RanBP2-Mediated SUMOylation Promotes Human DNA Polymerase Lambda Nuclear Localization and DNA Repair

Cellular DNA is under constant attack by a wide variety of agents, both endogenous and exogenous. To counteract DNA damage, human cells have a large collection of DNA repair factors. Among them, DNA polymerase lambda (Polλ) stands out for its versatility, as it participates in different DNA repair and damage tolerance pathways in which gap-filling DNA synthesis is required. In this work we show that human Polλ is conjugated with Small Ubiquitin-like MOdifier (SUMO) proteins both in vitro and in vivo, with Lys27 being the main target of this covalent modification. Polλ SUMOylation takes place in the nuclear pore complex and is mediated by the E3 ligase RanBP2. This post-translational modification promotes Polλ entry into the nucleus, which is required for its recruitment to DNA lesions and stimulated by DNA damage induction. Our work represents an advance in the knowledge of molecular pathways that regulate cellular localization of human Polλ, which are essential to be able to perform its functions during repair of nuclear DNA, and that might constitute an important point for the modulation of its activity in human cells

Regulation of human Polλ by ATM-mediated phosphorylation during Non-Homologous End Joining

DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated. In this study we identify the major NHEJ DNA polymerase, DNA polymerase lambda (Polλ), as a target for both ATM and DNA-PKcs in human cells. We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. Molecular evidence suggests that Polλ phosphorylation might favor Polλ interaction with the DNA-PK complex at DSBs. Altogether, our work provides the first demonstration of how Polλ is regulated by phosphorylation to connect with the NHEJ core machinery during DSB repair in human cells.España MINECO y la Comisión Europea (European Regional Development Fund) to J.F.R. RYC-2011-08752, BFU2013-44343-P) and to F.C-L. (SAF2014-55532-R)

Prevención de los trastornos de la conducta alimentaria en centros de educación secundaria

La prevención de los trastornos de la conducta alimentaria en los centros educativos de secundaria es importante ya que se dirige a alumnos con edades en las que el individuo es más vulnerable y el trastorno puede cronificarse. Tras la revisión de la evidencia fuera y dentro de nuestro país, se recogen una serie de recomendaciones que nos conducirán a obtener una mayor eficacia a la hora de implementar programas preventivos en la educación secundaria: uso de contenido interactivo, abordaje de factores de riesgo, prevención de la obesidad, aplicación en edades tempranas, intervenciones realizadas por el propio personal del centro, inclusión de la perspectiva de género y evaluación de los programas de forma controlada, rigurosa y científica. The prevention of eating disorders in secondary schools is important since it is aimed at students with ages in which the individual is most vulnerable and the disorder can become chronic. After reviewing the evidence, outside and within our country, the recommendations assembled will be helpful to design efficient preventive programs for implementation in secondary education. The use of interactive content, approach to risk factors, prevention of obesity, application in early ages, interventions carried out by the center’s own staff, inclusion of the gender perspective and evaluation of the programs in a controlled, rigorous and scientific way

Relationship of Gaming Disorder with parenting based on low affection-communication and personality trait of neuroticism in adolescents

Background: Gaming Disorder is increasingly common in adolescents. We aimed to evaluate the relationship between parenting, personality traits, and Gaming Disorder. Methods: An observational and cross-sectional study in six secondary schools of Castelló, obtaining a final sample of 397 students. Results: Adolescents with Gaming Disorder had lower scores in Adolescent Affection-Communication (F = 8.201; p < 0.001), Father’s Warmth (F = 3.459; p = 0.028), and Father’s Acceptance/Involvement (F = 5.467; p = 0.003), and higher scores in Mother’s Revoking Privileges (F = 4.277; p = 0.034) and Father’s Indifference (F = 7.868; p = 0.002) than healthy participants. Male sex was a risk factor for Gaming Disorder (OR = 12.221; p = 0.004), while Adolescent Affection-Communication (OR = 0.908; p = 0.001) and Agreeableness (OR = 0.903; p = 0.022) were protective factors. Data modeling described the protective effect that Adolescent Affection-Communication had on Gaming Disorder, which was both directly (B = -0.20; p < 0.001) and indirectly mediated by Neuroticism (B = -0.20; p < 0.001), while Neuroticism itself was a risk factor for Gaming Disorder (B = 0.50; p < 0.001). Conclusion: These results reflect that Parental style with low affection and communication was directly and indirectly related to the Gaming Disorder, as well as male sex and personality trait of Neuroticism

Prevención de los trastornos de la conducta alimentaria en la comunidad

Existen ciertos colectivos más vulnerables en la comunidad, como los adolescentes y jóvenes involucrados en actividades lúdicas o deportivas que implican una alta competitividad y que llevan asociada una elevada importancia del peso corporal, que tienen significativamente más riesgo de presentar un trastorno de la conducta alimentaria (TCA). Para una prevención primaria efectiva a nivel comunitario, la evidencia nos indica la conveniencia de dirigir nuestros esfuerzos hacia esos grupos con más riesgo, siendo el paradigma de la promoción de la salud la fórmula más indicada. Se sugiere poner en práctica un enfoque participativo, multimodal e interactivo, basando los programas en la terapia motivacional y la disonancia cognitiva, tratando de que estos sean sostenibles e intentando contar con el apoyo de líderes comunitarios. Certain groups in the community are more vulnerable, such as adolescents and young people involved in recreational or sports activities that involve high competitiveness and are associated with high importance of body weight, who are significantly more at risk of developing an eating disorder (TCA). For effective primary prevention at the community level, the evidence indicates the advisability of directing our efforts towards those groups with the highest risk, with the health promotion paradigm being the most indicated formula. Participatory, multimodal, and interactive approaches are recommended, basing the programs on motivational therapy and cognitive dissonance, while trying to make them sustainable to count on the support of community leaders

“Own doctor” presence in a web-based lifestyle intervention for adults with obesity and hypertension: A randomized controlled trial

Introduction: Online interventions have long been shown to be an effective means to promote a healthy lifestyle, thereby helping to control body weight and blood pressure figures. Likewise, using video modeling is also considered an effective way to guide patients through behavioral interventions. Nonetheless, to the best of our knowledge, this study is the first to analyze how the presence of patients' “own doctor” in the audiovisual content of a web-based lifestyle program (“Living Better”) aimed at promoting regular physical exercise and healthy eating behavior, compared with an “unknown doctor,” influences the outcomes of adults with obesity and hypertension. Materials and methods: A total of 132 patients were randomly assigned either to the experimental (n = 70) or control (n = 62) group (“own doctor” or “unknown doctor”, respectively). The body mass index, systolic and diastolic blood pressure, number of antihypertensive drugs used, physical activity level, and quality of life was assessed and compared at baseline and post-intervention (12 weeks).Results: The intention-to-treat analysis showed intragroup significant improvements in both groups in terms of the body mass index (control group: mean difference −0.3, 95% CI [−0.5, −0.1], p = 0.002; experimental group: −0.4 [−0.6, −0.2], p &amp;lt; 0.001) and systolic blood pressure (control group: −2.3 [−4.4, −0.2], p = 0.029; experimental group: −3.6 [−5.5, −1.6], p&amp;lt; 0.001). In addition, there were also significant improvements in the experimental group for the diastolic blood pressure (−2.5 [−3.7, −1.2], p &amp;lt; 0.001), physical activity (479 [9, 949], p = 0.046), and quality of life (5.2 [2.3, 8.2], p = 0.001). However, when comparing the experimental with the control group, no between-group significant differences were found in these variables.Conclusions: This study suggests that the presence of patients' “own doctor” in the audiovisual content of a web-based intervention, aimed at promoting a healthy lifestyle among adults with obesity and hypertension, do not show significant additional benefits over the efficacy of e–counseling.Trial registrationClinicalTrials.gov NCT04426877. First Posted: 11/06/2020. https://clinicaltrials.gov/ct2/show/NCT04426877

Sensitive targeted multiple protein quantification based on elemental detection of Quantum Dots

https://doi.org/10.1016/j.aca.2015.03.015A generic strategy based on the use of CdSe/ZnS Quantum Dots (QDs) as elemental labels for protein quantification, using immunoassays with elemental mass spectrometry (ICP-MS), detection is presented. In this strategy, streptavidin modified QDs (QDs-SA) are bioconjugated to a biotinylated secondary antibody (b-Ab2). After a multi-technique characterization of the synthesized generic platform (QDs-SAb-Ab2) it was applied to the sequential quantification of five proteins (transferrin, complement C3, apolipoprotein A1, transthyretin and apolipoprotein A4) at different concentration levels in human serum samples. It is shown how this generic strategy does only require the appropriate unlabeled primary antibody for each protein to be detected. Therefore, it introduces a way out to the need for the cumbersome and specific bioconjugation of the QDs to the corresponding specific recognition antibody for every target analyte (protein). Results obtained were validated with those obtained using UV–vis spectrophotometry and commercial ELISA Kits.This work was supported by the Spanish Ministry of Science and Innovation (MICINN, CTQ2010-16636), the European FEDER program co-financing, the “Plan de Ciencia, Tecnología e Innovación” of the Principado de Asturias (FICYT, IE13-031) and Agilent Technologies Foundation. A.R.M.B. and M.G.C thank the MICINN and “Gobierno del Principado de Asturias” for their Ph.D. funding through the FPU and Severo Ochoa (BP13-110) programs, respectively. M.C.P. “Catedrático Rafael del Pino en Oftalmología” and H.G.I. acknowledge financial support from the “Fundación Ma Cristina Masaveu Peterson” and The Glaucoma Foundation (NY, USA).https://doi.org/10.1016/j.aca.2015.03.01

Social media and cyberbullying in eating disorders

Los trastornos del comportamiento alimentario (TCA) son una patología multifactorial. En su inicio están implicadas múltiples variables a las que se les suma hoy en día un posible potenciador: la difusión y promoción de la cultura de la delgadez y la apología de los TCA a través de las redes sociales (RR. SS.) usadas por los más jóvenes. A través de las herramientas de feedback de las redes (likes, comments, visitas, retweets, etc.) y los elementos de comparación entre iguales de las RR. SS. más visuales, muchos usuarios llegan a desarrollar conductas de riesgo que a su vez retroalimentan a otros. Por otra parte, se crea la sensación de pertenencia a un grupo o tribu a través de comunidades cuyos miembros se sienten apoyados y donde se comparten de forma afectiva dietas muy restrictivas, así como formas de ocultarlas y otras conductas a quienes no pertenecen al grupo; ambos elementos dificultan la intervención por parte de los profesionales y la familia. Debido al uso extensivo de las RR. SS., a la rápida difusión de todo aquello que se publica y al escaso control que hay sobre el contenido que se comparte, resulta prácticamente imposible controlar los sitios donde se hace apología y se promueven las conductas que contribuyen al desarrollo o mantenimiento de los TCA. El ciberacoso o intimidación por medio de tecnologías digitales utiliza con frecuencia críticas sobre la imagen corporal que dañan la autoestima de los más vulnerables, y es un factor cada vez más presente en los jóvenes que han padecido un TCA. Se considera que la clave de la prevención reside en la alfabetización mediática del uso de las RR. SS., así como la supervisión parental de los más jóvenes. Las personas en riesgo o ya diagnosticadas de TCA encuentran en estas redes el apoyo social que buscan, pero sesgado hacia las conductas de riesgo, cuando sería posible explotarlas en beneficio de la promoción de hábitos saludables y para la recuperación de estos trastorno

Association between combinations of genetic polymorphisms and epidemiopathogenic forms of bovine paratuberculosis

[EN] Control of major mycobacterial diseases affecting livestock is a challenging issue that requires different approaches. The use of genetic markers for improving resistance to Mycobacterium avium subsp. paratuberculosis infection in cattle has been explored as a promising population strategy We performed paratuberculosis epidemiopathogenic phenotypic and genotypic characterization involving 24 SNPs in six candidate genes (NOD2, CD209, SLC11A1, SP110, TLR2 and TLR4) on 502 slaughtered Friesian cows. In the current study, we investigate whether recently proposed paratuberculosis (PTB) epidemiopathogenic (EP) forms (apparently free-AF, latent-LAT and patent-PAT) could be associated with some combination of these 24 SNPs. Best EP form grouping was obtained using a combination of 5 SNPs in four genes (CD209: rs210748127; SLC11A1: rs110090506; SP110: rs136859213 and rs110480812; and TLR2: rs41830058). These groups were defined according to the level of infection progression risk to patent epidemiopathogenic forms and showed the following distributions: LOWIN (low) with 39 (8%) cases (94.9% AF/5.1% LAT/0% PAT); LATIN (low) with 17 (3%) cases (5.9% AF/94.1% LAT/0% PAT); AVERIN (average) with 413 (82%) cases (52.1% AF/38.5% LAT/9.4% PAT) and PATIN (patent) with 33 (7%) cases (36.4% AF/24.2% LAT/39.4% PAT). Age of slaughter was significantly higher for LATIN (88.3 months) compared to AVERIN (65.3 months; p = 0.0007) and PATIN (59.1 months; p = 0.0004), and for LOWIN (73.9 months) compared to PATIN (p = 0.0233), and nearly significant compared to AVERIN (p = 0.0572) These results suggest that some selected genetic polymorphisms have a potential use as markers of PTB EP forms and thus add a new tool for the control of this widespread infectionSIThis work was supported by the Ministry of Economy and Competitiveness (MINECO) (projects AGL2006-14315-C02 and RTA2014-00009), Basque Government (GV/EJ) (SAIOTEK program: SA-2010/00102), European Regional Development Fund (ERDF), and European Social Fund (ESF) is also gratefully acknowledged. Patricia V azquez was holder of a graduate fellowship award (FPI) (BES-2007-17170) from the Spanish MINEC