Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. Conclusions: RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics

Untersuchungen zur Struktur und Dynamik von Einlagerungsverbindungen der Uebergangsmetalloxide MoO_3, h-WO_3 und WO_3.(H_2O)_1_/_3

SIGLEAvailable from TIB Hannover: MA 6407 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

An arena-based simulation of capacity planning in Stage I of the Voluntary Intermodal Sealift Agreement program

MBA Professional ReportThe Voluntary Intermodal Sealift Agreement (VISA) was established as an Emergency Preparedness Program on January 30, 1997 following the passage of the Maritime Security Act of 1996 that led to the subsequent establishment of the Maritime Security Program (MSP). VISA is complemented by MSP; which provides the Department of Defense (DOD) with assured access to 47 militarily useful U.S.-flag commercial vessels as a condition for receiving government incentives that include preference to peacetime shipping contracts and a $2.1 million subsidy per ship/year to help defray the cost of U.S. registry. Specifically, VISA augments the organic sealift capability of DOD during a contingency or national emergency by providing assured access to time-phased U.S.-flag commercial sealift capacity, mariners, global infrastructure and intermodal facilities. The objective of this thesis-project is to apply various shipping data relevant to VISA Stage I in an Arena-based simulation model. Specifically, the model will explore capacity-planning events as they may occur during a two major theater war scenario, as well as examine elements of variability and risk that may be inherent to VISA Stage I events.http://archive.org/details/anrenabasedsimul109459899Lieutenant Commander, United States NavyCommander, German NavyCivilian, South AfricaApproved for public release; distribution is unlimited

Periodic catatonia: confirmation of linkage to chromosome 15 and further evidence for genetic heterogeneity

We earlier reported significant evidence for linkage on chromosome 15q15 in periodic catatonia, a sub-phenotype of schizohrenic psychoses. The disorder is characteried by qualitative hyperkinetic and akinetic psychomotor disturbances through acute psychotic episodes and debilitating symptoms in the long term, with psychomotor weakness, grimacing facial movements and apathy. Here, we confirm mapping of a major gene locus on chromosome 15q15 in a second genome scan in a new set of four multiplex families. Non-parametric multipoint linkage analyses identified a broad region with a maximum peak of Zall =3.91 (P=0.006) and Zlr =3.04 at D15s1234 (P=0.001), satisfying conventional criteria for confirmed linkage. Parametric affected-only analyses under an autosomal dominant model gave a maximum HLOD score of 1.65 (D15S1234) with an estimated 47% of families being linked. Analysis of individuals families showed that one large family showed linkage, whereas two others could be clearly excluded, confirming genetic heterogeneity. No other locus reached suggestive levels of signifiance. Haplotype analysis on chromosome 15 in this and previously linked families placed the susceptibility region to a 11-cM interval between marker D15S1042 and D15S659. Periodic catatonia is the first sub-phenotype of schizophrenic psychoses with confirmed linkage despite the existence of considerable genetic heterogeneity

Mutations in RD3 are associated with an extremely rare and severe form of early onset retinal dystrophy

Purpose: To identify the underlying mutation and describe the phenotype in a consanguineous Kurdish family with Leber's congenital amaurosis (LCA)/early onset severe retinal dystrophy (EOSRD). Methods: Members of the index family were followed up to 22 years by ophthalmological examinations, including best corrected visual acuity (BCVA), Goldmann visual field (GVF), two-color-threshold perimetry (2CTP) and Ganzfeld electroretinogram (ERG), fundus photographs, fundus autofluorescence (FAF), and optical coherence tomography (OCT). After excluding seven of nine known LCA/EOSRD genes in the index patient, linkage analysis was performed in the family using a microarray followed by microsatellite fine mapping and direct sequencing of candidate genes. RD3 was screened by direct sequencing of 85 independent patients with LCA/EOSRD presenting with a BCVA ≥ 1.0 LogMAR before the age of 2 years to assess the prevalence of RD3 mutations in LCA/EOSRD. Since RD3 and RetGC1 have a functional relation, study authors screened for a modifying effect of RD3 mutations in 17 independent patients with mutations in GUCY2D. Results: BCVA was severely reduced from the earliest examinations (as early as 3 months), never exceeding 1.3 LogMAR. The disease presented as cone-rod dystrophy with dystrophic changes in the macula and bone spicules in the periphery on progression. Linkage analysis narrowed the region of interest towards the LCA12 locus. Direct sequencing of RD3 revealed a homozygous nonsense mutation (c.180C > A) in all affected members tested. Screening of additional unrelated LCA/EOSRD patients revealed only polymorphisms in RD3. Conclusions: This is the second family reported so far with mutations in RD3. Mutations in RD3 are a very rare cause of LCA associated with an extremely severe form of retinal dystrophy