Biology subjects

Hardy, K.

Publications and source records attributed to Hardy, K..

8 recordsLinked to original sources

bioRxiv2026

Beyond single-trait analysis: ancient genomes reveal coordinated evolution of dietary endophenotypes in Holocene Europe

Diet has been a major selective force throughout human evolution, yet dietary adaptation is often studied through individual loci rather than as interconnected systems of traits. Here, we integrated genome-wide association data for 58 diet-related phenotypes with genomes from 938 ancient Europeans spanning the last 10,000 years to reconstruct the evolution of dietary endophenotypes. We identified four major systems encompassing adiposity and metabolism, body composition, fatty-acid metabolism and food-related behaviours. Multiple endophenotypes showed significant temporal shifts during the Holocene departing from the expected under neutrality, including coordinated decreases in genetic architectures associated with adiposity, insulin regulation and lipid metabolism, alongside increases in traits related to docosahexaenoic acid metabolism. Moreover, these patterns showed marked geographic heterogeneity across Europe. Our results indicate that dietary adaptation proceeded through coordinated evolutionary changes across interconnected physiological systems, providing a systems-level perspective on how cultural and subsistence transitions reshaped human biology.

evolutionary biology↗

bioRxiv2025

No evidence for disassortative mating based on HLA genotype in a natural fertility population

Studies dating back several decades have suggested that humans prefer potential mates with dissimilar HLA genotypes. Evidence for actualized disassortative mating based on the human-specific MHC remains inconclusive. For instance, cosmopolitan populations have often exhibited the opposite trend whereby assortative mating at the MHC is observed, indicating that social stratification may overwhelm potential biological mate preferences. However, small-scale, endogamous populations-whose social structures more closely resemble those throughout most of human evolution-have been largely overlooked. Here, we assess HLA dissimilarity among Himba pastoralists from Namibia, where socially accepted concurrency allows individuals to maintain both arranged marital and self-selected ("love match") partnerships. This provides a rare opportunity to directly test HLA similarity across contrasting partnership types (arranged vs chosen) within the same social system (n = 249 observed partnerships). We find no difference in HLA dissimilarity (neither at the genotype nor protein divergence level) between partnership types, nor in their fitness benefits to potential offspring as assessed via computationally predicted pathogen binding affinities. The effects of the partnership types likewise do not differ from a random, background distribution of 18,487 possible unrelated pairings. Finally, we detect extensive haplotype sharing across the HLA region, suggesting that episodes of fluctuating positive selection may be a stronger force maintaining HLA polymorphism than disassortative mating, even in an evolutionarily relevant social context.

evolutionary biology↗

bioRxiv2025

Characterization of Woodsmoke Generated in the Air Pollution Exposure Lab and Comparison to Diesel Exhaust

To address the increasing concern of woodsmoke (WS) and better understand its effects on human health, a woodsmoke generation system was built in the Air Pollution Exposure Laboratory to facilitate future controlled human exposure studies. Two different woodsmoke conditions, flaming (WSFL) and smoldering (WSSM), were generated, and PM2.5 concentrations of approximately 500 g/m3 were achieved. The woodsmoke produced using the system was characterized in this study and compared with diesel exhaust (DE) generated and collected at the same facility. Within the gas phase generated by the pollutants, WS showed slight increases in CO and CO2 compared to filtered air (FA), while DE contained significantly higher levels of NOx, CO2, and total volatile organic compounds compared to FA. The WS aerosols were comprised of approximately 98% organics, 0.6% NH4, 0.9% NO3, and 0.2% SO4. Among the organic species, the CHO1 and CHOgt1 families encompassed around 60%, which was higher than the fraction of oxygenated families in DE aerosols. Moreover, the WS aerosols had higher concentrations of Cd compared to the DE aerosols. Greater oxidative potentials were also observed for WSFL and WSSM compared to DE, with DTT consumption rates normalized to the PM mass being 0.0099 and 0.0090 nmol/min/g, respectively. The difference in the compositions and properties of WS and DE suggests that it is critical to conduct further studies on how these pollutants can affect health differently.

pharmacology and toxicology↗

bioRxiv2024

A Coronaviral Pore-Replicase Complex Drives RNA Synthesis in Double Membrane Vesicles

Coronavirus-infected cells contain double-membrane vesicles (DMVs) that are key for viral RNA replication and transcription, perforated by hexameric pores connecting the vesicular lumen to the cytoplasm. How pores form and traverse two membranes, and how DMVs organize RNA synthesis, is unknown. Using structure prediction and functional assays, we show that the non-structural viral membrane protein nsp4 is the key DMV pore organizer, spanning the double membrane and forming most of the pore lining. Nsp4 interacts with nsp3 on the cytoplasmic side and with the viral replicase inside the DMV. Newly synthesized mRNAs exit the DMV into the cytoplasm, passing through a narrow ring of conserved nsp4 residues. Steric constraints imposed by the ring predict that modified nucleobases block mRNA transit, with broad spectrum anti-coronaviral activity.

biochemistry↗

bioRxiv2023

The first proof of concept demonstration of nanowarming in coral tissue

Climate change is causing ocean acidification and warming, resulting in mass bleaching and death of corals globally. Cryopreservation and biobanking to secure the genetics of threatened populations is currently limited to coral sperm and larvae, which are only available during brief annual spawning events and are impacted by ocean warming, so there is an urgent need for methods to enable biobanking activities year-round. Here, we used vitrification and nanowarming to successfully recover adult coral tissues in a novel sample type, the single-polyp microfragment (SPMF). Fluorescence and confocal microscopy showed clearly defined tissues and green fluorescent protein fluorescence around the polyp mouth post-warming in 43.3% of SPMFs at 24 hours post-warming, and 30.0% at one month. These advances provide a basis for continued research and development of a field-ready protocol for cryopreservation of adult coral tissues, to permit biobanking of threatened coral species throughout the year and support reef restoration efforts.

ecology↗

bioRxiv2021

Mapping the mechanical microenvironment in the ovary

Follicle development in the human ovary must be tightly regulated to ensure cyclical release of oocytes (ovulation), and disruption of this process is a common cause of infertility. Recent ex vivo studies suggest that follicle growth may be mechanically regulated, however the actual mechanical properties of the follicle microenvironment have remained unknown. Here we map and quantify the mechanical microenvironment in mouse ovaries using colloidal probe atomic force microscope (AFM) indentation, finding an overall mean Youngs Modulus 3.3 {+/-} 2.5 kPa. Spatially, stiffness is low at the ovarian edge and centre, which are dominated by extra-follicular ECM, and highest in an intermediate zone dominated by large follicles. This suggests that large follicles should be considered as mechanically dominant structures in the ovary, in contrast to previous expectations. Our results provide a new, physiologically accurate framework for investigating how mechanics impacts follicle development and will underpin future tissue engineering of the ovary.

biophysics↗

bioRxiv2020

KDM6B-dependent chromatin remodelling underpins effective virus-specific CD8+ T cell differentiation.

Naive CD8+ T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here we profiled genome-wide changes in chromatin accessibility, gene transcription and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ T cell activation. Rapid upregulation of the histone demethylase, KDM6B, prior to first cell division was required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limited the magnitude of an effective primary virus-specific CD8+ T cell response and the formation of memory CD8+ T cell populations. Accordingly, we define the early spatio-temporal events underpinning early lineage-specific epigenetic reprogramming that is necessary for autonomous CD8+ T cell proliferation and differentiation.

immunology↗

bioRxiv2017

Increased usage of antiseptics is associated with reduced susceptibility in clinical isolates of S. aureus

Hospital acquired infection is a major cause of morbidity and mortality and regimes to prevent infection are crucial in infection control. These include decolonisation of at-risk patients of carriage of MRSA which is commonly achieved by protocols that include the use of chlorhexidine, or octenidine as biocidal agents. There is however no standardised single decolonisation regime agreed upon in the UK or other countries and protocols include a variety of active agents. Antibiotic resistant bacteria cause major problems in hospital medicine and concern has been raised regarding the development of biocide resistance which would cause decolonisation regimes to become unreliable. In this study, we assembled a panel of isolates of S. aureus including isolates collected before the development of chlorhexidine and octenidine through to a contemporaneous panel of isolates from a major hospital trust in the UK during a period when the decolonisation regime was altered. We observed significant increases in the MIC and MBC of chlorhexidine in isolates collected from periods of high usage of chlorhexidine. No isolates had a significantly altered MIC or MBC of octenidine apart from those collected after octenidine was introduced into the trust where isolates with four-fold decreases in susceptibility emerged. There was no suggestion of cross-resistance between the two biocidal agents. A combination of VNTR, PCR for qac genes and whole genome sequencing was used to type isolates and examine possible mechanisms of resistance. The typing data showed no expansion of a single strain was associated with decreased biocide tolerance and isolates with increased chlorhexidine MIC and MBCs were found from different clonal complexes; CC8, CC22 and CC30. Biocide susceptibility did not correlate with carriage of qac efflux pump genes - carriage of qacA and qacB was detected but, with one exception was restricted to isolates of CC8. Analysis of genome sequence data for closely related pairs of strains with differential biocide susceptibility revealed no common mutations or carriage of accessory elements that correlated with biocide tolerance. Mutations with the NorA or NorB efflux pumps, previously associated with chlorhexidine export were identified suggesting this may be an important mechanism of biocide tolerance. The clinical relevance of decreased biocide tolerance in terms of efficacy of decolonisation therapies remains to be established but we present evidence here that isolates are evolving in the face of biocide challenge in patients and that changes to decolonisation regimes are reflected in changes in susceptibility of isolates. More work is needed to assess the impact of these changes to ensure effective and robust decolonisation protocols remain in place.

microbiology↗