Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.Research in the E.D.A. lab is supported by Asociación Española Contra el Cáncer (AECC), the Ministry of Science of Spain-FEDER (CIBERONC, PI1700464, PI2000003, RD06/0020/0059)S. D.G.D. and L.H.P. are supported by CIBERONC (CB16/12/00361). D.G.D., M.J.R. and L.H.P. are PhD researchers funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016, ECAI F2-0012-2018 and PI-0013-2018, respectively).Peer reviewe

Bentonite mechanical evolution – experimental work for the support of model development and validation

The objectives of the Beacon experimental studies are to provide input data and parameters for development and validation of models and to reduce uncertainties about conditions and phenomena influencing bentonite homogenisation. Both the homogenisation of an initially inhomogeneous bentonite system and the persistence or development of inhomogeneities in the bentonite system under various mechanical and hydraulic conditions are investigated. Eight experiment teams perform tests involving different bentonite materials and different hydraulic and mechanical boundary conditions. The experiments performed within Beacon address the hydro-mechanical behaviour of macroscopically homogeneous bentonite materials, (the influence of initial granulometry and of hydro-mechanical paths on the final properties of bentonite, constant load and constant volume tests on the Czech Cerny vrch bentonite), the issue of swelling into a limited void (experiments performed in constant volume cells partially filled with bentonite, at different scales and with different emphases), binary mixtures or artificial inhomogeneities (experiments using bentonite block/pellet or pellet/powder mixtures, and the influence of the degree of saturation on the shearing behaviour at a bentonite – steel interface. This report is the first Beacon WP4 deliverable on experimental work and presents the status at Beacon mid-term

Commentaries on viewpoint : physiology and fast marathons

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A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Textual-Content-Based Clas-sification of Bundles of Untranscribed Manuscript Images

Prieto, José Ramón, et al., “Textual-Content-Based Clas-sification of Bundles of Untranscribed Manuscript Images”, en 26th. Int. Conf. on Pattern Recognition, proceedings(Milán, 2021), 3162-3169Content-based classification of manuscripts is an important task that is generally performed in archives and libraries by experts with a wealth of knowledge on the manuscript's contents. Unfortunately, many manuscript collections are so vast that it is not feasible to rely solely on experts to perform this task. Current approaches for textual-content-based manuscript classification generally require the handwritten images to be first transcribed into text - but achieving sufficiently accurate transcripts are generally unfeasible for large sets of historical manuscripts. We propose a new approach to perform automatically this classification task which does not rely on any explicit image transcripts. It is based on “probabilistic indexing”, a relatively novel technology which allows to effectively represent the intrinsic word-level uncertainty generally exhibited by handwritten text images. We assess the performance of this approach on a large collection of complex manuscripts from the Spanish Archivo General de Indias, with promising results. To the best of our knowledge, this is the first published work proposing, developing and assessing a successful approach for content-based classification of untranscribed manuscript images

Estado actual de la Gestión Integrada de las Plagas y Enfermedades en melocotoneros, perales y cítricos en Argentina, Brasil, Chile, España, Portugal y Uruguay

La Gestión Integrada de Plagas (GIP) o el Manejo Integrado de Plagas (MIP) es un concepto que nació a mediados del siglo pasado gracias a los trabajos de dos grupos de investigación diferentes, uno norteamericano y otro europeo, que lo propusieron en el 10º C o n g r e s o I n t e r n a c i o n a l d e Entomología celebrado en Montreal, Canadá (Pickett et al., 1958; Kuenen, 1961). Un año después, la expresión “control integrado” fue propuesta por investigadores de California, siendo entonces internacionalmente aceptado (Stern et al., 1959). Este concepto, aplicado a un insecto plaga en el artículo citado, integraba el control químico existente en ese momento con el control biológico clásico, que se estaba desarrollando. La idea de integrar ambos sistemas procedió de la preocupación por los perjuicios ambientales producidos por los insecticidas de amplio espectro que se utilizaban entonces (DeBach y Bartllett, 1951; Smith y Allen, 1954), desarrollándose, posteriormente, diversos conceptos como el de nivel de daño y el de umbral económico de daño (Stern et al., 1959; Pedigo et al., 1986), muy importantes en el esquema de gestión.info:eu-repo/semantics/publishedVersio

Actividad física en relación con la obesidad y el sobrepeso en adolescentes

Estudio de la relación existente entre los niveles de actividad física con respecto al peso (sobrepeso y obesidad) detectados en una muestra significativa de adolescentes de la Comunidad de Madrid. Analiza los nutrientes en la alimentación, la dieta saludable en los adolescentes, recomendaciones generales de vida saludable y el ejercicio en el adolescentes, necesidades energética y dieta saludable en adolescentes en diferentes deportes, medidas preventivas de la obesidad en adolescentes y trastornos de la conducta alimentaria. Cada uno de estos aspectos está tratado por un especialistaES

Un brocense de cine

El trabajo obtuvo un Premio Tomás García Verdejo a las buenas prácticas educativas en la Comunidad Autónoma de Extremadura para el curso 2018/2019, Modalidad B.Se describe una experiencia llevada a cabo en el IES El Brocense (Cáceres) que consistió en desarrollar distintas acciones utilizando como recurso el cine. Además de aprender contenidos de las asignaturas impartidas a través del cine, se perseguía fomentar la convivencia escolar y promover la igualdad entre hombres y mujeres. Algunas de las actividades realizadas fueron: jornadas sobre el cine, elaboración y grabación de cortos cinematográficos, asistencia a un musical, participación en conferencias y jornadas sobre cine, elaboración de carteles, etc.ExtremaduraES