Expression of Wilms' tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function

The Wilms' tumor suppressor WT1 is a transcriptional regulator present in the fetal but not in the mature liver. Its expression and functional role in liver diseases remains unexplored. In this study, we analyzed WT1 expression by reverse-transcription polymerase chain reaction (RT-PCR) and by immunohistochemistry in normal and diseased livers. In addition, we performed in vitro studies in isolated rat hepatocytes to investigate WT1 regulation and function. We detected WT1 messenger RNA (mRNA) in 18% of normal livers, 17% of chronic hepatitis with minimal fibrosis, 49% of chronic hepatitis with bridging fibrosis, and 71% of cirrhotic livers. In cirrhosis, WT1 immunoreactivity was localized to the nucleus of hepatocytes. WT1 mRNA abundance correlated inversely with prothrombin time (P =.04) and directly with serum bilirubin (P =.002) and with the MELD score (P =.001) of disease severity. In rats, WT1 expression was present in fetal hepatocytes and in the cirrhotic liver but not in normal hepatic tissue. In vitro studies showed that isolated primary hepatocytes express WT1 when stimulated with transforming growth factor beta (TGF-beta) or when the cells undergo dedifferentiation in culture. Moreover, we found that WT1 down-regulates hepatocyte nuclear factor 4 (HNF-4), a factor that is essential to maintain liver function and metabolic regulation in the mature organ. Hepatic expression of HNF-4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels (P =.001). In conclusion, we show that WT1 is induced by TGF-beta and down-regulates HNF-4 in liver cells. WT1 is reexpressed in the cirrhotic liver in relation to disease progression and may play a role in the development of hepatic insufficiency in cirrhosis

Daily gridded datasets of snow depth and snow water equivalent for the Iberian Peninsula from 1980 to 2014

We present snow observations and a validated daily gridded snowpack dataset that was simulated from downscaled reanalysis of data for the Iberian Peninsula. The Iberian Peninsula has long-lasting seasonal snowpacks in its different mountain ranges, and winter snowfall occurs in most of its area. However, there are only limited direct observations of snow depth (SD) and snow water equivalent (SWE), making it difficult to analyze snow dynamics and the spatiotemporal patterns of snowfall. We used meteorological data from downscaled reanalyses as input of a physically based snow energy balance model to simulate SWE and SD over the Iberian Peninsula from 1980 to 2014. More specifically, the ERA-Interim reanalysis was downscaled to 10 km 10 km resolution using the Weather Research and Forecasting (WRF) model. The WRF outputs were used directly, or as input to other submodels, to obtain data needed to drive the Factorial Snow Model (FSM). We used lapse rate coefficients and hygrobarometric adjustments to simulate snow series at 100m elevations bands for each 10 km 10 km grid cell in the Iberian Peninsula. The snow series were validated using data from MODIS satellite sensor and ground observations. The overall simulated snow series accurately reproduced the interannual variability of snowpack and the spatial variability of snow accumulation and melting, even in very complex topographic terrains. Thus, the presented dataset may be useful for many applications, including land management, hydrometeorological studies, phenology of flora and fauna, winter tourism, and risk management. The data presented here are freely available for download from Zenodo (https://doi.org/10.5281/zenodo.854618). This paper fully describes the work flow, data validation, uncertainty assessment, and possible applications and limitations of the database.Esteban Alonso-González is supported by the Spanish Ministry of Economy and Competitiveness (BES- 2015-071466). This study was funded by the Spanish Ministry of Economy and Competitiveness projects CGL2014-52599-P 10 (Estudio del manto de nieve en la montaña española y su respuesta a la variabilidad y cambio climatico) and CGL2017- 82216-R (HIDROIBERNIEVE) and (with additional support from the European Community funds, FEDER) CGL2013-48539-R (Impactos del cambio climático en los recursos hídricos de la cuenca del Duero a alta resolución). Also, the Regional Government of Andalusia has funded this research with the project P11-RNM-7941 (Impactos del Cambio Climático en la cuenca del Guadalquivir, LICUA)

A precise measurement of the magnetic field in the corona of the black hole binary V404 Cygni

Observations of binary stars containing an accreting black hole or neutron star often show x-ray emission extending to high energies (>10 kilo­–electron volts), which is ascribed to an accretion disk corona of energetic particles akin to those seen in the solar corona. Despite their ubiquity, the physical conditions in accretion disk coronae remain poorly constrained. Using simultaneous infrared, optical, x-ray, and radio observations of the Galactic black hole system V404 Cygni, showing a rapid synchrotron cooling event in its 2015 outburst, we present a precise 461 ± 12 gauss magnetic field measurement in the corona. This measurement is substantially lower than previous estimates for such systems, providing constraints on physical models of accretion physics in black hole and neutron star binary systems. This article has a correction. Please see: http://science.sciencemag.org/content/360/6386/eaat927

The Gaia-ESO Survey: Homogenisation of stellar parameters and elemental abundances

The Gaia-ESO Survey is a public spectroscopic survey that targeted ≳105 stars covering all major components of the Milky Way from the end of 2011 to 2018, delivering its final public release in May 2022. Unlike other spectroscopic surveys, Gaia-ESO is the only survey that observed stars across all spectral types with dedicated, specialised analyses: from O (Teff ~ 30 000–52 000 K) all the way to K-M (≳3500 K). The physics throughout these stellar regimes varies significantly, which has previously prohibited any detailed comparisons between stars of significantly different types. In the final data release (internal data release 6) of the Gaia-ESO Survey, we provide the final database containing a large number of products, such as radial velocities, stellar parameters and elemental abundances, rotational velocity, and also, for example, activity and accretion indicators in young stars and membership probability in star clusters for more than 114 000 stars. The spectral analysis is coordinated by a number of working groups (WGs) within the survey, each specialised in one or more of the various stellar samples. Common targets are analysed across WGs to allow for comparisons (and calibrations) amongst instrumental setups and spectral types. Here we describe the procedures employed to ensure all survey results are placed on a common scale in order to arrive at a single set of recommended results for use by all survey collaborators. We also present some general quality and consistency checks performed on the entirety of the survey results.This work was partly supported by the European Union FP7 programme through ERC grant number 320360 and by the Leverhulme Trust through grant RPG-2012-541. We acknowledge the support from INAF and Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) in the form of the grant “Premiale VLT 2012”. L. Magrini and M. Van der Swaelmen acknowledge support by the WEAVE Italian consortium, and by the INAF Grant “Checs”. A.J. Korn acknowledges support by the Swedish National Space Agency (SNSA). A. Lobel acknowledges support in part by the Belgian Federal Science Policy Office under contract no. BR/143/A2/BRASS and by the European Union Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Sklodowska-Curie grant Agreement No. 823734. D.K. Feuillet was partly supported by grant no. 2016-03412 from the Swedish Research Council. D. Montes acknowledges financial support from the Agencia Estatal de Investigacion of the Ministerio de Ciencia, Innovation through project PID2019-109522GB-C54 /AEI/10.13039/501100011033. E. Marfil acknowledges financial support from the European Regional Development Fund (ERDF) and the Gobierno de Canarias through project ProID2021010128. J.I. Gonzalez Hernandez acknowledges financial support from the Spanish Ministry of Science and Innovation (MICINN) project PID2020-117493GB-I00. M. Bergemann is supported through the Lise Meitner grant from the Max Planck Society and acknowledges support by the Collaborative Research centre SFB 881 (projects A5, A10), Heidelberg University, of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). This project has received funding from the European Research Council (ERC) under the European Union, Horizon 2020 research and innovation programme (Grant agreement No. 949173). P. Jofré acknowledges financial support of FONDECYT Regular 1200703 as well as Nucleo Mile-nio ERIS NCN2021_017. R. Smiljanic acknowledges support from the National Science Centre, Poland (2014/15/B/ST/03981). S.R. Berlanas acknowledges support by MCIN/AEI/10.13039/501100011033 (contract FJC 2020-045785-I) and NextGeneration EU/PRTR and MIU (UNI/551/2021) through grant Margarita Salas-ULL. T. Bensby acknowledges financial support by grant No. 2018-04857 from the Swedish Research Council. T. Merle is supported by a grant from the Foundation ULB. T. Morel are grateful to Belgian F.R.S.-FNRS for support, and are also indebted for an ESA/PRODEX Belspo contract related to the Gaia Data Processing and Analysis Consortium and for support through an ARC grant for Concerted Research Actions financed by the Federation Wallonie-Brussels. W. Santos acknowledges FAPERJ for a Ph.D. fellowship. H.M. Tabernero acknowledges financial support from the Agencia Estatal de Investigation of the Ministerio de Ciencia, Innovation through project PID2019-109522GB-C51/AEI/10.13039/501100011033

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

The Gaia-ESO Public Spectroscopic Survey: Motivation, implementation, GIRAFFE data processing, analysis, and final data products

Context. The Gaia-ESO Public Spectroscopic Survey is an ambitious project designed to obtain astrophysical parameters and elemental abundances for 100 000 stars, including large representative samples of the stellar populations in the Galaxy, and a well-defined sample of 60 (plus 20 archive) open clusters. We provide internally consistent results calibrated on benchmark stars and star clusters, extending across a very wide range of abundances and ages. This provides a legacy data set of intrinsic value, and equally a large wide-ranging dataset that is of value for the homogenisation of other and future stellar surveys and Gaia's astrophysical parameters. Aims. This article provides an overview of the survey methodology, the scientific aims, and the implementation, including a description of the data processing for the GIRAFFE spectra. A companion paper introduces the survey results. Methods. Gaia-ESO aspires to quantify both random and systematic contributions to measurement uncertainties. Thus, all available spectroscopic analysis techniques are utilised, each spectrum being analysed by up to several different analysis pipelines, with considerable effort being made to homogenise and calibrate the resulting parameters. We describe here the sequence of activities up to delivery of processed data products to the ESO Science Archive Facility for open use. Results. The Gaia-ESO Survey obtained 202 000 spectra of 115 000 stars using 340 allocated VLT nights between December 2011 and January 2018 from GIRAFFE and UVES. Conclusions. The full consistently reduced final data set of spectra was released through the ESO Science Archive Facility in late 2020, with the full astrophysical parameters sets following in 2022. A companion article reviews the survey implementation, scientific highlights, the open cluster survey, and data products

The Gaia-ESO Public Spectroscopic Survey: Implementation, data products, open cluster survey, science, and legacy

Context. In the last 15 years different ground-based spectroscopic surveys have been started (and completed) with the general aim of delivering stellar parameters and elemental abundances for large samples of Galactic stars, complementing Gaia astrometry. Among those surveys, the Gaia-ESO Public Spectroscopic Survey, the only one performed on a 8m class telescope, was designed to target 100 000 stars using FLAMES on the ESO VLT (both Giraffe and UVES spectrographs), covering all the Milky Way populations, with a special focus on open star clusters. Aims. This article provides an overview of the survey implementation (observations, data quality, analysis and its success, data products, and releases), of the open cluster survey, of the science results and potential, and of the survey legacy. A companion article reviews the overall survey motivation, strategy, Giraffe pipeline data reduction, organisation, and workflow. Methods. We made use of the information recorded and archived in the observing blocks; during the observing runs; in a number of relevant documents; in the spectra and master catalogue of spectra; in the parameters delivered by the analysis nodes and the working groups; in the final catalogue; and in the science papers. Based on these sources, we critically analyse and discuss the output and products of the Survey, including science highlights. We also determined the average metallicities of the open clusters observed as science targets and of a sample of clusters whose spectra were retrieved from the ESO archive. Results. The Gaia-ESO Survey has determined homogeneous good-quality radial velocities and stellar parameters for a large fraction of its more than 110 000 unique target stars. Elemental abundances were derived for up to 31 elements for targets observed with UVES. Lithium abundances are delivered for about 1/3 of the sample. The analysis and homogenisation strategies have proven to be successful; several science topics have been addressed by the Gaia-ESO consortium and the community, with many highlight results achieved. Conclusions. The final catalogue will be released through the ESO archive in the first half of 2022, including the complete set of advanced data products. In addition to these results, the Gaia-ESO Survey will leave a very important legacy, for several aspects and for many years to come