Biology subjects

Hayes, N.

Publications and source records attributed to Hayes, N..

5 recordsLinked to original sources

bioRxiv2025

Examining Cross-Paradigm fNIRS Brain Activity in Neonates across The Gambia and UK

SignificanceNeonates undergo rapid development, yet the examination of emerging brain markers across paradigms, cognitive domains and diverse global populations remains limited. AimThis study investigated whether brain responses at one-month-of-age could be interrogated across paradigms to offer deeper context-specific insights into neurodevelopment. ApproachFunctional near-infrared spectroscopy (fNIRS) was used to assess frontal and temporal brain responses during natural sleep in 181 Gambian (GM) and 58 UK infants during three auditory paradigms: Social Selectivity, Habituation and Novelty Detection (HaND) and Functional Connectivity (FC). Paradigm-level brain responses were analysed using threshold-free cluster enhancement and cross-paradigm comparisons of individual responses. ResultsAt the group level, both GM and UK infants showed habituation but not novelty responses, higher inter-versus intra-hemispheric connectivity, stronger inter-hemispheric connectivity in temporal regions relative to frontal regions, stronger inter-regional connectivity between right temporal and left frontal regions, and UK infants also showed non-vocal > vocal selectivity. ConclusionsCross-cohort differences in the cross-paradigm analyses suggest context-specific developmental markers are evident within the first month of life and show high individual variability. Cross-paradigm analyses revealed that greater vocal selectivity (UK) was associated with higher inter-hemispheric connectivity, potentially allowing us to identify biomarkers of more mature neurodevelopment within the first weeks of postnatal life.

neuroscience↗

bioRxiv2025

A protective bispecific antibody targets both Nipah virus surface glycoproteins and limits viral escape

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses without approved human vaccines or therapies. Here, we report on a highly potent bispecific therapeutic that combines an anti-fusion (F) nanobody with an anti-receptor binding protein (RBP) antibody to deliver a dual-targeting biologic that is resistant to viral escape. We show that the nanobody, DS90, engages a unique, conserved site within prefusion F of NiV and HeV, and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP mAb m102.4 results in neutralization, elimination of viral escape and superior protection from NiV disease compared to leading monovalent approaches. These findings carry implications for the development of cross-neutralizing immunotherapies that limit the emergence of henipaviral escape mutants.

microbiology↗

bioRxiv2024

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Breast cancer (BC) is the most common cancer and the second cause of death in US women. Our lack of understanding of how genetic variants affect molecular mechanisms that mediate BC aggression poses a substantial obstacle to advancements in cancer diagnosis and therapy. To examine genetic variants on BC traits, a novel murine model was created with robust phenotypic and genomic variation. The FVB C3(1)-T-antigen ("C3Tag") mouse develops spontaneous tumors in the mammary glands of female mice with a mean latency of 4-5 months of age. This genetically engineered mouse model (GEMM) is well established to resemble human basal-like TNBC. TNBC is an aggressive subtype with few clinical approaches and poor patient outcomes. Thus, to model human heterogeneity in BC outcomes, we systematically crossed the C3Tag GEMM into the BXD recombinant inbred family - the largest and best characterized genetic reference population. The new model is termed "BXD-BC" and F1 hybrids of the cross have isogenic genomes that are reproducible. BXD-BCs are a potent tool to determine the impact of genetic modifiers on BC tumor traits. We hypothesized that examination of BXD-BC GEMMs will enable the identification of susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple BC phenotypes. Using N=29 BXD-BC strains, we demonstrated significant heritable variations in the severity of TNBC characteristics such as tumor latency, multiplicity, and survival. Interestingly, 2 BXD-BC strains never developed tumors out to 1 year of age. Thus, BXD-BC strains demonstrate variance in cancer susceptibility and progression compared to the parent C3Tag GEMM, indicating the presence of genetic modifiers. Through an unbiased systematic quantification of breast cancer severity across BXD-BC hybrids, we identified several significant quantitative trait loci (QTL) and candidate genes for specific tumor traits. In combination with public human GWAS datasets, we defined syntenic regions, candidate genes, and underlying networks through cross-species systems genetics analyses to demonstrate the translational validity of conserved, biologically relevant, and targetable candidates. Our findings suggest conserved candidates predicting TNBC patient survival. In sum, the BXD-BC resource is an innovative, reliable, and robust preclinical model that reflects robust genetic heterogeneity. Using cutting edge systems genetics, we have identified genetic modifiers of BC phenotypic variation that could be targeted to advance therapeutic limitations or as biomarkers of risk or response to therapy.

genetics↗

bioRxiv2022

Data based slurry treatment decision tree to minimize antibiotic resistance and pathogen transfer while maximizing nutrient recycling

Direct application of pig slurry to agricultural land, as a means of nutrient recycling, introduces pathogens, antibiotic resistant bacteria, or genes, to the environment. With global environmental sustainability policies mandating a reduction in synthetic fertilisation and a commitment to a circular economy it is imperative to find effective on-farm treatments of slurry that maximises its fertilisation value and minimises risk to health and the environment. We assessed and compared the effect of storage, composting, and anaerobic digestion on pig slurry microbiome, resistome and nutrient content. Shotgun metagenomic sequencing and HT-qPCR arrays were implemented to understand the dynamics across the treatments. Our results identified that each of the treatment methods had advantages and disadvantages, depending on the parameter measured. The data suggests that storage and composting are optimal for the removal of human pathogens and anaerobic digestion for the reduction in AMR genes and mobile genetic elements. The nitrogen content is increased in storage and AD and reduced in composting. Thus, depending on the requirement for increased or reduced nitrogen the optimum treatment varies. Combining the results indicates that composting provides the greatest gain by reducing risk to human health and the environment. Network analysis revealed reducing Proteobacteria and Bacteroidetes while increasing Firmicutes will reduce the AMR content. KEGG analysis identified no significant change in the pathways across all treatments. This novel study provides a data driven decision tree to determine the optimal treatment for best practice to minimise pathogen, AMR and excess or increasing nutrient transfer from slurry to environment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/481976v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@141af73org.highwire.dtl.DTLVardef@165bf42org.highwire.dtl.DTLVardef@ef86c5org.highwire.dtl.DTLVardef@1790fca_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

Characterization of Reactive Oxygen Species Signaling changes in a cell culture model of skeletal muscle ageing, and its application to screening pharmacokinetically-relevant exposures of dietary polyphenols for bioactivity.

Age-related frailty is a significant health and social care burden, however treatment options are limited. There is currently a lack of suitable cell culture model for screening large numbers of test compounds to identifying those which can potentially promote healthy skeletal muscle function. This paper describes the characterization of reactive oxygen and nitrogen species (RONS) signalling changes in young and aged myoblasts and myotubes using the C2C12 cell line, and the application of aged myoblast and myotube cultures to assess the effect of dietary polyphenols on RONS signalling. Aged myoblasts and myotubes were observed to have significantly increased reactive oxygen species levels (p<0.01 and p<0.001 respectively), increases in nitric oxide levels (p<0.05 for myoblasts and myotubes), and lipid peroxidation markers (p<0.05 for myoblasts and myotubes). A panel of nine polyphenols were assessed in aged myoblasts and myotubes using concentrations and incubation times consistent with known pharmacokinetic parameters for these compounds. Of these, although several polyphenols were seen to reduce single markers of RONS signalling, only kaempferol and resveratrol consistently reduced multiple markers of RONS signalling with statistical significance in both cell models. Modulation of cellular enzymatic antioxidant activities (superoxide and catalase) was assessed as a possible mechanism of action for these polyphenols, and although both superoxide and catalase activities were significantly reduced in aged (versus young) myotubes (p<0.01 and p<0.05 respectively), no effect of polyphenol treatment on these enzyme activities were observed. Overall, this research has shown the utility of the C2C12 model, as both myoblasts and myotubes, as a suitable cell model for screening compounds for modulating RONS signalling in aged muscle, and that resveratrol and kaempferol (using pharmacokinetically-informed exposures) can modulate RONS signalling in skeletal muscle cells after an acute exposure.

pharmacology and toxicology↗