Control of V(D)J Recombination through Transcriptional Elongation and Changes in Locus Chromatin Structure and Nuclear Organization

V(D)J recombination is the assembly of gene segments at the antigen receptor loci to generate antigen receptor diversity in T and B lymphocytes. This process is regulated, according to defined developmental programs, by the action of a single specific recombinase complex formed by the recombination antigen gene (RAG-1/2) proteins that are expressed in immature lymphocytes. V(D)J recombination is strictly controlled by RAG-1/2 accessibility to specific recombination signal sequences in chromatin at several levels: cellular lineage, temporal regulation, gene segment order, and allelic exclusion. DNA cleavage by RAG-1/2 is regulated by the chromatin structure, transcriptional elongation, and three-dimensional architecture and position of the antigen receptor loci in the nucleus. Cis-elements specifically direct transcription and V(D)J recombination at these loci through interactions with transacting factors that form molecular machines that mediate a sequence of structural events. These events open chromatin to activate transcriptional elongation and to permit the access of RAG-1/2 to their recombination signal sequences to drive the juxtaposition of the V, D, and J segments and the recombination reaction itself. This chapter summarizes the advances in this area and the important role of the structure and position of antigen receptor loci within the nucleus to control this process

Psychosocial interventions reduce cortisol in breast cancer patients: systematic review and meta-analysis

IntroductionCancer initiation, progression and recurrence are intricate mechanisms that depend on various components: genetic, psychophysiological, or environmental. Exposure to chronic stress includes fear of recurrence that can affect biological processes that regulate immune and endocrine systems, increase cancer risk, and influence the survival rate. Previous studies show that psychological interventions might influence the level of cortisol that has been extensively used as a biomarker for measuring hypothalamic-pituitary-adrenal axis functioning and body's immunity response. This meta-analysis aimed to provide a quantitative scrutiny of the effect of certain types of psychosocial interventions on cortisol as a neuroendocrine biomarker in saliva or blood and might predict breast cancer (BC) progression.MethodsA literature search was performed in the following databases: PubMed, The Cohrane Library, Scopus, WOS, PsychInfo, Google Scholar, Ovid Science Direct. After methodical selection of originally generated 2.021 studies, the search yielded eight articles that met inclusion criteria. All these studies explored effects of psychosocial interventions that measured cortisol in total of 366 participants with BC, stages 0-IV, in randomized control trial or quasi experimental study design setting. We applied random effects model to conduct meta-analyses on the parameters of salivary and plasma cortisol and used PRISMA Guidelines as validated methodology of investigation to report the results.ResultsEight studies selected for meta-analysis have shown the reduction of cortisol level due to applied psychosocial intervention. The random effects model showed that interventions produced large effect sizes in reductions of cortisol in blood (Cohen's d = −1.82, 95% Confidence Interval (CI): −3.03, −0.60) and slightly less in saliva (d = −1.73, 95%CI: −2.68, −0.78) with an overall effect of d = −1.76 (95%CI: −2.46, −1.07).ConclusionOur study concluded that certain types of psychosocial interventions reduce cortisol (indicator of chronic stress) in patients with BC. Application of specific psychosocial support as adjuvant non-invasive therapy for affected females with BC at all phases of treatment could contribute to more cost-effective health care

Patrimonio natural y cultural de Tepotzotlán

324 páginas. Especialización en Diseño, Planificación y Conservación de Paisajes y Jardines.El presente documento muestra el trabajo realizado para la intervención paisajística en pueblo de Tepotzotlán. Al ser catalogado en el programa de pueblos mágicos dada su riqueza tangible e intangible; resulta relevante su estudio a fin de rescatar y/o enaltecer algunas de las virtudes que lo resguardan. La zona de intervención se enfocó esencialmente en el polígono patrimonial del centro histórico, los caminos constituidos a lo largo de Rio Chiquito y calles aledañas que conectan los tesoros patrimoniales de la zona. Dicho estudio fue abordado principalmente por grupos de trabajo interdisciplinario, conformados por alumnos de la especialidad en Paisajes y Jardines Históricos de la UAM Azcapotzalco. Se cotejaron 5 proyectos detonadores: Centro Histórico/Atrio de los Olivos, Par vial, Rio Chiquito, Camino Real de Lluvias y Acequia Real. Durante la primera etapa, se establecieron las limitaciones y potencialidades del sitio. Se recopiló información cualitativa y cuantitativa para la formulación y ejecución de un plan maestro que regirían los parámetros y objetivos en cada proyecto. El desarrollo conceptual y anteproyecto para cada zona de intervención, se reflejó en la segunda etapa de este proceso. Paralelamente, la elaboración de la propuesta de vegetación, las fichas de cada especie vegetal y la preparación de catálogos de paisaje, complementan el carácter de este trabajo. El proyecto realizado en Tepotzotlán: “Patrimonio Natural y Cultural De Tepotzotlán”, emerge, como el título del trabajo indica: desde la visión del rescate patrimonial, constituido por elementos materiales y naturales relevantes para la población local y todos sus visitantes. La última etapa comprende la puesta en marcha del proyecto ejecutivo, donde se plasmaron los detalles que dan cuerpo a cada elemento de las propuestas de diseño, la información necesaria para su construcción y la síntesis de toda la documentación consultada y elaborada, como sostén de diseño. En las siguientes páginas y capítulos, se explicará de manera extensa y particular: la metodología planteada y utilizada en el abordaje de cada proyecto. En general, se podrá observar la construcción de un trabajo paisajístico integral, llevado a cabo a lo largo de un año de esfuerzo y dedicación, vertidos en la presente tesis.Consejo Nacional de Ciencia y Tecnología (México)

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

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Tcra enhancer activation by inducible transcription factors downstream of pre-TCR signaling

The Tcra enhancer (E¿) is essential for pre-TCR-mediated activation of germline transcription and V(D)J recombination. E¿ is considered an archetypical enhanceosome that acts through the functional synergy and cooperative binding of multiple transcription factors. Based on dimethylsulfate genomic footprinting experiments, there has been a long-standing paradox regarding E¿ activation in the absence of differences in enhancer occupancy. Our data provide the molecular mechanism of E¿ activation and an explanation of this paradox. We found that germline transcriptional activation of Tcra is dependent on constant phospholipase C¿, as well as calcineurin- and MAPK/ERK-mediated signaling, indicating that inducible transcription factors are crucially involved. NFAT, AP-1, and early growth response factor 1, together with CREB-binding protein/p300 coactivators, bind to E¿ as part of an active enhanceosome assembled during pre-TCR signaling. We favor a scenario in which the binding of lymphoid-restricted and constitutive transcription factors to E¿ prior to its activation forms a regulatory scaffold to recruit factors induced by pre-TCR signaling. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors dictates the E¿ function. This mechanism for enhancer activation may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.Peer Reviewe

Effects of mobile phone-related distraction on driving performance at roundabouts: Eye movements tracking perspective

Modern road infrastructures are complex networks featuring various elements such as roads, bridges, intersections, and roundabouts, with advanced control systems. Roundabouts have gained prominence as a safer alternative to traditional intersections promoting smoother traffic flow and fewer collisions by guiding traffic in one direction, encouraging reduced speed, and minimizing conflict points. This study investigated driver behavior within roundabouts, focusing on gaze behavior, particularly the left-side mirror and window, under mobile phone distraction conditions. In addition, the effects of roundabout specifications (i.e., number of lanes and size of the central island) and the drivers’ characteristics (i.e., driving experience) were examined. In total, 43 participants, aged 19–56 years including 30 males and 13 females, held a valid driving license, drove through a virtual simulated urban road containing four roundabouts, implemented in a static driving simulator, under baseline condition (no distraction) as well as mobile-induced distraction. Driving simulator data were collected and drivers’ gaze direction and fixation on nine areas of interest were captured with an eye tracker.This project was funded by FEDER European Regional Development Fund (Fondo Europeo de Desarrollo Regional—Junta de Castilla y León, Spain), grant number BU300P18. Title: Modelización mediante técnicas de "machine learning" de la influencia de las distracciones del conductor en la seguridad vial. Diseño de un sistema integrado: simulador de conducción, "eye tracker" y dispositivo de distracción

Effects of mobile phone-related distraction on driving performance at roundabouts: Eye movements tracking perspective

Modern road infrastructures are complex networks featuring various elements such as roads, bridges, intersections, and roundabouts, with advanced control systems. Roundabouts have gained prominence as a safer alternative to traditional intersections promoting smoother traffic flow and fewer collisions by guiding traffic in one direction, encouraging reduced speed, and minimizing conflict points.This study investigated driver behavior within roundabouts, focusing on gaze behavior, particularly the left-side mirror and window, under mobile phone distraction conditions. In addition, the effects of roundabout specifications (i.e., number of lanes and size of the central island) and the drivers’ characteristics (i.e., driving experience) were examined.In total, 43 participants, aged 19–56 years including 30 males and 13 females, held a valid driving license, drove through a virtual simulated urban road containing four roundabouts, implemented in a static driving simulator, under baseline condition (no distraction) as well as mobile-induced distraction. Driving simulator data were collected and drivers’ gaze direction and fixation on nine areas of interest were captured with an eye tracker. Results: showed that experienced drivers exhibit a more fixation on the left-side mirror and window and were less distracted. Moreover, the road environment, i.e., the number of cars and the roundabout size, significantly influenced the drivers’ attention. As regards the driving performance, the number of infractions increased when the drivers diverted focus from the left side of the car. The outcomes of the present study might help to improve traffic safety at roundabouts

RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism

The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion of the RhoA gene, we have now been exploring how the loss of RhoA affects gene expression. Performing transcription factor reporter assays, we found a significantly decreased activity of a RAR luciferase reporter in RhoA-null keratinocytes. Inhibition of the RhoA effector ROCK in control cells reproduced this phenotype. ATRA and retinal, but not retinol increased RAR reporter activity of keratinocytes with impaired RhoA/ROCK signaling, suggesting that retinol metabolism is regulated by RhoA/ROCK signaling. Furthermore a significant percentage of known ATRA target genes displayed altered expression in RhoA-null keratinocytes. These data reveal an unexpected link between the cytoskeletal regulator RhoA and retinoid signaling and uncover a novel pathway by which RhoA regulates gene expression.</p