquid_water_evaporation_flux_from_open_water open water evaporation kg m -2 s -1 upward T Y X 2 esn liquid_water_evaporation_flux_from_surface_snow snow evaporation kg m -2 s -1 upward T Y X 2 sbl surface_snow_and_ice_sublimation_flux snow sublimation kg m -2 s -1 upward T Y X 2 slbnosn sublimation_amount_assuming_no_snow sublimation of the snow free area kg m -2 s -1 upward T Y X 2 potet water_potential_evapotranspiration_flux potential evapotranspiration kg m -2 s -1 upward T Y X 1 mrro runoff_flux total runoff kg m -2 s -1 out T Y X 2 mrros surface_runoff_flux surface runoff kg m -2 s -1 out T Y X 1 mrrob subsurface_runoff_flux subsurface runoff kg m -2 s -1 out T Y X 1 snm surface_snow_and_ice_melt_flux snowmelt kg m -2 s -1 solid to liquid T Y X.
3. 2. 6). However, some individual terms show biases. This is especially true for the shortwave radiation, the latent heat flux (and consequently the evaporation) and the precipitation averaged over the sea surface. Note that ALDERA and ARPERA2 show very similar results, which is expected as they share most of their physical parameterizations. This also means that increasing the spatial resolution in the RCMs does not fundamentally change the mean biases at least from 50 to 12 km. This is confirmed when comparing ALDERA to the ALADIN-Climate simulation at 50 km resolution. ALADIN-Climate ran at 150 km is however closer to ERA-Interim with a weaker latent heat loss. Note that the  Pettenuzzo et al. (2010)  data set also achieves the Mediterranean sea heat budget balance but with lower values both for shortwave radiation and the latent heat loss.
Interannual variability and trends At the basin scale, the interannual variability of the various terms of the Mediterranean Sea heat budget can also be evaluated for the period 1985-2004 of the reference data set of Table 1  (Sevault et al. , 2014). For example, for the basin-averaged net shortwave radiation flux, the interannual standard deviation in ALDERA (1. 6 W m -2 ) is underestimated with respect to International Satellite Cloud Climatology Project (ISCCP; http://isccp. giss. nasa. gov/) observations (2. 8 W m -2 ) whereas the interannual temporal correlation is equal to 0. 84. For the latent heat loss, the 1985-2004 interannual standard deviation is equal to 5. 6 W m -2 in ALDERA within the range of the observations (4. 7 W m -2 for the NOCS data set -National Oceanography Centre Southampton -and 6.
7 W m -2 for the OAFlux data set -Objectively Analyzed air-sea Fluxes) and the interannual temporal correlation is good (0. 83 with NOCS and 0. 81 with OAFlux). Interannual standard deviations are lower for the net longwave radiation flux (1. 2 W m -2 in ALDERA), and for the sensible heat loss (1. 3 W m -2 in ALDERA) and the various observation-based estimates disagree (not shown). Trends in the surface forcing are relevant in long-term simulations as they can induce long-term trends in the water mass characteristics. Concerning the surface heat flux terms in ALDERA, only the trend in latent heat flux is significant with an increase in the heat loss by the sea equal to +4. 1 W m -2 decade -1 over the 1979-2012 period. This trend is similar to the one obtained in  Mariotti et al. (2008)  and is mostly driven by the SST trends  (Sevault et al.
The spatial fluctuations of the GIA are applied on the MDT to compensate for the local deformation of the geoid due to the ongoing deformation of the solid Earth  (Peltier et al. , 2008). For the global ocean on average, the correction is about -0. 3 mm year -1. In addition we also apply a correction to compensate the mass intake of continental ice melting in the Mediterranean basin. On average, the mass intake corresponds to a rise of 0. 85 mm year -1. In situ temperature and salinity profiles come from the CORA4  (Cabanes et al. , 2013)  in situ database provided by CORIOLIS data center from the start of the reanalysis up to December 2012. For the last 6 months we used the realtime database. A check through objective quality control and a data thinning have been done on the data set in CORA4.
It checks improvements between versions of a system, and ensures that a version is robust and its performance stable over time. First, we present assimilation statistics directly coming from SAM2 and then results from both NM12-FREE and MEDRYS (daily outputs for all variables and additional hourly outputs for sea surface variables) are presented. As CLASS1 diagnostic, we thus focus on the impact of the assimilation of SLA data on surface circulation. As CLASS3, the assessment of the interannual variability is made using integrated heat and salt contents. Then a CLASS4 diagnostic is made using the entire CORA4 database (without data thinning/quality check) and the high-frequency surface variability is presented through a comparison to a fixed mooring in the Gulf of Lions (CLASS2). Even if the assimilation process corrects a part of the distance between the model and the observation, the fluxes play a major role in determining the water masses in the Mediterranean Sea and are thereby a good indicator regarding the quality of an experiment.
Discussion and conclusion This study describes the configuration and the quality of the high-resolution reanalysis MEDRYS and its companion hindcast NM12-FREE, for the Mediterranean Sea over the period 1992-2013. Both simulations have a common configuration: a high-resolution oceanic model NEMOMED12 relaxed in the Atlantic buffer zone to ORAS4 interannual fields and forced at the surface with the homogeneous and highresolution ALDERA atmospheric fluxes. The 21 years of the reanalysis have been produced using in situ profiles from the CORA4 database, SST maps from the daily NOAA AVHRR-AMSR product and along-track SLA from SSALTO/DUACS associated with SAM2, the assimilation scheme from Mercator Océan. The 12 km and 3 h spatiotemporal resolution of ALDERA fields allows MEDRYS to explicitly reprowww.
Acknowledgements. We acknowledge the two anonymous reviewers for their comments and suggestions, which helped to improve this article. This work is a contribution to the  HyMeX program  (HYdrological cycle in The Mediterranean EXperiment) through  INSU-MISTRALS support and the Med-CORDEX program  (COordinated Regional climate Downscaling EXperiment -Mediterranean region, www. medcordex. eu). This research has received funding from the  French National Research Agency (ANR)  project  REMEMBER  (contract  ANR-12-SENV-001 ). Edited by:  N. Pinardi.
2, BD Biosciences), TNF-α-Brilliant violet 421 (clone MP6-XT22, BioLegend), IL17A-PE/Cy7 (clone TC11-18H10. 1, BD Biosciences). Aqua Viability Dye (Molecular Probes/Invitrogen) was added to distinguish live and dead cells. Cells were acquired using an LSRII flow cytometer (BD Biosciences) with FACSDiva software (BD Biosciences). Results were analyzed using FlowJo software (Tree Star).
The initial rate of fluorescence decrease was determined by linear fitting of the experimental data during the first 2 s of the reactions. The initial velocity data was fitted to Daltziel equation Mt Mt Mt [ PrxQ B] V =ϕ + ϕ [ROOH] + ϕ [ Trx C] + ϕ ([ROOH]. [ Trx C]) 0 0 1 2 1,2 (2) and the coefficients ϕ were obtained from Daltziel plots of [MtPrxQ B]/ V 0 vs [ROOH] at different fixed concentrations of Trx. In the case of ping-pong mechanism, where no ternary complex is formed, ϕ 1,2 is zero, so the primary plot gives parallel straight lines with slopes =ϕ 1 and intercepts =ϕ 0 +ϕ 2 /[MtTrx C]. ϕ 0 is the reciprocal value of k cat , and ϕ 1 and ϕ 2 are the reciprocal values of the net forward rate constants of the reaction of the enzyme with ROOH (k ROOH ') and with Trx (k Trx '), respectively  [8, 42].
b. Competition approaches. The second-order rate constant of the reaction between reduced MtPrxQ B and peroxynitrite was determined by two competition assays. In the first one, HRP was used as an alternative target for peroxynitrite as described previously  [44, 45]. Briefly, peroxynitrite (1 µM)-mediated HRP (2 µM) oxidation to Compound I in the absence or presence of increasing reduced MtPrxQ B concentrations was followed at 398 nm (Δε 398 =4. 2×10 4 M -1 cm -1  [46] ). The rate constant of peroxynitrite-mediated HRP oxidation to Compound I was determined as 3×10 6 M -1 s -1 under the experimental conditions employed herein (data not shown) in agreement with previously published data  [47]. The rate constant of peroxynitrite-mediated MtPrxQ B oxidation was calculated from HRP-Compound I yield obtained at different MtPrxQ B concentrations as previously  [45, 48, 49].
Hydrodynamic behavior The molecular weights of reduced or oxidized MtPrxQ B in solution were determined by multiangle light scattering (MALS). Enzyme samples (1 mg mL -1 ) were prepared in Tris-HCl (50 mM), NaCl (75 mM), pH 7. 4 (equilibration buffer). Reduced enzyme samples contained TCEP (2 mM). Oxidized enzyme consisted in reduced MtPrxQ B (desalted to eliminate excess TCEP) treated with equimolar concentrations of H 2 O 2. The samples were centrifuged at 4 °C and 16,000 rpm before injection on a SEC-FPLC System using a Superose 12 column (GE Healthcare) coupled to UV (Jasco Corporation, Japan) and MALS (Wyatt Technology) module detectors. The system was equilibrated at room temperature. The flow rate was set to 0. 3 mL min -1 and the injection volume was 100 μL. Data analysis was performed using the Astra 6.
Circular dichroism spectroscopy The ellipticity of reduced and oxidized MtPrxQ B was evaluated using a JASCO-810 spectropolarimeter (Jasco Corporation, Japan) equipped with a Peltier temperature controller. Samples were prepared in Tris-HCl (50 mM), NaCl (75 mM), pH 7. 4 in a final protein concentration of 10 and 50 µM for far-UV and near-UV, respectively. Spectra were recorded in the range of 200-250 and 240-340 nm using a 0. 1 and 1 cm path-length cell, respectively. Data acquisition was carried out at 25 °C and at least five spectra were acquired at a speed scan of 50 nm min -1 using a time constant of 0. 5 s, and averaged. Finally, a blank scan was properly smoothed and subtracted from the corresponding average spectrum and expressed to molar ellipticity as: θ θ Mt M l p [ ] (deg dmol cm )= [ PrxQ B]( ).
Classical molecular dynamics Classical molecular dynamics (MD) of MtPrxQ B were performed in both reduced (fully folded, FF) and oxidized (locally unfolded, LU) states. For the reduced state, the crystal structure of MtPrxQ B (PDBID: 5EPF) was used as starting structure. Cys44 was assumed to be in the reactive, deprotonated form. The disulfide model was generated starting from the reduced structure and by homology modeling of the entire α2 helix, i. e. residues from 39 to 64, as it is the protein region which suffers the more significant changes upon oxidation  [51]. The structure of oxidized α2 helix of Aeropyrum pernix PrxQ (PDBID: 2CX3) was used as the template, and the homology model was generated using the Swiss-Model package  [52]. Both, reduced and oxidized models were considered as monomers, as indicated by the multiangle light scattering experiments performed herein (see below).
The same MD protocol was applied for every system. Briefly, the system was solvated using a default method, with an octahedral box of 12 Å in radius with TIP3P water molecules  [53]. All used residue parameters correspond to the parm99 Amber force field  [54]. All simulations were performed using periodic boundary conditions with a 10 Å cutoff and particle mesh Ewald (PME) summation method for treating the electrostatic interactions. The hydrogen bond lengths were kept at their equilibrium distance by using the SHAKE algorithm, while temperature and pressure were kept constant with a Langevin thermostat and barostat, respectively, as implemented in the AMBER12 program  [54]. The system was optimized in 1000 steps (10 with steep gradient and the rest with conjugate gradient). Then, it was slowly heated from 0 K to 300 K for 20 ps at constant pressure, with Berendsen thermostat, and pressure was equilibrated at 1 bar for 5 ps.
Hydrodynamic behavior of reduced and oxidized MtPrxQ B in solution Members of the PrxQ subfamily behave either as monomers or dimers in solution. The reported structure of reduced MtPrxQ B indicated that it is monomeric in the crystal (PDBID: 5EPF) and so far, no data regarding the structure of the oxidized form of the enzyme has been reported. To determine the oligomeric state of reduced and oxidized MtPrxQ B in solution, we performed MALS experiments. Fig. 6  shows the elution profiles of reduced (in the presence of TCEP (2 mM)) and oxidized MtPrxQ B (50 µM). In both cases, the enzyme showed a similar elution profile and was predominantly monomeric as judged by the molecular mass of 16. 8 ± 0. 8 and 17. 9 ± 1. 6 kDa obtained for reduced and oxidized MtPrxQ B, respectively, which is in agreement with the theoretical mass of 19470 Da per subunit obtained by sequence analysis.
Discussion In M. tuberculosis databases, MtPrxQ B is annotated as a putative Prx of the PrxQ/BCP subfamily, but experimental evidence for the peroxidase function of the protein was lacking so far (http://genome. tbdb. org; http://tuberculist. epfl. ch). Data shown in Fig. 1  demonstrated the peroxidase activity of recombinant MtPrxQ B. As expected according to sequence homology, it acted as a 2-Cys Prx, Cys44 being C P, which is completely essential for activity, whereas Cys49 acted as C R , and as for many other 2-Cys Prxs, the catalytic activity importantly decreased but was not completely lost in its absence  [18, 37]. MtPrxQ B was able to reduce a broad spectrum of natural hydroperoxides including H 2 O 2 , FA-OOH (Fig. 1 ), t-bOOH, Cumene-OOH and peroxynitrite (Figs. 2 3 4 ), but kinetic measurements indicated a preference for FA-OOH followed by peroxynitrite, while reduction of H 2 O 2 was much slower (Table  1 ).
Acknowledgements We thank  Dr. Balaraman Kalyanaraman  from the  Medical College of Wisconsin, Milwaukee, USA , for kindly providing the CBA. We also thank  Dr. Ahmed Haouz  from  Institut Pasteur Paris ,  Dr. Marcelo Comini  from  Institut Pasteur Montevideo  and  Dr. Leopold Flohé , from  Universidad de la República, Uruguay and University of Padova, Italy , for providing the plasmids for the expression of the recombinant proteins used herein as described under Materials section.
5, anti-IFN-γ-AF700, anti-IL-2-FITC, anti-IL-17-AF647 (BD Biosciences); anti-CD127-PE-Cy7, anti-FoxP3-AF700 (eBiosciences); and anti-Ki-67-FITC (Dako). FcR Blocking Reagent (Miltenyi Biotec) was used to block unwanted binding of antibodies and increase the staining specificity of cell surface antigens. For intracellular staining of IFN-γ, IL-2, IL-17, FoxP3, or Ki-67, cells were fixed and permeabilized using the "FoxP3 Staining Buffer Set" (eBioscience) according to the manufacturer's recommendations. Analyses were performed using the FlowJo software (TreeStar).
Importantly, frequencies of HIV-specific CD4 T cellsas measured by IFN-γ, IL-2, or IL-17 expression following gag-p24 stimulation -were similar in HIA and LIA patients (data not shown). As natural regulatory T cells (Tregs) can dampen CD4 T-cell responses, it was of interest to assess the balance between effector CD4 T cells and Tregs. We thus measured the ex vivo frequency of Treg cells, defined as CD25 + CD127 low FoxP3 + CD4 T cells. Interestingly, HIA patients exhibited lower effector/ regulatory T-cell balance when considering the Th1/Treg ratio (Figure  1J ) as well as the Th17/Treg ratio [data not shown and Ref. (16) ].
effect of early arT initiation on hiV-specific cD4 T-cell responses We next assessed HIV-specific responses at month 6 of followup and compared untreated patients and ART-treated patients. At month 6, all treated patients had plasma HIV-RNA levels <400 copies/mL. Interestingly, the frequency of IFN-γ +but not of IL-2 + -p24-specific CD4 T cells significantly decreased between BL and month 6 in ART-treated patients but not in untreated patients (Figures  4A, B ). There was also a trend to a decrease in IL-17 + p24-specific CD4 T cells only in ART-treated patients (p = 0. 08), which was significant when considering CCR6 + IL-17 + cells (p = 0. 019) (data not shown). In addition, we evaluated the impact of the time interval between estimated date of infection and treatment initiation. Notably, the level of IFN-γ + p24-specific CD4 T cells at month 6 negatively correlated with the time to treatment (Figure  4C ).
4c ). Considering only those genes with a logFC41, we found 1,076 genes to be upregulated during these early stages of valve development. To assess the biological significance of these genes, we then performed Gene Ontology analysis using DAVID software  29. By clustering genes based on cellular compartment annotations we saw a strong enrichment for ECM protein terms (Fig. 4d ). Closer analysis of the 31 genes found in the 'extra-   cellular region' term demonstrated that, among others, fibronectin1b was significantly upregulated in the heart between 48 and 56 hpf (Fig. 4e ). Given the importance of fibronectin deposition in lymph valve formation  19  , we questioned whether it could also play a role in AVV formation. qPCR analysis of heartderived RNA showed fibronectin1b is indeed expressed in the heart during this period of its development and confirmed the increase of transcript levels between 48 and 56 hpf (Fig.
The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus  57  and are accessible through GEO Series accession number GSE79585 (https://www. ncbi. nlm. nih. gov/ geo/query/acc. cgi?acc ¼ GSE79585). Bioinformatics and gene ontology analysis. Read quality was assessed with FastQC (S. Andrews, http://www. bioinformatics. babraham. ac. uk/projects/fastqc/). Then reads were mapped onto the Zv9 assembly of the zebrafish genome using Tophat v1. 4. 1 (ref. 58) and the bowtie v0. 12. 7 aligner. Only uniquely aligned reads were retained for further analyses. Gene expression was quantified using HTSeq v0. 5. 3p5 (ref. 59) and gene annotations from Ensembl release 69. Read counts were normalized across libraries with the method proposed by Anders et al. 60. To identify significantly differentially expressed genes, we performed a test for differential expression within the experiment (that is, adjusting for baseline differences between the experiments) using the method proposed by Robinson and Smyth  61  and implemented in the Bioconductor edgeR v3.
0. 8 package  62. Adjustment for multiple testing was performed with the Benjamini and Hochberg 63 method. Functional analyses of genes with an adjusted P value smaller than 0. 05 were performed using DAVID software  64. Graphics were obtained with the R program (R Core Team, URL http://www. R-project. org/). qPCR. Products were amplified in a real-time PCR reaction with Light Cycler 480 Real-Time PCR System (Roche) using a UPL Probes Master mix (Roche) according to the manufacturer's instructions. Sequence of primer pairs were as follows: has2 forward 5 0 -AGCATCCCTGTTCAACTAACG-3 0 , reverse 5 0 -GCTGACCGCTTT ATCACATCT-3 0 ; klf2a forward 5 0 -CCGTCTATTTCCACATTTTCG-3 0 , reverse 5 0 -TCCAGTTCATCCTTCCACCT-3 0 ; fn1b forward 5 0 -TGGAAATGTGATGCC ATTGA-3 0 , reverse 5 0 -GGCCAATCTGGTAGAACACC-3 0 ; p53 forward 5 0 -GAGG TCGGCAAAATCAATTC-3 0 , reverse 5 0 -TGGGGGCTGAATAATCAAAT-3 0.
In vivo imaging. Zebrafish embryos were staged, anaesthetised with 0. 02% tricaine solution and 50 mM BDM, to stop the heart when necessary, and mounted in 0. 7% low melting-point agarose (Sigma Aldrich). Confocal imaging was performed on a Leica SP8 confocal microscope. Fast confocal and four-dimensional imaging (to image valve leaflets at 96 hpf and the AVC at 72 hpf) was performed using the resonant scanner mode of the same microscope. Images were acquired with a low-magnification water immersion objective (Leica HCX IRAPO L, 25X, N. A. 0. 95). For four-dimensional imaging, time series were acquired at a random time in the cardiac cycle at 35fps for 3 s. The optical plane was moved 2 mm between the z-sections until the whole AVC was acquired. Time series of two-dimensional sections were temporally synchronized using Matlab  27.
Nucleus to nucleus distance analysis was performed using Imaris software and the Measurement Points tool. Nuclei within the AVC were connected to all of their nearest neighbours and the average distances for defined regions were calculated. The extent of cell clustering, in klf2a mutants and fn1b morphants, was quantified by defining clustered cells as those cells closer than 8 mm to their neighbour (according to our analysis of nucleus-to-nucleus distances in controls; Fig. 2e ). The extent of fibronectin staining in the AVC was calculated using the Imaris Surfaces tool to define a volume of fibronectin staining and a volume of the whole AVC. The % of fibronectin coverage was then calculated ([Volume fibronectin staining/ Volume AVC]*100). Hearts were segmented using the surfaces tool and the segmented heart presented, for clarity.
Acknowledgements We thank  D. Riveline ,  J. Pestel ,  D. Stainier  and the  Vermot laboratory  for discussion and thoughtful comments on the manuscript. We thank  K. Yaniv ,  H. G. Belting  and  M. Affolter  for providing the fish stocks, antibodies and protocols for immunohistochemistry. M. Charpentier  is acknowledged for help with talen construction. We thank the  IGBMC fish facility  ( S. Geschier  and  S. Gredler ) and the IGBMC imaging center, in particular  B. Gurchenkov ,  P. Kessler ,  M. Koch  and  D. Hentsch. We thank  M. Philipps ,  B. Jost ,  C. Keime  and  A. Velt  in the IGBMC Microarrays deep sequencing platform, a member of the ' France Genomique' consortium  ( ANR-10-INBS-0009 ), for performing mRNA sequencing experiments and for helpful advice on analysis. This work was supported by  HFSP ,  INSERM, AFM, FRM , the  seventh framework program  ( MC-IRG256549 ) and by the grant  ANR-10-LABX-0030-INRT , a  French State  fund managed by the  Agence Nationale de la Recherche  under the  frame program Investissements d'Avenir labeled   ANR-10-IDEX-0002-02.