Biology subjects

Armitage, J.

Publications and source records attributed to Armitage, J..

5 recordsLinked to original sources

bioRxiv2026

Circadian modulation of spontaneous dopamine release shapes reward-evoked signaling in the nucleus accumbens

The circadian system is an important regulator of reward-related neural function and behavior. Dopamine (DA) release in the nucleus accumbens is a key component of reward processing, yet how circadian timing shapes DA release in relation to reward behavior remains unclear. Here, we investigated circadian rhythms in DA release and reward behavior using long-term fiber photometry paired with an automated reward delivery and measurement system. We found two distinct circadian rhythms in DA release: spontaneous DA, reflecting ongoing DA release not associated with reward, and reward-evoked DA, reflecting transient DA response during reward. Spontaneous DA peaked during the early subjective day, whereas reward-evoked peak DA peaked near the day-to-night transition. Both rhythms were distinct from reward behavior, which peaked during the early subjective night. Linear modeling further showed that the relationship between reward-evoked DA and reward behavior depended on circadian time, with greater DA responses occurring between late subjective day and early subjective night. Spontaneous baseline and reward-evoked DA were also negatively correlated, and this relationship was likewise modulated across circadian time. Together, these findings support a model in which circadian modulation of baseline DA may alter the gain of reward-evoked signaling, amplifying DA responses across behaviorally relevant times of day.

neuroscience↗

bioRxiv2024

Decipher: A computational pipeline to extract context-specific mechanistic insights from single-cell profiles

The advent of single-cell profiling technologies has revolutionized our understanding of the cellular and molecular states that underpin disease. However, current computational tools struggle to recover both known and novel mechanistic insights at distinct layers of biological regulation. Here, we present Decipher, a novel computational pipeline that builds integrated cell signalling networks from single-cell profiles in a context-specific, data-driven manner and identifies the key cellular and molecular events that drive disease. We benchmarked Decipher against existing tools and found it could recover known, experimentally determined cytokine signalling pathways, whilst maintaining the flexibility to detect novel pathways and context-specific effects. Notably, Decipher produces global cell-to-cell signalling maps that are interpretable. We utilised Decipher to unveil the cellular and molecular mechanisms driving a novel population of inflammatory monocytes enriched with interferon stimulated genes that is markedly increased in frequency following secondary immunization with the Pfizer-BioNTech COVID-19 mRNA vaccine. Finally, we employed Decipher to interrogate regulon profiles from covid-19 patients with mild versus severe disease, and we found that progression to severe disease was associated with a loss of interferon signalling transcription factors (Irf7, Irf9, STAT1, STAT2) and a gain of factors that drive inflammation and cellular stress responses (NFkB, HIF-1a, ATF3, ATF4). Taken together, our findings demonstrate that Decipher can decode signalling pathways and report on ligand-receptor mediated transcription factor-target gene networks that underlie processes in homeostasis, disease, and cellular responses to therapies. We present Decipher as an invaluable new tool for the discovery of novel therapeutic targets and the development of new medicines.

bioinformatics↗

bioRxiv2023

A comprehensive analysis of APOE genotype effects on human brain structure in the UK Biobank

Alzheimers disease (AD) risk is increased in carriers of the apolipoprotein E (APOE) {varepsilon}4 allele and decreased in {varepsilon}2 allele carriers compared with the {varepsilon}3{varepsilon}3 genotype. The aim of this study was to determine whether: APOE genotype affects brain grey (GM) or white matter (WM) structure; and if differences exist, the age when they become apparent and whether there are differential effects by sex. We used cross-sectional magnetic resonance imaging data from ~43,000 (28,494 after pre-processing) white British cognitively healthy participants (7,446 APOE {varepsilon}4 carriers) aged 45-80 years from the UK Biobank cohort and investigated image-derived phenotypes (IDPs). We observed no statistically significant effects of APOE genotype on GM structure volumes or median T2* in subcortical structures, a measure related to iron content. Volume of white matter hyperintensities differed significantly between APOE genotype groups with higher volumes in APOE {varepsilon}4{varepsilon}4 (effect size 0.14 standard deviations [SD]) and {varepsilon}3{varepsilon}4 carriers (effect size 0.04 SD) but no differences in {varepsilon}2 carriers compared with {varepsilon}3{varepsilon}3 carriers. WM integrity measures in the dorsal (mean diffusivity [MD]) and ventral cingulum (MD and intracellular volume fraction), posterior thalamic radiation (MD and isotropic volume fraction) and sagittal stratum (MD) indicated lower integrity in APOE {varepsilon}4{varepsilon}4 carriers (effect sizes around 0.2-0.3 SD) and {varepsilon}3{varepsilon}4 (effect sizes around 0.05 SD) carriers but no differences in {varepsilon}2 carriers compared with the APOE {varepsilon}3{varepsilon}3 genotype. Effects did not differ between men and women. APOE {varepsilon}4 homozygotes appeared to have lower WM integrity specifically at older ages with a potentially steeper decline of WM integrity from the age of 60 that corresponds to around 5 years greater "brain age". APOE genotype affects various white matters measures, which might be indicative of preclinical AD processes. This hypothesis can be assessed in future when clinical outcomes become available.

neuroscience↗

bioRxiv2023

Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years.

Human perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution. In this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)). We found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and IFN-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation. Additionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life.

immunology↗

bioRxiv2017

Effect of vitamin D supplementation on biomarkers of inflammation and immune function: functional genomics analysis of the BEST-D trial

Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomised trials may afford an opportunity to systematically assess molecular responses to treatments. In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D34000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-{gamma}, IL-10, IL-8, IL-6 and TNF-) at baseline and after 12 months, were measured. The trial had >90% power to detect a 2-fold change in gene expression. Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D), but had no significant effect on whole-blood gene expression (FDR <5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose but not on the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose), but had no significant effect on cis-eQTLs specific to vitamin D supplementation. The trial demonstrates the feasibility of application of functional genomics approaches in randomised trials to assess the effects of vitamin D on immune function.\n\nOne sentence summarySupplementation with high-dose vitamin D in older people for 12 months in a randomised, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of cytokines.\n\nTrial registrationSRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24).\n\nFundingMedical Research Council, British Heart Foundation, Wellcome Trust, European Research Council and Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom\n\nCopyrightOpen access article under the terms of CC BY.

clinical trials↗