Molecular mechanisms underlying cerebral small vessel disease associated with mutations in COL4A1

Cerebral small vessel diseases (cSVDs) are the leading cause of stroke and vascular dementia, but the underlying pathogenic mechanisms are unknown. Humans and mice with autosomal dominant mutations in the collagen-encoding gene COL4A1 present with brain pathology that typifies cSVD. Data in this thesis reveals divergent pathogenic mechanisms in two Col4a1 mutant mouse models and offers viable therapeutic strategies for treating related cSVDs. Col4a1G1344D cSVD was associated with the loss of myogenic tone due to blunted pressure-induced smooth muscle cell (SMC) depolarization. Dysregulation of membrane potential was linked to impaired Ca2+-dependent activation of transient receptor potential melastatin 4 (TRPM4) channels caused by disruption in sarcoplasmic reticulum (SR) Ca2+ signaling. Deficits were prevented by treating mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins from the SR, suggesting accumulation of mutant collagen in the SR contributes to the pathogenesis. The fundamental defect in Col4a1G394V cSVD was the depletion of phosphatidylinositol 4,5 bisphosphate (PIP2), a necessary cofactor for TRPM4 and inwardly-rectifying K+ (KIR) channels, in vascular SMCs and endothelial cells. This caused a loss of myogenic tone and neurovascular coupling contributing to cSVD. PIP2 depletion was linked to increased phosphoinositide 3-kinase (PI3K) activity acting downstream of transforming growth factor-beta (TGF-β) receptors. Restoring PIP2 by blocking PI3K or TGF-β receptors restored myogenic tone, neurovascular coupling, and memory function. Differences in pathogenic mechanisms between mutations within the same gene highlight the diverse causes and the need for specific treatments of cSVDs

A search for optical transients associated with fast radio burst 150418†‡

We have searched for optical variability in the host galaxy of the radio variable source possibly associated with fast radio burst (FRB) 150418. We compare images of the galaxy taken 1 day after the burst using Subaru/Suprime-Cam with images taken ∼1 yr after the burst using Gemini-South/GMOS. No optical variability is found between the two epochs with a limiting absolute magnitude ≳ -19 (AB). This limit applies to the optical variability of the putative active galactic nucleus in the galaxy on a timescale of ∼1 yr, and also to the luminosity of an optical counterpart of FRB 150418 one day after the burst should it have occurred in this galaxy

Computational Models of Stellar Collapse and Core-Collapse Supernovae

Core-collapse supernovae are among Nature's most energetic events. They mark the end of massive star evolution and pollute the interstellar medium with the life-enabling ashes of thermonuclear burning. Despite their importance for the evolution of galaxies and life in the universe, the details of the core-collapse supernova explosion mechanism remain in the dark and pose a daunting computational challenge. We outline the multi-dimensional, multi-scale, and multi-physics nature of the core-collapse supernova problem and discuss computational strategies and requirements for its solution. Specifically, we highlight the axisymmetric (2D) radiation-MHD code VULCAN/2D and present results obtained from the first full-2D angle-dependent neutrino radiation-hydrodynamics simulations of the post-core-bounce supernova evolution. We then go on to discuss the new code Zelmani which is based on the open-source HPC Cactus framework and provides a scalable AMR approach for 3D fully general-relativistic modeling of stellar collapse, core-collapse supernovae and black hole formation on current and future massively-parallel HPC systems. We show Zelmani's scaling properties to more than 16,000 compute cores and discuss first 3D general-relativistic core-collapse results.Comment: 16 pages, 5 figures, to appear in the proceedings of the DOE/SciDAC 2009 conference. A version with high-resolution figures is available from http://stellarcollapse.org/papers/Ott_SciDAC2009.pd

A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (praw = 2.3×10−6, pgenome = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p<0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation