Suchergebnisse

Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses. ; C. López-Rodríguez was supported by the Ramón y Cajal and I3 Researchers Programmes and grants from the Spanish Government (SAF2006-04913 and SAF2009-08066) and European Union (MCIRG516308). J. Aramburu was supported by grants from the Spanish Government (BFU2008-01070 and SAF2011-24268), and Distinció de la Generalitat de Catalunya per a la Promoció de la Recerca Universitària. Research in the laboratories of C. López-Rodríguez and J. Aramburu is also supported by Fundació la Marató TV3 (030230/31, 080730), Spanish Ministry of Health (ISCIII-RETIC RD06/0009-FEDER), and Generalitat de Catalunya (2009 SGR 601). M. Buxadé was supported by a Beatriu de Pinós postdoctoral contract from Generalitat de Catalunya. S. Iborra was supported by a Sara Borrell postdoctoral contract from the Ministry of Health of Spain. J. Minguillón and R. Berga-Bolaños were supported by predoctoral fellowships from the Spanish Government.

The term "social enterprise" was first used, at the end of the 1980s, by organisations that promoted the social and labour integration of persons at risk of social and labour exclusion and other similar social activities. The social economy sector has since slowly introduced this term to describe its entities in order to gain recognition by society, and it is working to promote a generally accepted definition of social enterprise's behaviour based on the principles and values of the social economy (participation, general interest.). According to Article 5 of Spanish Law 5/2011 on the Social Economy, work integration social enterprises and so-called "special employment centres" are part of the social economy, and so are all firms and entities carrying out activities following the values and principles of the social economy sector. In this context, organisations of the social economy sector also are beginning to use the "social enterprise" concept. In Spain, a debate still exists regarding its exact definition. A mix of perspectives on this concept, with different nuances, can be observed. Besides, the current context of reduced governmental budgets and social services in Spain causes social organisations to adopt new approaches to this term of social enterprise, as this type of organisation is more likely to receive funds from the European Union. This paper's objective is to analyse all perspectives on the concept of social enterprise as well as the various social enterprise models existing in Spain. The document structure is organized as follow. In the first section, we present the context and the main concepts related to social enterprises in this country. In the second section, we provide an analysis of changes in the evolution of social enterprise criteria to identify established models and emerging patterns. In the third section, we put forward another typology, based on institutionalisation stages. Finally, we conclude by recommending an approach to future work and provide a basic bibliography on the subject.

We announce the discovery of two planets orbiting the M dwarfs GJ 251 (0.360 ± 0.015M-) and HD 238090 (0.578 ± 0.021M-) based on CARMENES radial velocity (RV) data. In addition, we independently confirm with CARMENES data the existence of Lalande 21185 b, a planet that has recently been discovered with the SOPHIE spectrograph. All three planets belong to the class of warm or temperate super-Earths and share similar properties. The orbital periods are 14.24 d, 13.67 d, and 12.95 d and the minimum masses are 4.0 ± 0.4 M-, 6.9 ± 0.9 M-, and 2.7 ± 0.3 M- for GJ 251 b, HD 238090 b, and Lalande 21185 b, respectively. Based on the orbital and stellar properties, we estimate equilibrium temperatures of 351.0 ± 1.4 K for GJ 251 b, 469.6 ± 2.6 K for HD 238090 b, and 370.1 ± 6.8 K for Lalande 21185 b. For the latter we resolve the daily aliases that were present in the SOPHIE data and that hindered an unambiguous determination of the orbital period. We find no significant signals in any of our spectral activity indicators at the planetary periods. The RV observations were accompanied by contemporaneous photometric observations. We derive stellar rotation periods of 122.1 ± 2.2 d and 96.7 ± 3.7 d for GJ 251 and HD 238090, respectively. The RV data of all three stars exhibit significant signals at the rotational period or its first harmonic. For GJ 251 and Lalande 21185, we also find long-period signals around 600 d, and 2900 d, respectively, which we tentatively attribute to long-term magnetic cycles. We apply a Bayesian approach to carefully model the Keplerian signals simultaneously with the stellar activity using Gaussian process regression models and extensively search for additional significant planetary signals hidden behind the stellar activity. Current planet formation theories suggest that the three systems represent a common architecture, consistent with formation following the core accretion paradigm. ; With funding from the Spanish government through the "María de Maeztu Unit of Excellence" accreditation (MDM-2017-0737)

During its four years of photometric observations, the Kepler space telescope detected thousands of exoplanets and exoplanet candidates. One of Kepler's greatest heritages has been the confirmation and characterization of hundreds of multi-planet systems via transit timing variations (TTVs). However, there are many interesting candidate systems displaying TTVs on such long timescales that the existing Kepler observations are of insufficient length to confirm and characterize them by means of this technique. To continue with Kepler's unique work, we have organized the "Kepler Object of Interest Network" (KOINet), a multi-site network formed of several telescopes located throughout America, Europe, and Asia. The goals of KOINet are to complete the TTV curves of systems where Kepler did not cover the interaction timescales well, to dynamically prove that some candidates are true planets (or not), to dynamically measure the masses and bulk densities of some planets, to find evidence for non-transiting planets in some of the systems, to extend Kepler's baseline adding new data with the main purpose of improving current models of TTVs, and to build a platform that can observe almost anywhere on the northern hemisphere, at almost any time. KOINet has been operational since March 2014. Here we show some promising first results obtained from analyzing seven primary transits of KOI-0410.01, KOI-0525.01, KOI-0760.01, and KOI-0902.01, in addition to the Kepler data acquired during the first and second observing seasons of KOINet. While carefully choosing the targets we set demanding constraints on timing precision (at least 1 min) and photometric precision (as good as one part per thousand) that were achieved by means of our observing strategies and data analysis techniques. For KOI-0410.01, new transit data revealed a turnover of its TTVs. We carried out an in-depth study of the system, which is identified in the NASA Data Validation Report as a false positive. Among others, we investigated a gravitationally bound hierarchical triple star system and a planet-star system. While the simultaneous transit fitting of ground- andspace-based data allowed for a planet solution, we could not fully reject the three-star scenario. New data, already scheduled in the upcoming 2018 observing season, will set tighter constraints on the nature of the system. © ESO 2018. ; Russian Science Foundation, RSF: 14-50-00043 ; LAT-08/2016, 2014-0707 ; Russian Foundation for Basic Research, RFBR: 17-02-00542 ; Lietuvos Mokslo Taryba ; Deutsche Forschungsgemeinschaft, DFG ; Norges ForskningsrÃ¥d: 188910 ; National Science Foundation, NSF: AST-1615315 ; Deutsche Forschungsgemeinschaft, DFG: DR 281/30-1 ; Science and Technology Facilities Council, STFC ; European Regional Development Fund, FEDER: ESP2016-80435-C2-1-R ; European Commission, EC ; NNH05ZDA001C ; Danmarks Grundforskningsfond, DNRF: DNRF106 ; Education, Audiovisual and Culture Executive Agency, EACEA ; Ministério da Educação e Ciência, MEC ; National Aeronautics and Space Administration, NASA: NNX13A124G, NNX13AF62G ; Science and Technology Facilities Council, STFC: ST/P000312/1, ESP2015-65712-C5-4-R ; Ministerio de Economía y Competitividad, MINECO ; Acknowledgements. Funding for the Stellar Astrophysics Centre is provided by The Danish National Research Foundation (Grant DNRF106). This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. E.A. acknowledges support from NASA Grants NNX13A124G, NNX13AF62G; from National Science Foundation (NSF) grant AST-1615315; and from the NASA Astrobiology Institutes Virtual Planetary Laboratory, supported by NASA under cooperative agreement NNH05ZDA001C. S.W. acknowledges support from the Research Council of Norway grant 188910 to finance service observing at the NOT, and support for International Team 265 (Magnetic Activity of M-type Dwarf Stars and the Influence on Habitable Extra-solar Planets) funded by the International Space Science Institute (ISSI) in Bern, Switzerland. J.F. acknowledges funding from the German Research Foundation (DFG) through grant DR 281/30-1. Based on observations made with the Nordic Optical Telescope, operated by the Nordic Optical Telescope Scientific Association at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofísica de Canarias. The data presented here were obtained in part with ALFOSC, which is provided by the Instituto de Astrofísica de Andalucía (IAA) under a joint agreement with the University of Copenhagen and NOTSA. Based on observations obtained with the Apache Point Observatory 3.5-m telescope, which is owned and operated by the Astrophysical Research Consortium. Based on observations collected at the German-Spanish Astronomical Center, Calar Alto, jointly operated by the Max-Planck-Institut für Astronomie Heidelberg and the Instituto de Astrofísica de Andalucía (CSIC). This work was supported in part by the Ministry of Education and Science (the basic part of the State assignment, RK no. AAAA-A17-117030310283-7) and by Act no. 211 of the Government of the Russian Federation, agreement no. 02.A03.21.0006. E.H. and I.R. acknowledge support by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Fondo Europeo de Desarrollo Regional (FEDER) through grant ESP2016-80435-C2-1-R, as well as the support of the Generalitat de Catalunya/CERCA programme. E.P., G.T., and Š.M. acknowledge support from the Research Council of Lithuania (LMT) through grant LAT-08/2016. C.D.C. is supported by the Erasmus Mundus Joint Doctorate Program by grant number 2014-0707 from the EACEA of the European Commission. S.E. acknowledges support by the Russian Science Foundation grant No. 14-50-00043 for conducting photometric observations of exoplanets of Kepler's mission. S.I. acknowledges Russian Foundation for Basic Research (project No. 17-02-00542) for support in the processing of the observations. K.P. acknowledges support from the UK Science and Technology Facilities Council through STFC grant ST/P000312/1. H.J.D. acknowledges support by grant ESP2015-65712-C5-4-R of the Spanish Secretary of State for R&D&i (MINECO). KOINet thanks the telescope operators for their invaluable help during some of the observing campaigns at the IAC80 telescope. The IAC80 telescope is operated on the island of Tenerife by the Instituto de Astrofísica de Canarias in the Spanish Observatorio del Teide. C.v.E. is grateful for the invaluable help and contribution of all the telescope operators involved in this work. Eric Agol acknowledges support from a Guggenheim Fellowship.

Aim We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. Material and methods Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. Results Overall, 2, 408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8–97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. Conclusions Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.

The design, study conduct, and financial support for the study were provided by AbbVie (https://www.abbvie.com/). AbbVie participated in the interpretation of data, review, and approval of the manuscript. Medical writing and editing services were provided by Medical Statistics Consulting (MSC) and funded by AbbVie. ; Aim We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. Material and methods Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. Results Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of −2.2% (90% CI, −4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. Conclusions ...

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19. ; This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202). ; Peer reviewed