A biochemical and ultrastructural evaluation of the type 2 Gaucher mouse

Gaucher mice, created by targeted disruption of the glucocerebrosidase gene, are totally deficient in glucocerebrosidase and have a rapidly deteriorating clinical course analogous to the most severely affected type 2 human patients. An ultrastructural study of tissues from these mice revealed glucocerebroside accumulation in bone marrow, liver, spleen, and brain. This glycolipid had a characteristic elongated tubular structure and was contained in lysosomes, as demonstrated by colocalization with both ingested carbon particles and cathepsin D. In the central nervous system (CNS), glucocerebroside was diffusely stored in microglia cells and in brainstem and spinal cord neurons, but not in neurons of the cerebellum or cerebral cortex. This rostralcaudal pattern of neuronal lipid storage in these Gaucher mice replicates the pattern seen in type 2 human Gaucher patients and clearly demonstrates that glycosphingolipid catabolism and/or accumulation varies within different brain regions. Surprisingly, the cellular pathology of tissue from these Gaucher mice was relatively mild, and suggests that the early and rapid demise of both Gaucher mice and severely affected type 2 human neonates may be the result of both a neurotoxic metabolite, such as glucosylsphingosine, and other factors, such as skin water barrier dysfunction secondary to the absence of glucocerebrosidase activity

Crossover from two- to three-dimensional critical behavior for nearly antiferromagnetic itinerant electrons

The crossover from two- to three-dimensional critical behavior of nearly antiferromagnetic itinerant electrons is studied in a regime where the inter-plane single-particle motion of electrons is quantum-mechanically incoherent because of thermal fluctuations. This is a relevant regime for very anisotropic materials like the cuprates. The problem is studied within the Two-Particle Self-Consistent approach (TPSC), that has been previously shown to give a quantitative description of Monte Carlo data for the Hubbard model. It is shown that TPSC belongs to the $n\rightarrow \infty$ limit of the $O\left( n\right)$ universality class. However, contrary to the usual approaches, cutoffs appear naturally in the microscopic TPSC theory so that parameter-free calculations can be done for Hubbard models with arbitrary band structure. A general discussion of universality in the renormalized-classical crossover from $d=2$ to $d=3$ is also given.Comment: Revtex, 23 pages + 6 postcript figures (with epsfile

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

Timescales for pluton growth, magma-chamber formation and super-eruptions

Generation of silicic magmas leads to emplacement of granite plutons, huge explosive volcanic eruptions and physical and chemical zoning of continental and arc crust1,2,3,4,5,6,7. Whereas timescales for silicic magma generation in the deep and middle crust are prolonged8, magma transfer into the upper crust followed by eruption is episodic and can be rapid9,10,11,12. Ages of inherited zircons and sanidines from four Miocene ignimbrites in the Central Andes indicate a gap of 4.6 Myr between initiation of pluton emplacement and onset of super-eruptions, with a 1-Myr cyclicity. We show that inherited zircons and sanidine crystals were stored at temperatures <470 °C in these plutons before incorporation in ignimbrite magmas. Our observations can be explained by silicic melt segregation in a middle-crustal hot zone with episodic melt ascent from an unstable layer at the top of the zone with a timescale governed by the rheology of the upper crust. After thermal incubation of growing plutons, large upper-crustal magma chambers can form in a few thousand years or less by dike transport from the hot-zone melt layer. Instability and disruption of earlier plutonic rock occurred in a few decades or less just before or during super-eruptions

Kindergarten children’s genetic vulnerabilities interact with friends’ aggression to promote children’s own aggression

OBJECTIVE: To examine whether kindergarten children's genetic liability to physically aggress moderates the contribution of friends' aggression to their aggressive behaviors. METHOD: Teacher and peer reports of aggression were available for 359 6-year-old twin pairs (145 MZ, 212 DZ) as well as teacher and peer reports of aggression of the two best friends of each twin. Children's genetic risk for aggression was based on their cotwin's aggression status and the pair's zygosity. RESULTS: Children's aggression was highly heritable. Unique environment accounted for most of the variance in friends' aggression, although there was also a small genetic contribution (15%). Both genetic liability to aggression and having aggressive friends predicted twins' aggression. However, the contribution of aggressive friends to children's aggression was strongest among genetically vulnerable children. This result was similar for boys and girls, despite sex differences in both aggression and the level of aggression of friends. CONCLUSIONS: Affiliation with aggressive friends at school entry is a significant environmental risk factor for aggression, especially for children genetically at risk for aggressive behaviors. Developmental models of aggression need to take into account both genetic liability and environmental factors in multiple settings, such as the peer context, to more precisely describe and understand the various developmental pathways to aggression. The implications for early prevention programs are discussed. Copyright 2007 © American Academy of Child and Adolescent Psychiatry