The role of flightless protein in hypertrophic scarring and its potential as a target for a novel therapy

Hypertrophic scarring is a poorly understood condition which affects the lives of millions of people around the world annually. Despite its common occurrence following burn injury, trauma or surgery the present treatments are of limited efficacy. Research over the past decade in the Cowin laboratory has identified Flightless (Flii), a highly conserved cytoskeletal protein, as a negative regulator of wound healing. Wounding leads to an increased expression of Flii, while Flii has been shown to inhibit cellular migration and proliferation. Reducing Flii in vivo leads to improved wound healing. The aim of this study was to investigate the role of Flii in the fibroproliferative process underlying hypertrophic scarring. Chapter three shows for the first time that Flii expression in increased in human burn and hypertrophic scar tissue. Chapter four details the development of a novel murine model of hypertrophic scarring. Previous animal models have focused on reproducing the clinical characteristics of the human hypertrophic scar, which often required significant derangement of the animal immune response. The novel model used bleomycin to stimulate the fibroproliferative process that underlies hypertrophic scarring. Results in this chapter use histology and immunohistochemistry to verify the bleomycin model as a valid model of hypertrophic scarring. Chapter five uses the bleomycin mode to demonstrate that Flii is a key determinant of the extent of fibroproliferation that underlies hypertrophic scarring. Increasing Flii genetically in this animal model leads to increased dermal thickening and increases in key determinants of hypertrophic scarring, such as myofibroblasts, transforming growth factorβ-1 (TGFβ-1) and scar collagen composition. Decreasing Flii genetically causes a reduction in hypertrophic scarring using the same measures. Decreasing Flii using a monoclonal antibody therapy in the bleomycin model also led to a reduction in hypertrophic scarring, confirming Flii as a potential target for a novel therapy for hypertrophic scarring. Chapter six investigates potential mechanisms for the findings observed in previous chapters by using in vivo techniques. Focusing on the fibroblast, the key cell type in fibroproliferation, immunocytochemistry and cell migration assays, were used to show that decreasing Flii genetically or using a monoclonal antibody, reverses the fibroblast-myofibroblast phenotypic change that characterizes fibroproliferartive pathology. Flii appears to be a key determinant of the fibroproliferative process underlying hypertrophic scarring. This study uses human tissue, a novel small animal model and in vivo techniques to demonstrate this and identify Flii as a potential target for a novel therapy to reduce or prevent hypertrophic scarring.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011

Stellar models simulating the disk-locking mechanism and the evolutionary history of the Orion Nebula cluster and NGC 2264

Rotational evolution in young stars is described by pMS evolutionary tracks including rotation, conservation of angular momentum (AM), and simulations of disk-locking (DL). By assuming that DL is the regulation mechanism for the stellar angular velocity during the early stages of pMS, we use our models and observational data to constrain disk lifetimes (Tdisk) of a sample of low-mass stars in the ONC and NGC2264. The period distributions of the ONC and NGC2264 are bimodal and depend on the stellar mass. To follow the rotational evolution of these two clusters' stars, we generated some sets of evolutionary tracks. We assumed that the evolution of fast rotators can be modeled by considering conservation of AM during all stages and of moderate rotators by considering conservation of angular velocity during the first stages of evolution. With these models we estimate a mass and an age for all stars. For the ONC, we assume that the secondary peak in the period distribution is due to high-mass objects locked in their disks, with a locking period (Plock) of ~8 days. For NGC2264 we make two hypotheses: (1) the stars in the secondary peak are locked with Plock=5 days, and (2) NGC2264 is in a later stage in the rotational evolution (this implies in a DL scenario with Plock=8 days, a Tdisk of 1 Myr and, after that, constant AM evolution). We simulated the period distribution of NGC2264 when its mean age was 1 Myr. Dichotomy and bimodality appear in the simulated distribution, presenting one peak at 2 days and another one at 5-7 days, indicating that the assumption of Plock=8 days is plausible. Our hypotheses are compared with observational disk diagnoses available in the literature. DL models with Plock=8 days and 0.2 Myr<=Tdisk<=3 Myr are consistent with observed periods of moderate rotators of the ONC. For NGC2264, hyphotesis 2 is the more promising explanation for its period distribution.Comment: 20 pages and 24 figure

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes.</p