Genomics and metabonomics in severe alcoholic hepatitis

Severe alcoholic hepatitis is a florid presentation of alcohol-related liver disease and is associated with very high short-term mortality, in excess of 20% within 28 days. Severe alcoholic hepatitis occurs in a minority of patients who develop alcohol-related liver disease. A combination of genetic and environmental factors is likely to predispose to severe alcoholic hepatitis. To date the clinical phenotype has not been extensively examined in candidate gene studies and has been the subject of a single, small genome-wide association study. A genome-wide association study of severe alcoholic hepatitis identified two loci potentially associated with the risk of developing severe alcoholic hepatitis: i) A strong association with PNPLA3, a well-recognised risk locus for alcohol-related liver disease, and ii) a novel but weaker association with SLC38A4, an amino acid transporter. The primary genetic variant at each locus was evaluated to determine whether there was an influence on disease phenotype or outcome. The primary variant in PNPLA3, rs738409, is a missense variant. Analyses indicated a deleterious effect of homozygosity on medium-term survival in addition to more severe disease on baseline histology and a slower recovery in liver function over the short-term period; consistent with established literature in alcohol-related cirrhosis. In contrast the primary variant in SLC38A4, rs11183620, is intronic with no clear evidence for an effect on gene expression or function. Analyses did not indicate an influence on histology, clinical phenotypes or outcomes. In light of the locus’ novelty further work was undertaken to determine any potential contribution to disease pathogenesis. SLC38A4 was down-regulated in whole liver tissue in severe alcoholic hepatitis. Experiments with cell lines in culture suggested the pro-inflammatory cytokine IL-1 as a potential driver. SLC38A4 knockdown resulted in upregulation of some cellular responses associated with nutrient deprivation. There was no influence of the variant on serum amino acid profiles. The functional significance of SLC38A4 down-regulation remains the subject of ongoing work.Open Acces

Global Innovation Policy Index

Ranks fifty-five nations' strategies to boost innovation capacity: policies on trade, scientific research, information and communications technologies, tax, intellectual property, domestic competition, government procurement, and high-skill immigration

From Progressive Planning to Progressive Urbanism: Planning\u27s Progressive Future and the Legacies of Fragmentation

Since the 1980’s numerous urban scholars have taken to proclaiming one city or another as being ‘progressive.’ Planning websites like American Planning Association, Planetizen or Progressive Planning Magazine are inundated with examples of progressive planning in action. The examples of touted progressive cities are many: Burlington, Berkeley, Cleveland, Boston, L.A., Chicago, Cincinnati, Portland, Minneapolis, Austin, Denver, and Seattle have all been championed as progressive cities. Most of them come with brackets: Boston was progressive [under Mayor Flynn]; Chicago was progressive [under Mayor Washington]; Burlington was progressive [under Mayor Sanders]. There is also no shortage of descriptors about what makes a city progressive: linkage policies, minimum wages, rent control, affirmative action policies, and more recently public transit, mixed-use development, and pro-density growth policies. A more recent articulation of the progressive city tends to use phrases like ‘right-thinking,’ ‘cool,’ ‘hip,’ or ‘walkability’ and locates progressiveness in its ‘urbanity’

Iniciación de un joven entrenador de fútbol en la aplicación del Modelo Táctico de Juego

This paper utilizes a collaborative action research design to investigate one youth soccer coach’s maiden implementation of the Tactical Games Model (TGM). Consequently, this study aims to add to the paucity of research regarding coaches use of Game-Centered Approaches (GCAs), in particular the TGM. The study took place over eight, one-hour coaching sessions, which were conducted with a U12 competitive (travel) soccer team. The coach, Ian, was a licensed soccer coach and an undergraduate physical education student who had previously been exposed to the TGM in his university coursework. Data were collected through observation of model benchmarks in three of the TGM sessions (2, 4 and 6), the completion of Post-Session Teaching Reflective Analyses (PTRA; Dyson, 1994) and three semi-structured interviews. Model benchmark data were analyzed descriptively while PTRA and interview data were analyzed using the Lexminacer text mining software to generate themes and concepts. Findings showed that model benchmark fidelity improved as the coach became more familiar with TGM in his coaching setting. The main concepts generated from the Leximancer analysis were: ‘players’, ‘session’, ‘time’, ‘games’, and ‘physical’, which suggests a major shift in coaching practice occurred in alignment with Light’s (2013) four features of game-centered pedagogy. This current study makes two main contributions. First, it adds further contextual evidence of the benefits and challenges of incorporating TGM into other neophyte youth sports coaches’ practice. Second, it serves as a methodological template for further investigations into the micropedagogies of youth sport coaches’ practice when using GCAs such as the TGM.Este artículo presenta un estudio de investigación acción colaborativa en torno a la implementación del Modelo Táctico del Juego (TGM) llevada a cabo por un joven entrenador de fútbol. En dicho contexto, este trabajo trata de contribuir a llenar el vacío en la investigación relativa al uso, por parte de los entrenadores, de los Enfoques Centrados en el Juego (Game-Centered Approaches) y, en particular, del TGM. El estudio se desarrolló durante ocho sesiones de entrenamiento, de una hora de duración cada una, con un equipo competitivo de fútbol[1] de la categoría U12 (12 años). El joven entrenador de fútbol titulado, Ian, había entrado en contacto con el TGM en el curso de sus estudios universitarios de Educación Física. Los datos fueron recogidos mediante la observación de los estándares (benchmarks) del modelo en tres de las sesiones (la 2, 4 y 6), la realización de la Sesión de Análisis Reflexivo de la Enseñanza (Post-Session Teaching Reflective Analyses –PTRA–; Dyson, 1994) y mediante tres entrevistas semiestructuradas. Los datos de los estándares del modelo fueron analizados descriptivamente; para los de la PTRA y los de las entrevistas se utilizó el programa Lexminacer, que descompone los textos y genera categorías y conceptos. Los resultados mostraron que la fidelidad a los estándares del modelo mejoró a medida que el entrenador se familiarizaba con el TGM en el contexto del entrenamiento. Los principales conceptos generados por el Leximancer fueron: ‘jugadores’, ‘sesión’, ‘tiempo’, ‘juegos deportivos’ y ‘físico’. Esto sugiere un cambio importante en la práctica del entrenador en línea con las cuatro características de la pedagogía centrada en el juego propuestas por Light (2014). Dos son las contribuciones más importantes del presente estudio. Primero, aporta evidencias contextuales de los beneficios y retos que conlleva la aplicación del TGM por parte de los entrenadores neófitos en los deportes de jóvenes; y, segundo, puede ser útil como base metodológica de futuras investigaciones sobre las micro-pedagogías de los entrenadores de dichos deportes que utilizan Enfoques Centrados en el Juego, como el TGM. [1] “Travel soccer team”, en el original. En Estados Unidos, el adjetivo “travel”, aplicado a un deporte, indica un nivel competitivo superior al del deporte recreativo. (Nota del traductor

Risks to Hospitality Firms in the International Arena

Much potential for growth in hospitality firms exists in foreign countries, but expansion abroad typicality bears additional risks that could be detrimental to the operations. The authors explore those risks, currency exchange risk, and country risk, and offer practical techniques to access, manage, control, and reduce them. Deriving benefits from global opportunities requires effective management of these area

Localization of adaptive variants in human genomes using averaged one-dependence estimation.

Statistical methods for identifying adaptive mutations from population genetic data face several obstacles: assessing the significance of genomic outliers, integrating correlated measures of selection into one analytic framework, and distinguishing adaptive variants from hitchhiking neutral variants. Here, we introduce SWIF(r), a probabilistic method that detects selective sweeps by learning the distributions of multiple selection statistics under different evolutionary scenarios and calculating the posterior probability of a sweep at each genomic site. SWIF(r) is trained using simulations from a user-specified demographic model and explicitly models the joint distributions of selection statistics, thereby increasing its power to both identify regions undergoing sweeps and localize adaptive mutations. Using array and exome data from 45 ‡Khomani San hunter-gatherers of southern Africa, we identify an enrichment of adaptive signals in genes associated with metabolism and obesity. SWIF(r) provides a transparent probabilistic framework for localizing beneficial mutations that is extensible to a variety of evolutionary scenarios