New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Ockham on being

This chapter has two aims. The first aim is to present an overview of Bolzano's universe from the point of view of his metaphysics and its relationship to logic, relying fundamentally on Bolzano's Wissenschaftslehre. The author's preferred reading of Bolzano is one according to which he is a 'platonistic nominalist': a platonist about propositions and a nominalist about properties. Bolzano's nominalistic tendencies are particularly conspicuous in his mereological analyses, which play a major role in every aspect of his philosophy. The author's second aim is to answer the open question of whether in Bolzano there is any 'ontology of truth'. This chapter argues for a negative answer. Bolzano does not make room for any special object which plays the role of the counterpart of a truth-bearer, or at least his propositions do not connect semantically in a direct way to anything that would count as such a special object

Microstructural changes in DLC films due to tribological contact

The hydrogenated (a-C:H) and hydrogen free (ta-C) films were tested in sliding wear tests. The tests were carried out in air at room temperature (RH 1565%). The coefficient of friction in the tests was in the range 0.03 x 0.12 for the a-C:H films and 0.17 x 0.28 for the ta-C films. The wear volume of the DLC films was sufficiently low to enable the direct comparison of the film properties of the worn film to the original film. The microstructure of the films after wear tests has been characterized by micro RAMAN, the mechanical properties were measured by nano indentation and the elastic modulus was measured with the laser-acoustic method. No change of the micro structure of the DLC films was observed. The observed reduction of the elastic modulus of the ta-C film is explained by the evolution of mechanical defects such as micro-cracks and cracking at the nodular defects typical in non filtered vacuum arc depositions

Electronic properties and quantum transport in Graphene-based nanostructures

61.46.-w Structure of nanoscale materials, 73.63.-b Electronic transport in nanoscale materials and structures,