Biology subjects

Vaughan, R.

Publications and source records attributed to Vaughan, R..

3 recordsLinked to original sources

bioRxiv2020

Brown Adipose Tissue is Associated with Improved Cardiometabolic Health and Regulates Blood Pressure

White fat stores excess energy, while brown and beige fat dissipate energy as heat1. These thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, though the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear2, 3, 4. Here, we categorized 139,224 18F-FDG PET/CT scans from 53,475 patients by presence or absence of BAT and used propensity score matching to assemble a study cohort. Individuals with BAT showed lower prevalences of cardiometabolic diseases. Additionally, BAT independently correlated with lower odds of type II diabetes, coronary artery disease and congestive heart failure. These findings were supported by improved glucose, triglyceride and high-density lipoprotein values. The effects of BAT were more pronounced in overweight and obesity, indicating that BAT can offset the deleterious effects of obesity. Strikingly, we also found lower rates of hypertension among patients with BAT. Studies in a mouse model with genetic ablation of beige fat demonstrated elevated blood pressure due to increased sensitivity to angiotensin II in peripheral resistance arteries. In addition to highlighting a role for BAT in promoting overall cardiometabolic health, this study reveals a new link between thermogenic adipose tissue and blood pressure regulation.

physiology↗

bioRxiv2019

Clinical severity in Fanconi anemia correlates with residual function of FANCB missense variants

Fanconi anemia (FA) is the most common genetic cause of bone marrow failure, and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry (IFAR). Those with FANCB deletion or truncation demonstrate earlier than average onset of bone marrow failure, and more severe congenital abnormalities compared to a large series of FA individuals in the published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization was associated with two missence variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays showed earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is linked to the extent of residual FANCD2 monoubiquitination.\n\nKEY POINTSO_LIX-linked FANCB pathogenic variants predominantly cause acute, early onset bone marrow failure and severe congenital abnormalities\nC_LIO_LIBiochemical and cell-based assays with patient variants reveal functional properties of FANCB that associate with clinical severity\nC_LI

molecular biology↗

bioRxiv2019

Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations

The integrin V{beta}3 receptor has been implicated in several important diseases, but no V{beta}3 antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit V{beta}3-mediated cell adhesion to V{beta}3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds demonstrated the favorable property of inhibiting bone resorption in vitro, supporting potential value in treating osteoporosis. Neither, however, had the unfavorable property of the V{beta}3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC50, which correlates with cilengitides enhancement of tumor growth in vivo.\n\nSignificance StatementV{beta}3 is a potential therapeutic target for several important human diseases, but there are currently no V{beta}3 antagonists approved for human therapy. Current candidates are primarily based on the Arg-Gly-Asp (RGD) motif and act as partial agonists in that they induce V{beta}3 to undergo a conformational change that converts it into a high-affinity ligand-binding state. We have used structure-guided design to produce pure small-molecule V{beta}3 antagonists that do not induce the conformational change as judged by protein crystallography, electron microscopy, and receptor priming. These compounds inhibit V{beta}3-mediated bone resorption in vitro, but unlike the partial agonist cilengitide, do not enhance angiogenesis at low doses, a property that correlates with low-dose cilengitides enhancement of tumor growth in vivo. These pure V{beta}3 antagonists can help define V{beta}3s role in animal models. If they demonstrate benefits over partial agonists in these model systems, they may be appropriate to consider for human therapy.

pharmacology and toxicology↗