Biology subjects

Harris, D. A.

Publications and source records attributed to Harris, D. A..

3 recordsLinked to original sources

bioRxiv2019

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits

Inherited genetic variants in tumour suppressors and oncogenes can increase the cancer risk, but little is known about their influence on anthropometric traits. Through the integration of inherited and somatic cancer genetic data, we define functional single nucleotide polymorphisms (SNPs) associated with cancer risk and explore potential pleiotropic associations with anthropometic traits in a cohort of 500,000 individuals. We identify three regulatory SNPs for three important cancer genes that associate with both anthropometric traits and cancer risk. We describe a novel association of a SNP in TP53 (rs78378222) with height, lean body mass measures and basal metabolic rate, as well as validating its known associations with brain and non-melanomatous skin cancer susceptibility. Our results clearly demonstrate that heritable variants in key cancer genes can associate with both differential cancer risk and anthropometric traits in the general population, thereby lending support for a role of genetics in linking these human phenotypes.

genetics↗

bioRxiv2019

Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

Oligomeric forms of amyloid-{beta} (A{beta}) peptide are known to be the primary neurotoxic species in Alzheimers disease (AD), but how they interact with neurons to produce their deleterious effects is unclear. Over ten different cell-surface receptors for A{beta} have been described, but their molecular interactions with A{beta} assemblies and their relative contributions to mediating AD pathology have remained uncertain. In the present work, we have used super-resolution microscopy to directly visualize A{beta}-receptor interactions at the nanometer scale. We report that one documented A{beta} receptor, the cellular prion protein, PrPC, specifically inhibits the polymerization A{beta} fibrils via a unique mechanism in which it binds specifically to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other candidate A{beta} receptors, Fc{gamma}RIIb and LilrB2, affect A{beta} fibril growth in a manner similar to PrPC. Taken together, our results suggest that neurotoxic signaling by several different receptors may be activated by common molecular interactions with both fibrillar and oligomeric A{beta} ligands. Targeting such interactions with small molecules represents an attractive therapeutic strategy for treatment of AD.

neuroscience↗

bioRxiv2019

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

ObjectiveSleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements.\n\nMethodsNon-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis.\n\nResultsIn this model, SG induced durable improvements in glucose tolerance despite not causing lasting changes in weight, fat/lean mass, or food intake. Indirect calorimetry revealed post-SG animals had respiratory exchange ratios (RER) nearing 1.0 on average and had daily RER excursions above 1.0, indicating preferential glucose utilization and increased energy demand, respectively. Sham operated mice demonstrate normal RER feeding/fasting excursions. PET/CT showed increased avidity within white adipose depots. Finally, SG led to an upregulation in the transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation within the visceral adipose tissue.\n\nConclusionsSG induces a rapid, weight-loss independent shift towards glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue.

physiology↗