Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells. Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis

Cosmovisión de la minería en la Mitad del Mundo

This study of peasant indigenous worldview is founded on risk analysis around a productive activity, in this case, mining in the Middle of the World. Based on the current context of concomitance caused by mining, without supervision coordination and planning, lack of security for third parties, apathy and neglect for the environment, this document analyzes the worldview of the involved people in the short and medium term. This study consisted of a series of field observations "in situ", collection of life stories, interviews with focus groups, individual interviews with villagers, miners, community leaders, mine owners, men and women who live daily life in this pilgrimage to a pseudo contradictory modernity, to achieve for themselves and their children living standards probably more worthy, not aware that they are defining their own future. The study is oriented to determine perceptions of indigenous people and peasants, in their routines of life with all stakeholders involved in the current context around mining.El presente estudio, de cosmovisión indígena campesina, tiene su fundamento en el análisis de riesgo alrededor de una actividad productiva, en este caso, la minería en la Mitad del Mundo. Partiendo del contexto actual de los albures provocados por la explotación minera sin supervisión coordinada, planificación y falta de seguridad para terceros, así como desidia y desamparo por el medio ambiente, se analiza la cosmovisión de la población involucrada a corto y mediano plazo. Este estudio consistió en una serie de observaciones de campo “in situ”, recopilación de historias de vida, entrevistas a grupos focales, entrevistas individuales a comuneros, mineros, dirigentes comunitarios, dueños de minas, hombres y mujeres que viven la cotidianidad en este contradictorio peregrinaje a una pseudo modernidad, para alcanzar, para ellos y sus hijos niveles de vida probablemente más dignos, sin concienciar que ellos mismos están marcando su propio futuro. Está orientado a determinar las percepciones de la población indígena-campesina, en sus rutinas de vida con todos los actores sociales involucrados en el contexto actual alrededor de la actividad minera

Estrategias praxias bits para mejorar la oralidad en niños de 5 años de una institución educativa de Lima, 2022

La oralidad es una habilidad muy importante desarrollar en los infantes con el propósito de insertarse a las situaciones comunicativas, además como una habilidad transversal en la formación integral de los educandos. En el estudio se planteó como objetivo principal determinar cómo influyen las estrategias praxias bits en la mejora de la oralidad de los niños de 5 años de una institución educativa de Lima, 2022. Cuantitativo fue el enfoque del estudio, pre experimental el diseño de investigación. Se trabajó con una muestra de 20 infantes de 5 años. Los resultados principales indican que, comparando las medias, se asume que durante el pre test, el desarrollo de la oralidad fue menor versus el post test (M1= 10,177vs. M2=18,856). Además, al realizar la prueba de T de student, se obtuvo un valor de significancia de 0,000, siendo esta menor de 0.05, por lo tanto, se concluye que las praxias bits influyen de forma significativa en la mejora de la oralidad de los preescolares de una institución educativa privada en Lima 2022

RAD51 and mitotic function of MUS81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death

Perfil lipídico y su asociación con las enfermedades isquémicas del corazón.

Ischemic heart diseases are the third cause of death worldwide according to the statistical registry of general deaths, with the highest rate in the adult population in the male gender. That is why the present research aimed to establish the relationship between the lipid profile and ischemic heart diseases. For this research, the descriptive documentary design was used. This information was compiled from different scientific databases such as: Scielo, PubMed, Redalyc, Elservier, Biomed Central, Science Direct and official websites such as the World Health Organization, Pan American Health Organization, National Institute of Statistics and Census, in turn scientific articles, books, journals published in English and Spanish announced 5 years before, for the search the use of keywords was used through Boolean operators such as OR and AND. The results obtained show that among the main risk factors are diabetes, obesity, smoking, etc. Also, values outside the normal range of the lipid profile can be found, especially in the parameters of total cholesterol and triglycerides. The diagnostic method most used by specialists was computed tomography. Therefore, several investigations have shown the importance of the lipid profile within ischemic heart disease.  Las enfermedades isquémicas al corazón forman parte de la tercera causa de muerte a nivel mundial según el registro estadístico de defunciones generales, con mayor índice en la población adulta en el género masculino. Es por ello que el presente trabajo de investigación tuvo como objetivo establecer la relación que existe entre el perfil lipídico y las enfermedades isquémicas al corazón. Para el presente estudio se utilizó el diseño documental de tipo descriptivo. Esta información fue recopilada de diferentes bases de datos científicos como: Scielo, PubMed, Redalyc, Elservier, Biomed Central, Science Direct y páginas web oficiales como la Organización Mundial de la Salud, Organización Panamericana de la Salud, Instituto Nacional de Estadística y Censo, a su vez artículos científicos, libros, revistas publicados en inglés y español anunciados con 5 años de anterioridad, para la búsqueda se empleó el uso de palabras claves a través de los operadores booleanos como OR y AND. Los resultados obtenidos demuestran que entre los principales factores de riesgo se encuentran la diabetes, obesidad, tabaquismo, etc. También, se pueden hallar valores fuera del rango normal del perfil lipídico, sobre todo en los parámetros del colesterol total y triglicéridos. A su vez, que el método diagnóstico más empleado por los especialistas fue la tomografía computarizada. Por lo que, diversas investigaciones han demostrado la importancia del perfil lipídico dentro de las cardiopatías isquémicas. &nbsp

PADRÕES CLIMATOLÓGICOS ASSOCIADOS A EVENTOS DE SECA NO LESTE DO ESTADO DE SÃO PAULO

Os mecanismos de ocorrência de secas no Sudeste do Brasil são complexos, pois a região encontra-se em uma zona de transição entre os regimes atmosféricos tropical e extratropical. Este trabalho apresenta as condições climatológicas médias sazonais no início de eventos de seca na faixa leste do estado de São Paulo no período de 1901 a 2010. Estes eventos foram identificados utilizando o índice de evapotranspiração-precipitação padronizado (SPEI) calculado a partir dos dados da reanálise ERA20C. Durante o verão e o outono, os eventos de seca são associados a uma teleconexão atmosférica originada por anomalias quentes do oceano na região da Indonésia. Um padrão de bloqueio no Pacífico Sul desfavorece o avanço de perturbações de médios e altos níveis em direção à América do Sul, e o transporte de umidade das regiões tropicais em direção a São Paulo é desfavorecido pelo enfraquecimento do Jato de Baixos Níveis. No inverno, as secas se iniciam com a intensificação da Alta Subtropical sobre a costa do Sudeste por um trem de ondas barotrópico propagando-se desde o Índico, e com o aumento das temperaturas e da evapotranspiração provocados pela fase negativa da Oscilação Antártica. Nos eventos de seca da primavera, o escoamento de grande escala remete ao padrão de teleconexão da La Niña. Os índices climáticos melhor correlacionados à série temporal do SPEI na faixa leste de São Paulo são da Oscilação Antártica (outono e inverno), da oscilação do Atlântico Tropical Sul (outono e primavera), e do El Niño-Oscilação Sul (primavera)

Early and Highly Suppressive ART are Main Factors Associated with Low Viral Reservoir in European Perinatally HIV Infected Children

Abstract BACKGROUND: Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. SETTING: We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting ART <6 months of age. METHODS: Total HIV-1 DNA was measured from 51 long-term suppressed children 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. RESULTS: At ART initiation, children were aged median [IQR] 2.3 [1.2,4.1] months, CD4% 37 [24,45] %, CD8% 28 [18,36] %, log10 plasma viral load (VL) 5.4 [4.4,5.9] copies/ml. Time to viral suppression was 7.98 [4.6,19.3] months. Following suppression, 13 (25%) children had suboptimal response [ 652 consecutive VL50-400 followed by VL<50] and/or experienced periods of virological failure [ 652 consecutive VL 65400 followed by VL<50]. Median total HIV-1 DNA was 43 [6,195] copies/10 PBMC.Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, p=0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, p=0.0022) and absence of viral failure/suboptimal response (AC 0.34 for those with fail/ suboptimal response, p=0.0483) were associated with lower total HIV-1 DNA. CONCLUSION: Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1 infected children minimize the size of viral reservoir.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal

The CARMA study: early infant antiretroviral therapy-timing impacts on total HIV-1 DNA quantitation 12 Years later

Background Strategies aimed at antiretroviral therapy (ART)–free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV). Methods Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) consortium who commenced ART aged 5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association. Results Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3–15.4) years after ART initiation. Eleven had total HIV-1 DNA 6 logs. The effect of CD4% (coefficient = 0.03 ± 0.01, P = .049) was not maintained >40%. Conclusions In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy

RAD51 and mitotic function of MUS81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death

TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown