Peroxisome Proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR) is a master regulator of fatty acid catabolism, and PPAR activators delay the onset of type 2 diabetes. We examined association between three PPAR gene polymorphisms (an AC variant in intron 1, the L162V variant, and the intron 7 GC variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPAR gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 AC (P < 0.001) and intron 7 GC (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPAR haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis 45 years) of 3.75 (95% CI 1.65–8.56, P = 0.002). Intron 1 C-allele carriers also progressed more rapidly to insulin monotherapy (AA 9.4 ± 1.5 and AC + CC 5.3 ± 1.1 years, P = 0.002). These data indicate that PPAR gene variation influences the onset and progression of type 2 diabetes

Moving boulders in flash floods and estimating flow conditions using boulders in ancient deposits

Boulders moving in flash floods cause considerable damage and casualties. More and bigger boulders move in flash floods than predicted from published theory. The interpretation of flow conditions from the size of large particles within flash flood deposits has, until now, generally assumed that the velocity (or discharge) is unchanging in time (i.e. flow is steady), or changes instantaneously between periods of constant conditions. Standard practice is to apply theories developed for steady flow conditions to flash floods, which are however inherently very unsteady flows. This is likely to lead to overestimates of peak flow velocity (or discharge). Flash floods are characterised by extremely rapid variations in flow that generate significant transient forces in addition to the mean-flow drag. These transient forces, generated by rapid velocity changes, are generally ignored in published theories, but they are briefly so large that they could initiate the motion of boulders. This paper develops a theory for the initiation of boulder movement due to the additional impulsive force generated by unsteady flow, and discusses the implications. Keywords

Mission Concept for the Single Aperture Far-Infrared (SAFIR) Observatory

The Single Aperture Far-InfraRed (SAFIR) Observatory's science goals are driven by the fact that the earliest stages of almost all phenomena in the universe are shrouded in absorption by and emission from cool dust and gas that emits strongly in the far-infrared and submillimeter. Over the past several years, there has been an increasing recognition of the critical importance of this spectral region to addressing fundamental astrophysical problems, ranging from cosmological questions to understanding how our own Solar System came into being. The development of large, far-infrared telescopes in space has become more feasible with the combination of developments for the James Webb Space Telescope and of enabling breakthroughs in detector technology. We have developed a preliminary but comprehensive mission concept for SAFIR, as a 10 m-class far-infrared and submillimeter observatory that would begin development later in this decade to meet the needs outlined above. Its operating temperature (<4K) and instrument complement would be optimized to reach the natural sky confusion limit in the far-infrared with diffraction-limited peformance down to at least 40 microns. This would provide a point source sensitivity improvement of several orders of magnitude over that of Spitzer or Herschel, with finer angular resolution, enabling imaging and spectroscopic studies of individual galaxies in the early universe. We have considered many aspects of the SAFIR mission, including the telescope technology, detector needs and technologies, cooling method and required technology developments, attitude and pointing, power systems, launch vehicle, and mission operations. The most challenging requirements for this mission are operating temperature and aperture size of the telescope, and the development of detector arrays.Comment: 36 page

Photon-axion conversion in intergalactic magnetic fields and cosmological consequences

Photon-axion conversion induced by intergalactic magnetic fields causes an apparent dimming of distant sources, notably of cosmic standard candles such as supernovae of type Ia (SNe Ia). We review the impact of this mechanism on the luminosity-redshift relation of SNe Ia, on the dispersion of quasar spectra, and on the spectrum of the cosmic microwave background. The original idea of explaining the apparent dimming of distant SNe Ia without cosmic acceleration is strongly constrained by these arguments. However, the cosmic equation of state extracted from the SN Ia luminosity-redshift relation remains sensitive to this mechanism. For example, it can mimic phantom energy.Comment: (14 pages, 9 eps figures) Contribution to appear in a volume of Lecture Notes in Physics (Springer-Verlag) on Axion

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness