Biology subjects

Harney, D. J.

Publications and source records attributed to Harney, D. J..

3 recordsLinked to original sources

bioRxiv2024

Genetic variance in the murine defensin locus modulates glucose homeostasis

Insulin resistance is a heritable risk factor for many chronic diseases; however, the genetic drivers remain elusive. In seeking these, we performed genetic mapping of insulin sensitivity in 670 chow-fed Diversity Outbred in Australia (DOz) mice and identified a genome-wide significant locus (QTL) on chromosome 8 encompassing 17 defensin genes. By taking a systems genetics approach, we ultimately identified alpha-defensin 26 (Defa26) as the causal gene in this region. To validate these findings, we synthesized Defa26 and performed diet supplementation experiments in two mouse strains with distinct endogenous Defa26 expression levels. In the strain with relatively lower endogenous expression (C57BL/6J) supplementation improved insulin sensitivity and reduced gut permeability, while in the strain with higher endogenous expression (A/J) it caused hypoinsulinemia, glucose intolerance and muscle wasting. Based on gut microbiome and plasma bile acid profiling this appeared to be the result of disrupted microbial bile acid metabolism. These data illustrate the danger of single strain over-reliance and provide the first evidence of a link between host-genetics and insulin sensitivity which is mediated by the microbiome.

systems biology↗

bioRxiv2023

Hepatic Lipid Droplet-Associated Proteome Changes Distinguish Dietary-Induced Fatty Liver from Insulin Resistance in Male Mice.

Fatty liver is characterised by the expansion of lipid droplets and is associated with the development of many metabolic diseases, including insulin resistance, dyslipidaemia and cardiovascular disease. We assessed the morphology of hepatic lipid droplets and performed quantitative proteomics in lean, glucose-tolerant mice compared to high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD and HStD-fed mice had more and larger lipid droplets than Chow-fed animals. We observed striking differences in liver lipid droplet proteomes of HFD and HStD-fed mice compared to Chow-fed mice, with fewer differences between HFD and HStD. Taking advantage of our diet strategy, we identified a fatty liver lipid droplet proteome consisting of proteins common in HFD- and HStD-fed mice. Likewise, a proteome associated with glucose tolerance that included proteins common in Chow and HStD but not HFD-fed mice was identified. Notably, glucose intolerance was associated with changes in the ratio of adipose triglyceride lipase (ATGL) to perilipin 5 (PLIN5) in the lipid droplet proteome, suggesting dysregulation of neutral lipid homeostasis in glucose-intolerant fatty liver, which supports bioactive lipid synthesis and impairs hepatic insulin action. We conclude that our novel dietary approach uncouples ectopic lipid burden from insulin resistance-associated changes in the hepatic lipid droplet proteome.

cell biology↗

bioRxiv2020

Selecting Student-Authored Questions for Summative Assessments

Production of high-quality multiple-choice questions (MCQs) for both formative and summative assessment is a time-consuming task requiring great skill, creativity, and insight. The transition to online examinations, with the concomitant exposure of previously tried-and-tested MCQs, exacerbates the challenges of question production, and highlights the need for innovative solutions. Several groups have shown that it is practical to leverage the student cohort to produce a very large number of syllabus-aligned MCQs for study banks. Although student-generated questions are well suited for formative feedback and practice activities, they are generally not thought to be suitable for high-stakes assessments. In this study, we aimed to demonstrate that training can be provided to students in a scalable fashion to generate questions of similar quality to those produced by experts, and that identification of suitable questions can be achieved with minimal academic review and editing. Biochemistry and Molecular Biology students were assigned a series of activities designed to coach them in the art of writing and critiquing MCQs. This training resulted in the production of over one thousand MCQs that were then gauged for potential by either expert academic judgement, or via a data-driven approach in which the questions were trialled objectively in a low-stakes test. Questions selected by either method were then deployed in a high-stakes in-semester assessment alongside questions from two academically authored sources: textbook-derived MCQs, and past paper questions. A total of 120 MCQs from these four sources were deployed in assessments attempted by over 600 students. Each question was subjected to rigorous performance analysis, including the calculation of standard metrics from classical test theory and more sophisticated Item Response Theory (IRT) measures. The results showed that MCQs authored by students and selected at low cost performed as well as questions authored by academics, illustrating the potential of this strategy for the efficient creation of large numbers of high quality MCQs for summative assessment.

scientific communication and education↗