Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10-81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10-8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies. © 2011 Wijsman et al

New onshore insights into the role of structural inheritance during Mesozoic opening of the Inner Moray Firth Basin, Scotland

The Inner Moray Firth Basin (IMFB) forms the western arm of the North Sea trilete rift system that initiated mainly during the Late Jurassic–Early Cretaceous with the widespread development of major NE–SW-trending dip-slip growth faults. The IMFB is superimposed over the southern part of the older Devonian Orcadian Basin. The potential influence of older rift-related faults on the kinematics of later Mesozoic basin opening has received little attention, partly owing to the poor resolution of offshore seismic reflection data at depth. New field observations augmented by drone photography and photogrammetry, coupled with U–Pb geochronology, have been used to explore the kinematic history of faulting in onshore exposures along the southern IMFB margin. Dip-slip north–south- to NNE–SSW-striking Devonian growth faults are recognized that have undergone later dextral reactivation during NNW–SSE extension. The U–Pb calcite dating of a sample from the synkinematic calcite veins associated with this later episode shows that the age of fault reactivation is 130.99  ±  4.60 Ma (Hauterivian). The recognition of dextral-oblique Early Cretaceous reactivation of faults related to the underlying and older Orcadian Basin highlights the importance of structural inheritance in controlling basin- to sub-basin-scale architectures and how this influences the kinematics of IMFB rifting

Experimental application to a water delivery canal of a distributed MPC with stability constraints

In this work, a novel distributed MPC algorithm, denoted D-SIORHC, is applied to upstream local control of a pilot water delivery canal. The D-SIORHC algorithm is based on MPC control agents that incorporate stability constraints and communicate only with their adjacent neighbors in order to achieve a coordinated action. Experimental results that show the effect of the parameters configuring the local controllers are presented

New onshore insights into the role of structural inheritance during Mesozoic opening of the Inner Moray Firth Basin, Scotland

The Inner Moray Firth Basin (IMFB) forms the western arm of the North Sea trilete rift system that initiated mainly during the Late Jurassic–Early Cretaceous with the widespread development of major NE–SW-trending dip-slip growth faults. The IMFB is superimposed over the southern part of the older Devonian Orcadian Basin. The potential influence of older rift-related faults on the kinematics of later Mesozoic basin opening has received little attention, partly owing to the poor resolution of offshore seismic reflection data at depth. New field observations augmented by drone photography and photogrammetry, coupled with U–Pb geochronology, have been used to explore the kinematic history of faulting in onshore exposures along the southern IMFB margin. Dip-slip north–south- to NNE–SSW-striking Devonian growth faults are recognized that have undergone later dextral reactivation during NNW–SSE extension. The U–Pb calcite dating of a sample from the synkinematic calcite veins associated with this later episode shows that the age of fault reactivation is 130.99  ±  4.60 Ma (Hauterivian). The recognition of dextral-oblique Early Cretaceous reactivation of faults related to the underlying and older Orcadian Basin highlights the importance of structural inheritance in controlling basin- to sub-basin-scale architectures and how this influences the kinematics of IMFB rifting

The potential of trading activity income to fund third sector organisations operating in deprived areas

In the United Kingdom, as in other countries, Third Sector Organisations (TSOs) have been drawn towards income sources associated with trading activities (Teasdale, 2010), but many remain reliant on grant funding to support such activities (Chell, 2007). Using a multivariate analysis approach and data from the National Survey of Charities and Social Enterprises (NSCSE), it is found that trading activities are used relatively commonly in deprived areas. These organisations are also more likely to attempt to access public sector funds. This suggests policy-makers need to consider the impact of funding cuts on TSOs in the most deprived areas as TSOs are unlikely achieve their objectives without continuing support