Five blood pressure loci identified by an updated genome-wide linkage scan: meta-analysis of the Family Blood Pressure Program.

BACKGROUND: A preliminary genome-wide linkage analysis of blood pressure in the Family Blood Pressure Program (FBPP) was reported previously. We harnessed the power and ethnic diversity of the final pooled FBPP dataset to identify novel loci for blood pressure thereby enhancing localization of genes containing less common variants with large effects on blood pressure levels and hypertension. METHODS: We performed one overall and 4 race-specific meta-analyses of genome-wide blood pressure linkage scans using data on 4,226 African-American, 2,154 Asian, 4,229 Caucasian, and 2,435 Mexican-American participants (total N = 13,044). Variance components models were fit to measured (raw) blood pressure levels and two types of antihypertensive medication adjusted blood pressure phenotypes within each of 10 subgroups defined by race and network. A modified Fisher's method was used to combine the P values for each linkage marker across the 10 subgroups. RESULTS: Five quantitative trait loci (QTLs) were detected on chromosomes 6p22.3, 8q23.1, 20q13.12, 21q21.1, and 21q21.3 based on significant linkage evidence (defined by logarithm of odds (lod) score ≥3) in at least one meta-analysis and lod scores ≥1 in at least 2 subgroups defined by network and race. The chromosome 8q23.1 locus was supported by Asian-, Caucasian-, and Mexican-American-specific meta-analyses. CONCLUSIONS: The new QTLs reported justify new candidate gene studies. They may help support results from genome-wide association studies (GWAS) that fall in these QTL regions but fail to achieve the genome-wide significance

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Searches for electroweak neutralino and chargino production in channels with Higgs, Z, and W bosons in pp collisions at 8 TeV

Searches for supersymmetry (SUSY) are presented based on the electroweak pair production of neutralinos and charginos, leading to decay channels with Higgs, Z, and W bosons and undetected lightest SUSY particles (LSPs). The data sample corresponds to an integrated luminosity of about 19.5 fb(-1) of proton-proton collisions at a center-of-mass energy of 8 TeV collected in 2012 with the CMS detector at the LHC. The main emphasis is neutralino pair production in which each neutralino decays either to a Higgs boson (h) and an LSP or to a Z boson and an LSP, leading to hh, hZ, and ZZ states with missing transverse energy (E-T(miss)). A second aspect is chargino-neutralino pair production, leading to hW states with E-T(miss). The decays of a Higgs boson to a bottom-quark pair, to a photon pair, and to final states with leptons are considered in conjunction with hadronic and leptonic decay modes of the Z and W bosons. No evidence is found for supersymmetric particles, and 95% confidence level upper limits are evaluated for the respective pair production cross sections and for neutralino and chargino mass values

A simple approximation for a moving interface in a coastal aquifer

An approximate analytical solution for a moving interface in a confined coastal aquifer is found by solving a nonlinear first-order partial differential equation. The solution, which assumes that flow approaching the interface changes discontinuously with time from one constant value to another, coincides with exact steady-flow solutions obtained from the Dupuit approximation at both t = 0 and t = ∞. A comparison with numerical solutions suggests that maximum errors of about ten percent occur in the toe location for intermediate values of time and that the approximate solution tends to overestimate both the rate of advance and retreat of the toe. The approximation has a very simple form and, in contrast to numerical solutions, is easy to evaluate. Additional comparisons with numerical solutions also suggest that the analytical approximation can be applied with confidence to an unconfined flow only when the sudden change in approaching flow rate occurs at distances from the interface toe that are not too great. This is because free-surface storage effects slow the movement of the flow rate change before its effects are eventually felt downstream at the interface toe

Resource Advantage Theory and Fair Trade Social Enterprises

This paper will investigate the competitive position of both fair trade (FT) social enterprises Divine Chocolate Ltd (Divine) and Cafédirect in their respective UK markets, namely chocolate confectionery and hot beverages. Using Eisenhardt’s (1989, 1991, and 2007) approach to building theory from multiple case studies, this four-year PhD study aims to identify the resources that enable FT social enterprises to compete. This research draws on recent developments in competition theory such as resource advantage theory (R-A theory), termed a general theory of competition. The paper will critically analyse if the social and ethical elements of these firm’s product offerings really constitute meaningful differentiators (i.e. comparative advantage) as required by R-A theory (Hunt and Morgan 1995, Hunt 2001). Hunt and Derozier (2004) argue that R-A theory can ground theories of business and marketing strategy and therefore identifying the competitive resources of FT social enterprises will have important strategic implications. The research findings show that both Divine and Cafédirect have established a mainstream competitive position in specific product segments and distribution channels. Thus illustrating intra-industry demand to be heterogeneous. In addition, both companies have been a catalyst for change by influencing the strategies and policies of both branded manufactures and retailers such as Cooperative Food (CF). The key theoretical contribution validates ‘social resources’ and its three inter-related components: ethical and social commitments, connections with partners and consistency of behaviour as a resource to extend R-A theory. These ‘social resources’ in combination with both relational resources and threshold capabilities (e.g. product quality) result in a competitive position for both case organisations. The ethical and social commitments of ‘social resources’ also appears to provide an example of an ethical underpinning to Relationship Marketing. The identification of ‘social resources’ has important wider implications for both other social enterprises and those companies who are aiming to achieve a competitive position based on social commitments

Annual research review: Developmental computational psychiatry

Most psychiatric disorders emerge during childhood and adolescence. This is also a period that coincides with the brain undergoing substantial growth and reorganisation. However, it remains unclear how a heightened vulnerability to psychiatric disorder relates to this brain maturation. Here, we propose ‘developmental computational psychiatry’ as a framework for linking brain maturation to cognitive development. We argue that through modelling some of the brain's fundamental cognitive computations, and relating them to brain development, we can bridge the gap between brain and cognitive development. This in turn can lead to a richer understanding of the ontogeny of psychiatric disorders. We illustrate this perspective with examples from reinforcement learning and dopamine function. Specifically, we show how computational modelling deepens an understanding of how cognitive processes, such as reward learning, effort learning, and social learning might go awry in psychiatric disorders. Finally, we sketch the promises and limitations of a developmental computational psychiatry