1,643 research outputs found

    Methylation by Set9 Modulates FoxO3 Stability and Transcriptional Activity

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    The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools in mammals, which may contribute to longevity. The activity of FoxO3 is controlled by a variety of post-translational modifications that have been proposed to form a ‘code’ affecting FoxO3 subcellular localization, DNA binding ability, protein-protein interactions and protein stability. Lysine methylation is a crucial post-translational modification on histones that regulates chromatin accessibility and is a key part of the ‘histone code’. However, whether lysine methylation plays a role in modulating FoxO3 activity has never been examined. Here we show that the methyltransferase Set9 directly methylates FoxO3 in vitro and in cells. Using a combination of tandem mass spectrometry and methyl-specific antibodies, we find that Set9 methylates FoxO3 at a single residue, lysine 271, a site previously known to be deacetylated by Sirt1. Methylation of FoxO3 by Set9 decreases FoxO3 protein stability, while moderately increasing FoxO3 transcriptional activity. The modulation of FoxO3 stability and activity by methylation may be critical for fine-tuning cellular responses to stress stimuli, which may in turn affect FoxO3's ability to promote tumor suppression and longevity

    Primary skin fibroblasts as a model of Parkinson's disease

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    Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

    Self-Repairable Smart Grids Via Online Coordination of Smart Transformers

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    The introduction of active devices in Smart Grids, such as smart transformers, powered by intelligent software and networking capabilities, brings paramount opportunities for online automated control and regulation. However, online mitigation of disruptive events, such as cascading failures, is challenging. Local intelligence by itself cannot tackle such complex collective phenomena with domino effects. Collective intelligence coordinating rapid mitigation actions is required. This paper introduces analytical results from which two optimization strategies for self-repairable Smart Grids are derived. These strategies build a coordination mechanism for smart transformers that runs in three healing modes and performs collective decision-making of the phase angles in the lines of a transmission system to improve reliability under disruptive events, i.e., line failures causing cascading failures. Experimental evaluation using self-repairability envelopes in different case networks, ac power flows, and varying number of smart transformers confirms that the higher the number of smart transformers participating in the coordination, the higher the reliability and the capability of a network to self-repair

    Occupational injuries and the “student syndrome” (or procrastination) on a large construction Project

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    Resumen Introducción: Hay una mayor incidencia de lesiones en los primeros días hábiles de la semana, y entre las 13:00 y las 17:00 horas. Se ha descrito una asociación entre algunas fechas especiales y cambios en la ocurrencia de muertes o enfermedades en diferentes países y regiones. Nuestra hipótesis fue que el cumplimiento de las obligaciones contractuales de una empresa puede convertirse en un desencadenante que aumenta la ocurrencia de lesiones laborales. Métodos: Nosotros analizamos los registros de lesiones e informes de nómina mensuales consolidados (de enero de 2012 a septiembre de 2013) para el personal que trabajaba en empresas que participaron en un megaproyecto para construir una carretera en Colombia. Este análisis informa una posible asociación entre las fechas de hitos contractuales financieramente importantes y una mayor ocurrencia de lesiones laborales. Pruebas binomiales de una cola se usaron para comparar la ocurrencia de lesiones uno y dos meses antes vs un mes después de cuatro fechas límite, correspondientes al 14, 3, 1 y 1% del presupuesto general, respectivamente. Resultados: La mayor incidencia de lesiones se observó durante el mes anterior a la fecha límite correspondiente al 14% del presupuesto (p=0,07). Discusión: Los hitos contractuales podrían actuar como determinantes distales, mientras que los errores humanos son determinantes proximales de las lesiones.Abstract Introduction: There is a higher occurrence of injuries on the first working days of the week, and between 13:00 and 17:00 hours. An association between some special dates and changes in the occurrence of deaths or diseases have been described in different countries and regions. Our hypothesis was that completing contractual obligations with a company may become triggers that increase the occurrence of occupational injuries. Methods: Injury records were analyzed and consolidated monthly payroll reports (from January 2012 to September 2013) for personnel operations who worked in companies that were involved in a megaproject to build a road in Colombia. This analysis reports a possible association between dates of financially important contractual milestones and a higher occurrence of occupational injuries. One-tailed binomial tests were used to compare the occurrence of injuries one and two months before and one month after four deadlines, corresponding to 14, 3, 1 and 1% of the overall budget, respectively. Results: The highest occurrence of injuries was observed during the month before the deadline corresponding to 14% of the budget (p=0.07). Discussion: Contractual milestones could act as distal determinant whereas human errors are proximal determinants of injuries

    Exploring the socio-ecological factors behind the (in)active lifestyles of Spanish post-bariatric surgery patients

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    Purpose: Physical activity (PA) is considered essential for the treatment of morbid obesity and the optimization of bariatric surgery outcomes. The objective of this article was to identify the facilitators and barriers that bariatric patients perceived to do PA one year after finishing a PA programme for the promotion of a long-term active lifestyle. This objective was addressed from a socio-ecological and qualitative perspective. Methods: Nine patients (eight women and one man), aged between 31 and 59 years, participated in semi-structured interviews directly following the PA programme and one year after it. A content analysis was carried out to analyze the qualitative data. Results: Weight loss, improvement of physical fitness, perceived competence, and enjoyment were the main facilitators of PA. Complexes related to skin folds, osteoarthritis, perceived unfavourable weather conditions, lack of social support and economic resources, long workdays, lack of specific PA programmes, and other passive leisure preferences were the main barriers to participate in PA. Conclusions: Results highlight the important interplay between personal, social environmental, and physical environmental factors to explain (in)active behaviours of bariatric patients. The findings of this article could be useful for future research and interventions aimed at promoting PA in bariatric patients

    Drought impact on forest carbon dynamics and fluxes in Amazonia

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    In 2005 and 2010 the Amazon basin experienced two strong droughts, driven by shifts in the tropical hydrological regime possibly associated with global climate change, as predicted by some global models. Tree mortality increased after the 2005 drought, and regional atmospheric inversion modelling showed basin-wide decreases in CO2 uptake in 2010 compared with 2011 (ref. 5). But the response of tropical forest carbon cycling to these droughts is not fully understood and there has been no detailed multi-site investigation in situ. Here we use several years of data from a network of thirteen 1-ha forest plots spread throughout South America, where each component of net primary production (NPP), autotrophic respiration and heterotrophic respiration is measured separately, to develop a better mechanistic understanding of the impact of the 2010 drought on the Amazon forest. We find that total NPP remained constant throughout the drought. However, towards the end of the drought, autotrophic respiration, especially in roots and stems, declined significantly compared with measurements in 2009 made in the absence of drought, with extended decreases in autotrophic respiration in the three driest plots. In the year after the drought, total NPP remained constant but the allocation of carbon shifted towards canopy NPP and away from fine-root NPP. Both leaf-level and plot-level measurements indicate that severe drought suppresses photosynthesis. Scaling these measurements to the entire Amazon basin with rainfall data, we estimate that drought suppressed Amazon-wide photosynthesis in 2010 by 0.38 petagrams of carbon (0.23-0.53 petagrams of carbon). Overall, we find that during this drought, instead of reducing total NPP, trees prioritized growth by reducing autotrophic respiration that was unrelated to growth. This suggests that trees decrease investment in tissue maintenance and defence, in line with eco-evolutionary theories that trees are competitively disadvantaged in the absence of growth. We propose that weakened maintenance and defence investment may, in turn, cause the increase in post-drought tree mortality observed at our plots.Gordon and Betty Moore FoundationNatural Environment Research Council (NERC)EU FP7 Amazalert (282664) projectEU FP7GEOCARBON (283080) projectNational Council for Scientific and Technological Development (CNPq, Brazil)ARC - fellowship awardERC - Advanced Investigator AwardRoyal Society - Wolfson Research Merit AwardJackson FoundationJohn Fell Fun

    Unraveling the Molecular Determinants of Manual Therapy: An Approach to Integrative Therapeutics for the Treatment of Fibromyalgia and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

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    Application of protocols without parameter standardization and appropriate controls has led manual therapy (MT) and other physiotherapy-based approaches to controversial outcomes. Thus, there is an urgency to carefully define standard protocols that elevate physiotherapy treatments to rigorous scientific demands. One way in which this can be achieved is by studying gene expression and physiological changes that associate to particular, parameter-controlled, treatments in animal models, and translating this knowledge to properly designed, objective, quantitatively-monitored clinical trials (CTs). Here, we propose a molecular physiotherapy approach (MPTA) requiring multidisciplinary teams, to uncover the scientific reasons behind the numerous reports that historically attribute health benefits to MT-treatments. The review focuses on the identification of MT-induced physiological and molecular responses that could be used for the treatment of fibromyalgia (FM) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The systemic effects associated to mechanical-load responses are considered of particular relevance, as they suggest that defined, low-pain anatomic areas can be selected for MT treatment and yet yield overall benefits, an aspect that might result in it being essential to treat FM. Additionally, MT can provide muscle conditioning to sedentary patients without demanding strenuous physical effort, which is particularly detrimental for CFS/ME patients, placing MT as a real option for integrative medicine programs to improve FM and CFS/ME.This research was funded by the Fundación Universidad Católica de Valencia San Vicente Mártir (UCV) Research Grant Program grant number 2018-121-001.Fisioterapi

    Confirmatory factor analysis of the Valencia scale on attitudes and beliefs toward hypnosis, therapist version

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    Health professionals' beliefs and attitudes toward hypnosis may make them reluctant to use it or even to foster misapplications and iatrogenic uses of hypnosis. The Valencia Scale on Attitudes and Beliefs toward Hypnosis-Therapist version (VSABH-T) is a specific instrument to evaluate therapists' attitudes and beliefs. The aims of this study are to evaluate the 8-factor structure of the VSABH-T proposed from a confirmatory perspective. The sample comprised 1,661 licensed psychologists who are members of the Spanish Psychological Association for the initial test and 787 for the retest. Results confirmed the 8-factor structure obtained in a previous exploratory study, namely: Fear, Memory, Help, Control, Collaboration, Interest, Magic, and Marginal. The scale also showed adequate psychometric properties, including good internal consistency and test-retest reliability
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