Biology subjects

Corbin, L.

Publications and source records attributed to Corbin, L..

4 recordsLinked to original sources

bioRxiv2023

Temporal and spatial characterization of HIV/SIV infection at anorectal mucosa using rhesus macaque rectal challenge model

The study described herein is a continuation of our work in which we developed a methodology to identify small foci of transduced cells following rectal challenge of rhesus macaques with a non-replicative luciferase reporter virus. In the current study, the wild-type virus was added to the inoculation mix and twelve rhesus macaques were necropsied 2-4 days after the rectal challenge to study the changes in infected cell phenotype as the infection progressed. Relying on luciferase reporter we noted that both anus and rectum tissues are susceptible to the virus as early as 48h after the challenge. Small regions of the tissue containing luciferase-positive foci were further analyzed microscopically and were found to also contain cells infected by wild-type virus. Phenotypic analysis of the Env and Gag positive cells in these tissues revealed the virus can infect diverse cell populations, including but not limited to Th17 T cells, non Th17 T cells, immature dendritic cells, and myeloid-like cells. The proportions of the infected cell types, however, did not vary much during the first four days of infection when anus and rectum tissues were examined together. Nonetheless, when the same data was analyzed on a tissue-specific basis, we found significant changes in infected cell phenotypes over the course of infection. For anal tissue, a statistically significant increase in infection was observed for Th17 T cells and myeloid-like cells, while in the rectum, the non-Th17 T cells showed the biggest temporal increase, also of statistical significance. IMPORTANCEMen who have sex with men are at the highest risk of acquiring HIV via receptive anal intercourse. Understanding what sites are permissive to the virus, and what the early cellular targets are is critical for development of effective prevention strategies to control HIV acquisition amid receptive anal intercourse. Our work sheds light on the early HIV/SIV transmission events at the rectal mucosa by identifying the infected cells and highlights the distinct roles that different tissues play in virus acquisition and control.

immunology↗

bioRxiv2020

Modelling FtsZ nucleation, hydrolysis and treadmilling activity with Monte Carlo methods

Bacterial cell division is tightly coupled to the dynamic behavior of FtsZ, a tubulin homolog. Recent experimental work in vitro and in vivo has attributed FtsZs assembly dynamics to treadmilling, where subunits add to the bottom and dissociate from the top of protofilaments. However, the molecular mechanisms producing treadmilling have yet to be characterized and quantified. We have developed a Monte Carlo model for FtsZ assembly that explains treadmilling and assembly nucleation by the same mechanisms. A key element of the model is a conformational change from R (relaxed), which is highly favored for monomers, to T (tense), which is favored for subunits in a protofilament. This model was created in MATLAB. Kinetic parameters were converted to probabilities of execution during single, small time steps, and these were used to stochastically determine FtsZ dynamics. Our model is able to accurately describe the results of several in vitro and in vivo studies for a variety of FtsZ flavors. With standard conditions, the model FtsZ polymerized and produced protofilaments that treadmilled at 28 nm/s, hydrolyzed GTP at 2.8 to 4.2 GTP min-1 FtsZ-1, and had an average length of 25 to 54 subunits, all similar to experimental results. Adding a bottom capper resulted in shorter protofilaments and higher GTPase, similar to the effect of the known the bottom capper protein MciZ. The model could match nucleation kinetics of several flavors of FtsZ using the same parameters as treadmilling and varying only the R to T transition of monomers. SIGNIFICANCEFtsZ assembly dynamics are now known to be governed by treadmilling, where subunits add to the bottom and dissociate from the top of protofilaments. We have generated a Monte Carlo model of treadmilling based on (a) a conformational transition of FtsZ subunits between two states, and (b) stochastic GTP hydrolysis. Importantly, the nucleation of new protofilaments is explained by the same mechanisms as treadmilling. We have determined kinetic parameters that match a wide range of experimental data. The model is available to users for their own in silico experiments.

biophysics↗

bioRxiv2018

Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications.

Introductory paragraphThe inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.\n\nWe found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.

genetics↗

bioRxiv2017

Investigating the role of insulin in increased adiposity: Bi-directional Mendelian randomization study

Insulin may serve as a key causal agent which regulates fat accumulation in the body. Here we assessed the causal relationship between fasting insulin and adiposity using publicly-available results from two large-scale genome-wide association studies for body mass index and fasting insulin levels in a two-sample, bidirectional Mendelian Randomized approach. This approach is only valid on the condition that the two instruments are independent of one another. In analysis excluding overlapping loci, there was an increase of 0.20 (0.17, 0.23) log pmol/L fasting insulin per SD increase in BMI (P= 2.80 x 10-36), while there was a null effect of fasting insulin on BMI, with a 0.01 (-0.39, 0.38) SD decrease in BMI per log pmol/L increase in fasting insulin (P= 0.98). Furthermore, a high degree of heterogeneity in the causal estimates was obtained from the insulin-related variants, which may be attributed to varying mechanisms of action of the insulin-associated variants. Results were largely consistent when an Egger regression technique and weighted median and mode estimators were applied. Findings suggest that the positive correlation between adiposity and fasting insulin levels are at least in part explained by the causal effect of adiposity on increasing insulin, rather than vice versa.

epidemiology↗