184 research outputs found

    Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

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    The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn’s disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease

    Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity

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    The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain. This model is consistent with many of the biological aspects of energy balance, but struggles to explain the many significant environmental and social influences on obesity, food intake and physical activity. More importantly, the set point model does not effectively explain the ‘obesity epidemic' - the large increase in body weight and adiposity of a large proportion of individuals in many countries since the 1980s. An alternative model, called the settling point model, is based on the idea that there is passive feedback between the size of the body stores and aspects of expenditure. This model accommodates many of the social and environmental characteristics of energy balance, but struggles to explain some of the biological and genetic aspects. The shortcomings of these two models reflect their failure to address the gene-by-environment interactions that dominate the regulation of body weight. We discuss two additional models - the general intake model and the dual intervention point model - that address this issue and might offer better ways to understand how body fatness is controlled

    Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

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    Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

    Understanding political responsibility in corporate citizenship: towards a shared responsibility for the common good

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    In this article, we explore the debate on corporate citizenship and the role of business in global governance. In the debate on political corporate social responsibility it is assumed that under globalization business is taking up a greater political role. Apart from economic responsibilities firms assume political responsibilities taking up traditional governmental tasks such as regulation of business and provision of public goods. We contrast this with a subsidiarity-based approach to governance, in which firms are seen as intermediate actors who have political co-responsibilities in society endowed upon them by (inter)national governmental institutions. We argue that both approaches face conceptual and empirical problems, and do not make clear the content and scope of political corporate responsibility. Based on Iris Marion Young’s account of political responsibility we argue that corporate actors and governmental actors have a shared responsibility to tackle societal problems. Taking political corporate responsibility not only entails engaging in private action or engaging in public–private partnerships, but it also includes aiding governmental actors to remedy injustice or even create public institutions where they do not yet exist. By adding this perspective we contribute to the debate on responsibility in corporate citizenship and clarify the political role business can play in global governance.</p

    Stratosphere‐troposphere coupling and annular mode variability in chemistry‐climate models

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    The internal variability and coupling between the stratosphere and troposphere in CCMVal‐2 chemistry‐climate models are evaluated through analysis of the annular mode patterns of variability. Computation of the annular modes in long data sets with secular trends requires refinement of the standard definition of the annular mode, and a more robust procedure that allows for slowly varying trends is established and verified. The spatial and temporal structure of the models’ annular modes is then compared with that of reanalyses. As a whole, the models capture the key features of observed intraseasonal variability, including the sharp vertical gradients in structure between stratosphere and troposphere, the asymmetries in the seasonal cycle between the Northern and Southern hemispheres, and the coupling between the polar stratospheric vortices and tropospheric midlatitude jets. It is also found that the annular mode variability changes little in time throughout simulations of the 21st century. There are, however, both common biases and significant differences in performance in the models. In the troposphere, the annular mode in models is generally too persistent, particularly in the Southern Hemisphere summer, a bias similar to that found in CMIP3 coupled climate models. In the stratosphere, the periods of peak variance and coupling with the troposphere are delayed by about a month in both hemispheres. The relationship between increased variability of the stratosphere and increased persistence in the troposphere suggests that some tropospheric biases may be related to stratospheric biases and that a well‐simulated stratosphere can improve simulation of tropospheric intraseasonal variability

    Children must be protected from the tobacco industry's marketing tactics.

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