Differential activity of Drosophila Hox genes induces myosin expression and can maintain compartment boundaries

Compartments are units of cell lineage that subdivide territories with different developmental potential. In Drosophila, the wing and haltere discs are subdivided into anterior and posterior (A/P) compartments, which require the activity of Hedgehog, and into dorsal and ventral (D/V) compartments, needing Notch signaling. There is enrichment in actomyosin proteins at the compartment boundaries, suggesting a role for these proteins in their maintenance. Compartments also develop in the mouse hindbrain rhombomeres, which are characterized by the expression of different Hox genes, a group of genes specifying different structures along their main axis of bilaterians. We show here that the Drosophila Hox gene Ultrabithorax can maintain the A/P and D/V compartment boundaries when Hedgehog or Notch signaling is compromised, and that the interaction of cells with and without Ultrabithorax expression induces high levels of non-muscle myosin II. In the absence of Ultrabithorax there is occasional mixing of cells from different segments. We also show a similar role in cell segregation for the Abdominal-B Hox gene. Our results suggest that the juxtaposition of cells with different Hox gene expression leads to their sorting out, probably through the accumulation of non-muscle myosin II at the boundary of the different cell territories. The increase in myosin expression seems to be a general mechanism used by Hox genes or signaling pathways to maintain the segregation of different groups of cells.Peer Reviewe

The elimination of an adult segment by the Hox gene Abdominal-B

Hox gene activity leads to morphological diversity of organs or structures in different species. One special case of Hox function is the elimination of a particular structure. The Abdominal-B Hox gene of Drosophila melanogaster provides an example of such activity, as this gene suppresses the formation of the seventh abdominal segment in the adult. This elimination occurs only in males, and is characteristic of more advanced Diptera. The elimination requires the differential expression or activity of genes that are downstream Abdominal-B, or that work togetherwith it, andwhich regulate cell proliferation or cell extrusion. Here,we reviewthe mechanisms responsible for such elimination and provide some new data on processes taking place within this segment. © 2015 Elsevier Ireland Ltd. All rights reserved.Ministerio de Economía y Competitividad (BFU2008-00632 and BFU2011-26075), the Consolider Program (CSD2007-0008) and an Institutional Grant from the Ramon Areces FoundationPeer Reviewe

Más allá de la docencia: la unidad de atención psicológica y salud mental del universitario (UAPSMU) en la Universidad de Salamanca (1996-2004)

College Mental Health Counselling is a specialized service offered in several Spanish Universities some decades ago. Salamanca University is between the pioneers to offer university community a specialized service of Psychological Aid and First Intervention on Mental Health within their own campus, for a population group characterized by rootlessness of their family environment, usually far from their home environment, and with an age between 18 and 25, a period with life crises and severe pathological onsets. In this paper some data on the history of this Unit in Salamanca University is offered, from the beginning of the service in 1996 to their change in 2003. The service was free-cost, only for university people, and the professional staff included professors and professional psychologists under a scheme of non-profit collaborations. The main indicators of the interventions and people attended during this period are exposed, and also the main intervention programs developed: Facing Exams Anxiety; Care on rootlessness from family environment and attachment problems, between others. Finally we made some considerations on the structure and objectives for this type of services.ResumenLa Atención Psicológica al Universitario se ofrece como un Servicio especializado en algunas Universidades españolas desde hace dos décadas. La Universidad de Salamanca está entre las pioneras en ofertar a la comunidad universitaria un servicio específico de atención psicológica y primera intervención en salud mental en su propio entorno, a un grupo poblacional definido principalmente por el desarraigo de su domicilio familiar, ya que una elevada proporción de su alumnado procede de otras comunidades, a veces muy distantes, así como por las características del propio tramo etario de los jóvenes universitarios, entre 18 y 25 años, un momento de eclosión, tanto de crisis vitales evolutivas, como de patologías graves. En este trabajo se ofrecen datos sobre la historia de esta Unidad en la Universidad de Salamanca, desde su puesta en marcha en el año 1996, hasta su reformulación en 2004. El servicio fue de carácter gratuito y exclusivo para todos los miembros de la comunidad universitaria. La atención fue desarrollada mediante un equipo de psicólogos y profesores que colaboraron con carácter voluntario y gratuito. Se analiza la demanda atendida en este período, y se detallan los principales programas de intervención desarrollados: Enfrentamiento de la ansiedad ante los exámenes e Intervención ante la problemática del desarraigo, entre otros. Finalmente se hacen una serie de consideraciones sobre la organización y objetivos de este tipo de servicios.AbstractCollege Mental Health Counselling is a specialized service offered in several Spanish Universities some decades ago. Salamanca University is between the pioneers to offer university community a specialized service of Psychological Aid and First Intervention on Mental Health within their own campus, for a population group characterized by rootlessness of their family environment, usually far from their home environment, and with an age between 18 and 25, a period with life crises and severe pathological onsets. In this paper some data on the history of this Unit in Salamanca University is offered, from the beginning of the service in 1996 to their change in 2003. The service was free-cost, only for university people, and the professional staff included professors and professional psychologists under a scheme of non-profit collaborations. The main indicators of the interventions and people attended during this period are exposed, and also the main intervention programs developed: Facing Exams Anxiety; Care on rootlessness from family environment and attachment problems, between others. Finally we made some considerations on the structure and objectives for this type of services

Bacteria-instructed B cells cross-prime naïve CD8+ T cells triggering effective cytotoxic responses.

In addition to triggering humoral responses, conventional B cells have been described in vitro to cross-present exogenous antigens activating naïve CD8+ T cells. Nevertheless, the way B cells capture these exogenous antigens and the physiological roles of B cell-mediated cross-presentation remain poorly explored. Here, we show that B cells capture bacteria by trans-phagocytosis from previously infected dendritic cells (DC) when they are in close contact. Bacterial encounter "instructs" the B cells to acquire antigen cross-presentation abilities, in a process that involves autophagy. Bacteria-instructed B cells, henceforth referred to as BacB cells, rapidly degrade phagocytosed bacteria, process bacterial antigens and cross-prime naïve CD8+ T cells which differentiate into specific cytotoxic cells that efficiently control bacterial infections. Moreover, a proof-of-concept experiment shows that BacB cells that have captured bacteria expressing tumor antigens could be useful as novel cellular immunotherapies against cancer.We are grateful to advanced light microscopy and cytometry facilities of CNB for technical supporting. The research is supported by grants: SAF2017-84091- R, and PID2020-116393RB-I00/AEI/10.13039/501100011033, financed by MCIN, BFERO2020.04, financed by FERO foundation and PI20/0036 from ISCIII. RGF is supported by BES-2016-076526 from the Spanish Ministry of Economy Industry and Competitiveness, JOP is supported by fellowship LCF/BQ/SO16/ 52270012 from La Caixa, BHF is supported by FPU18/00895 and AMP by FPU18/03199 from Ministry of Science, Innovation and Universities. LdC has been supported by Juan de la Cierva grant IJC2018-035386-I and a contract associated to SEV-2017-0712. EVC, AMP, AMAM, and NMM belong to the Spanish National Research Council (CSIC)’s Cancer Hub. Synopsis image made with biorender.com by Eduardo Roman Camacho and Esteban Veiga. We thanks Prof. Dan Portnoy who kindly provided bacterial strains.S

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

This is an open-access paper.-- et al.Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.Peer Reviewe

Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group

This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms

Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Producción CientíficaBackground: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.Asociación Española Contra el Cáncer (Proyecto AIOA110296BLAN).Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13

The CARMENES search for exoplanets around M dwarfs Guaranteed time observations Data Release 1 (2016-2020)

I. Ribas et al.[Context] The CARMENES instrument, installed at the 3.5 m telescope of the Calar Alto Observatory in Almería, Spain, was conceived to deliver high-accuracy radial velocity (RV) measurements with long-term stability to search for temperate rocky planets around a sample of nearby cool stars. Moreover, the broad wavelength coverage was designed to provide a range of stellar activity indicators to assess the nature of potential RV signals and to provide valuable spectral information to help characterise the stellar targets.[Aims] We describe the CARMENES guaranteed time observations (GTO), spanning from 2016 to 2020, during which 19 633 spectra for a sample of 362 targets were collected. We present the CARMENES Data Release 1 (DR1), which makes public all observations obtained during the GTO of the CARMENES survey.[Methods] The CARMENES survey target selection was aimed at minimising biases, and about 70% of all known M dwarfs within 10 pc and accessible from Calar Alto were included. The data were pipeline-processed, and high-level data products, including 18 642 precise RVs for 345 targets, were derived. Time series data of spectroscopic activity indicators were also obtained.[Results] We discuss the characteristics of the CARMENES data, the statistical properties of the stellar sample, and the spectroscopic measurements. We show examples of the use of CARMENES data and provide a contextual view of the exoplanet population revealed by the survey, including 33 new planets, 17 re-analysed planets, and 26 confirmed planets from transiting candidate follow-up. A subsample of 238 targets was used to derive updated planet occurrence rates, yielding an overall average of 1.44 ± 0.20 planets with 1 M⊕ < Mpl sin i < 1000 M⊕ and 1 day < Porb < 1000 days per star, and indicating that nearly every M dwarf hosts at least one planet. All the DR1 raw data, pipeline-processed data, and high-level data products are publicly available online.[Conclusions] CARMENES data have proven very useful for identifying and measuring planetary companions. They are also suitable for a variety of additional applications, such as the determination of stellar fundamental and atmospheric properties, the characterisation of stellar activity, and the study of exoplanet atmospheres.CARMENES is an instrument at the Centro Astronómico Hispano en Andalucía (CAHA) at Calar Alto (Almería, Spain), operated jointly by the Junta de Andalucía and the Instituto de Astrofísica de Andalucía (CSIC). CARMENES was funded by the Max-Planck-Gesellschaft (MPG), the Consejo Superior de Investigaciones Científicas (CSIC), the Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (ERDF) through projects FICTS-2011-02, ICTS-2017-07-CAHA-4, and CAHA16-CE-3978, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Königstuhl, Institut de Ciències de l’Espai, Institut für Astrophysik Göttingen, Universidad Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología and Centro Astronómico Hispano-Alemán), with additional contributions by the MINECO, the Deutsche Forschungsgemeinschaft (DFG) through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars”, the Klaus Tschira Stiftung, the states of Baden-Württemberg and Niedersachsen, and by the Junta de Andalucía. We acknowledge financial support from the Spanish Agencia Estatal de Investigación of the Ministerio de Ciencia e Innovación (AEI-MCIN) and the ERDF “A way of making Europe” through projects PID2020-117493GB-I00, PID2019-109522GB-C5[1:4], PID2019-110689RB-I00, PID2019-107061GB-C61, PID2019-107061GB-C64, PGC2018-098153-B-C33, PID2021-125627OB-C31/AEI/10.13039/501100011033, and the Centre of Excellence “Severo Ochoa” and “María de Maeztu” awards to the Institut de Ciències de l’Espai (CEX2020-001058-M), Instituto de Astrofísica de Canarias (CEX2019-000920-S), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astrobiología (MDM-2017-0737). We also benefited from additional funding from: the Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and the Agència de Gestió d’Ajuts Universitaris i de Recerca of the Generalitat de Catalunya, with additional funding from the European FEDER/ERDF funds, and from the Generalitat de Catalunya/CERCA programme; the DFG through the Major Research Instrumentation Programme and Research Unit FOR2544 “Blue Planets around Red Stars” (RE 2694/8-1); the University of La Laguna through the Margarita Salas Fellowship from the Spanish Ministerio de Universidades ref. UNI/551/2021-May-26, and under the EU Next Generation funds; the Gobierno de Canarias through projects ProID2021010128 and ProID2020010129; the Spanish MICINN under Ramón y Cajal programme RYC-2013-14875; the “Fondi di Ricerca Scientifica d’Ateneo 2021” of the University of Rome “Tor Vergata”; and the programme “Alien Earths” supported by the National Aeronautics and Space Administration (NASA) under agreement No. 80NSSC21K0593. TPeer reviewe

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio