Overexpression of the scaffold WD40 protein WRAP53β enhances the repair of and cell survival from DNA double-strand breaks

Altered expression of the multifunctional protein WRAP53β (WD40 encoding RNA Antisense to p53), which targets repair factors to DNA double-strand breaks and factors involved in telomere elongation to Cajal bodies, is linked to carcinogenesis. While loss of WRAP53β function has been shown to disrupt processes regulated by this protein, the consequences of its overexpression remain unclear. Here we demonstrate that overexpression of WRAP53β disrupts the formation of and impairs the localization of coilin to Cajal bodies. At the same time, the function of this protein in the repair of DNA double-strand breaks is enhanced. Following irradiation, cells overexpressing WRAP53β exhibit more rapid clearance of phospho-histone H2AX (γH2AX), and more efficient homologous recombination and non-homologous end-joining, in association with fewer DNA breaks. Moreover, in these cells the ubiquitylation of damaged chromatin, which is known to facilitate the recruitment of repair factors and subsequent repair, is elevated. Knockdown of the ubiquitin ligase involved, ring-finger protein 8 (RNF8), which is recruited to DNA breaks by WRAP53β, attenuated this effect, suggesting that overexpression of WRAP53β leads to more rapid repair, as well as improved cell survival, by enhancing RNF8-mediated ubiquitylation at DNA breaks. Our present findings indicate that WRAP53β and RNF8 are rate-limiting factors in the repair of DNA double-strand breaks and raise the possibility that upregulation of WRAP53β may contribute to genomic stability in and survival of cancer cells

A Mechanism-Based Explanation of the Institutionalization of Semantic Technologies in the Financial Industry

Part 3: Creating Value through ApplicationsInternational audienceThis paper explains how the financial industry is solving its data, risk management, and associated vocabulary problems using semantic technologies. The paper is the first to examine this phenomenon and to identify the social and institutional mechanisms being applied to socially construct a standard common vocabulary using ontology-based models. This standardized ontology-based common vocabulary will underpin the design of next generation of semantically-enabled information systems (IS) for the financial industry. The mechanisms that are helping institutionalize this common vocabulary are identified using a longitudinal case study, whose embedded units of analysis focus on central agents of change—the Enterprise Data Management Council and the Object Management Group. All this has important implications for society, as it is intended that semantically-enabled IS will, for example, provide stakeholders, such as regulators, with better transparency over systemic risks to national and international financial systems, thereby mitigating or avoiding future financial crises

Coulomb Explosion and Thermal Spikes

A fast ion penetrating a solid creates a track of excitations. This can produce displacements seen as an etched track, a process initially used to detect energetic particles but now used to alter materials. From the seminal papers by Fleischer et al. [Phys. Rev. 156, 353 (1967)] to the present [C. Trautmann, S. Klaumunzer and H. Trinkaus, Phys. Rev. Lett. 85, 3648 (2000)], `Coulomb explosion' and thermal spike models are treated as conflicting models for describing ion track effects. Here molecular dynamics simulations of electronic-sputtering, a surface manifestation of ion track formation, show that `Coulomb explosion' produces a `heat' spike so that these are early and late aspects of the same process. Therefore, differences in scaling are due to the use of incomplete spike models.Comment: Submitted to PRL. 4 pages, 3 figures. For related movies see: http://dirac.ms.virginia.edu/~emb3t/coulomb/coulomb.html PACS added in new versio

Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions

Implementación de procedimientos operacionales estándares de sanitización en la Empresa Agropecuaria Popoyan Proyecto La Carreta

La presente investigación se realizó en la Empresa Agropecuaria Popoyán S. A., ubicada en la zona 11, ciudad de Guatemala, "Proyecto La Carretera", su principal objetivo es el desarrollo de nuevos productos tipo. Mediante el diagnostico se pudo observar las distintas ensalada con variedades de lechuga que se desarrollan mediante la técnica del triple lavado, para asegurar la inocuidad y calidad del producto, en donde innovando se estudió el empaque de las atmósferas modificadas con la inyección de gases inerte para mantener y asegurar la calidad del producto, y durante la investigación se llevo a definir las cantidades de tiempos de inyección, vacío y sellado para que sean los niveles óptimos de empaque. Se evaluaron los parámetros microbiológicos, turgencia y color se determinó la vida de anaquel, las variedades de lechuga utilizadas fueron: lechuga romana, escarola amarilla y morada, las cuales previamente clasificadas con una inspección física, se determinaron aptas para desarrollar la fase descrita anteriormente. Los Procedimientos Operacionales Estándares de Sanitización (POES), son un eslabón de la cadena para garantizar el producto. Este describe el qué hacer en cada operación, las cuales van desde prevención de la contaminación cruzada hasta vigilar la salud de los empleados, las responsabilidades en cada procedimiento, la verificación y las concentraciones de producto utilizadas en cada área. Todo esto para mantener un estándar en las áreas y que los colaboradores tengan presente el propósito de cada procedimiento. La piña es un producto que al ser cortada para consumo en fresco tiene una vida de anaquel de cuatro días, con la aplicación de preservantes se alarga la vida de 8 días. Se realizó una evaluación sensorial para medir el agrado del consumidor del producto con aplicación de que preservantes prefiere y según el análisis, el bisulfito de sodio es de mayor preferencia por encima de la mezcla de: sorbato de potasio, ácido cítrico y bisulfito de sodio. El último tratamiento fue tomado del manual de la Food and Agriculture Organization (FAO) para la conservación de productos, Al evaluar la vida de anaquel retiene los parámetros como pH y grados Brix, ya que al comparar con el testigo este sufre una elevación de los parámetros al día tres, el cual es el día clave para detener estos procesos, la boleta en la cual se le hizo un análisis sensorial al consumidor día a día, la detección de olor como fermento, sabor en la clasificación de dulce y no aceptable, la textura la turgencia del producto en el nivel de pérdida día a día. Obteniendo de esta forma la información necesaria para tomar las medidas correspondientes para cada producto. En la fase de Producción más limpia se hace una propuesta de mejora de instalaciones y plan de mejoras. Con la implementación de esta fase se tendría un ahorro mensual de 20 m³ de agua. El metro cúbico tiene un precio de Q 60,00, teniendo un ahorro equivalente a Q 1 200,00

Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the combination of a rapid intravenous infusion of cold saline and endovascular hypothermia in a closed chest pig infarct model.</p> <p>Methods</p> <p>Pigs were randomized to pre-reperfusion hypothermia (n = 7), post-reperfusion hypothermia (n = 7) or normothermia (n = 5). A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min. Hypothermia was started after 25 min of ischemia or immediately after reperfusion by infusion of 1000 ml of 4°C saline and endovascular hypothermia. Area at risk was evaluated by in vivo SPECT. Infarct size was evaluated by ex vivo MRI.</p> <p>Results</p> <p>Pre-reperfusion hypothermia reduced infarct size/area at risk by 43% (46 ± 8%) compared to post-reperfusion hypothermia (80 ± 6%, p < 0.05) and by 39% compared to normothermia (75 ± 5%, p < 0.05). Pre-reperfusion hypothermia infarctions were patchier in appearance with scattered islands of viable myocardium. Pre-reperfusion hypothermia abolished (0%, p < 0.001), and post-reperfusion hypothermia significantly reduced microvascular obstruction (10.3 ± 5%; p < 0.05), compared to normothermia: (30.2 ± 5%).</p> <p>Conclusion</p> <p>Rapid hypothermia with cold saline and endovascular cooling before reperfusion reduces myocardial infarct size and microvascular obstruction. A novel finding is that hypothermia at the onset of reperfusion reduces microvascular obstruction without reducing myocardial infarct size. Intravenous administration of cold saline combined with endovascular hypothermia provides a method for a rapid induction of hypothermia suggesting a potential clinical application.</p

Analysis protocols for MRI mapping of the blood oxygenation-sensitive parameters T(2)* and T(2) in the kidney

Renal hypoxia is generally accepted as a key pathophysiologic event in acute kidney injury of various origins and has also been suggested to play a role in the development of chronic kidney disease. Here we describe step-by-step data analysis protocols for MRI monitoring of renal oxygenation in rodents via the deoxyhemoglobin concentration sensitive MR parameters T(2)* and T(2)-a contrast mechanism known as the blood oxygenation level dependent (BOLD) effect.This chapter describes how to use the analysis tools provided by vendors of animal and clinical MR systems, as well as how to develop an analysis software. Aspects covered are: data quality checks, data exclusion, model fitting, fitting algorithm, starting values, effects of multiecho imaging, and result validation.This chapter is based upon work from the PARENCHIMA COST Action, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol chapter is complemented by two separate chapters describing the basic concept and data analysis

Effects of a training program after surgically treated ankle fracture: a prospective randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Despite conflicting results after surgically treated ankle fractures few studies have evaluated the effects of different types of training programs performed after plaster removal. The aim of this study was to evaluate the effects of a 12-week standardised but individually suited training program (training group) versus usual care (control group) after plaster removal in adults with surgically treated ankle fractures.</p> <p>Methods</p> <p>In total, 110 men and women, 18-64 years of age, with surgically treated ankle fracture were included and randomised to either a 12-week training program or to a control group. Six and twelve months after the injury the subjects were examined by the same physiotherapist who was blinded to the treatment group. The main outcome measure was the Olerud-Molander Ankle Score (OMAS) which rates symptoms and subjectively scored function. Secondary outcome measures were: quality of life (SF-36), timed walking tests, ankle mobility tests, muscle strength tests and radiological status.</p> <p>Results</p> <p>52 patients were randomised to the training group and 58 to the control group. Five patients dropped out before the six-month follow-up resulting in 50 patients in the training group and 55 in the control group. Nine patients dropped out between the six- and twelve-month follow-up resulting in 48 patients in both groups. When analysing the results in a mixed model analysis on repeated measures including interaction between age-group and treatment effect the training group demonstrated significantly improved results compared to the control group in subjects younger than 40 years of age regarding OMAS (p = 0.028), muscle strength in the plantar flexors (p = 0.029) and dorsiflexors (p = 0.030).</p> <p>Conclusion</p> <p>The results of this study suggest that when adjusting for interaction between age-group and treatment effect the training model employed in this study was superior to usual care in patients under the age of 40. However, as only three out of nine outcome measures showed a difference, the beneficial effect from an additional standardised individually suited training program can be expected to be limited. There is need for further studies to elucidate how a training program should be designed to increase and optimise function in patients middle-aged or older.</p> <p>Trial Registration</p> <p>Current Controlled Trials ACTRN12609000327280</p

Political Mediation and American Old-Age Security Exceptionalism

Debates over America’s heavy reliance on employer-provided private pensions have understated the profound role organized labor played after World War II. Archival evidence from prominent unions and business associations suggests that the shift in organized labor’s strategy after the New Deal toward electoral activity helps explain critical interventions by Northern Democrats into the system of private pensioning in the postwar period that laid the foundation for America’s old-age security system. Such a strategy was insufficient, however, to expand Social Security. This article offers a political mediation account of electoral activity as a source of labor influence on social policy that draws on political institutionalist and class power theories