Biology subjects

Drummond, G. R.

Publications and source records attributed to Drummond, G. R..

12 recordsLinked to original sources

bioRxiv2026

Integrated Multiomics Reveals Intergenerational Brain Sensory System Remodeling Induced by Parental Intermittent Fasting

Intermittent fasting (IF) is increasingly recognized as a potent modulator of metabolic health, but its effects on brain function across generations remain poorly understood. Here, we show that parental IF, administered to both mothers and fathers before mating, is associated with coordinated molecular remodeling in the cerebral cortex of fathers and their offspring, with shared molecular signatures identified between these generations and a pronounced enrichment of sensory-associated pathways. Using whole-genome bisulfite sequencing, transcriptomic profiling, and proteomic analysis, we found that IF elicited widespread cortical epigenetic remodeling in fathers, accompanied by transcriptional and protein-level changes enriched for olfactory, taste, synaptic, and neurometabolic pathways. Strikingly, related molecular signatures were detected in F1 offspring that had never been directly exposed to fasting, consistent with intergenerational transmission of IF-associated cortical remodeling. Offspring responses were sex dependent, with female and male progeny exhibiting distinct patterns of DNA methylation, gene expression, and protein abundance. Integrated multiomic analyses identified conserved candidate networks involved in sensory perception, glutamatergic signaling, synaptic organization, intracellular trafficking, cytoskeletal regulation, and stress-response pathways. Together, these findings identify sensory-associated cortical remodeling as a prominent molecular feature associated with parental IF and reveal persistent, sex-dependent molecular alterations in the offspring brain.

genomics↗

bioRxiv2025

S100A8/A9 Inhibition Reduces Splenic Myelopoiesis and Improves Outcomes After Stroke

BackgroundNeutrophils are among the earliest immune cells to infiltrate the ischemic brain and contribute to secondary neuronal damage. The alarmin S100 calcium-binding protein A8/A9 (S100A8/A9), predominantly released by neutrophils, is upregulated during this process. Although the bone marrow is recognised as the principal site of neutrophil production via myelopoiesis, the role of the spleen as an immune-responsive organ remains incompletely understood. MethodsIn this study, we employed a transient middle cerebral artery occlusion (MCAO) model in male C57Bl/6 mice and examined immune responses 24 hours post-stroke in the blood, bone marrow and spleen using flow cytometry. To understand the role of S100A8/A9 in modulating stroke-induced myelopoiesis, we administered a small molecule inhibitor of S100A8/A9, ABR-215757, before and after stroke. ResultsNeutrophils and S100A8/A9 were found in the infarcted brain tissue. Interestingly, we observed a marked increase in splenic neutrophils, accompanied by an expansion of myeloid progenitors, indicating activation of extramedullary myelopoiesis. Given our previous work showing that S100A8/A9 promotes myelopoiesis, we pharmacologically inhibited S100A8/A9 to determine if this would modulate stroke-induced myelopoiesis. Treatment with ABR-215757 at 24 hours post-stroke led to reduced splenic myelopoiesis, reversed neutrophilia, enhanced forelimb grip strength, and a one-third reduction in infarct size. ConclusionThese findings identify the spleen as a key contributor to neutrophil production following stroke and suggest that targeting S100A8/A9 may attenuate post-stroke inflammation and improve neurological recovery. HighlightsO_LIStroke induces extramedullary myelopoiesis in the spleen, not femoral bone marrow. C_LIO_LINeutrophil-derived S100A8/A9 drives splenic myelopoiesis after ischemic stroke. C_LIO_LIPharmacological blockade of S100A8/A9 with ABR-215757 reduces neutrophilia. C_LIO_LIInhibition of S100A8/A9 lessens infarct size and improves neurological recovery. C_LIO_LIHuman stroke tissue confirms S100A8/A9 accumulation with neutrophil infiltration. C_LI

neuroscience↗

bioRxiv2025

Marginal zone B cells are antigenically activated, infiltrate the kidneys, and exacerbate angiotensin II-dependent hypertension in mice

AimsB cells contribute to the development of hypertension, yet, the specific B cell subsets involved, the mechanism underlying their activation, and the relevance of these responses to human disease remain poorly defined. Methods and resultsWe used single-cell RNA sequencing, single-cell B cell receptor (BCR) VDJ sequencing, and high dimensional flow cytometry to characterise B cell responses in murine angiotensin II-induced hypertension. Chronic angiotensin II infusion in male and female mice increased systolic blood pressure and selectively expanded marginal zone B (MZB) cells, with evidence of antigen-dependent activation, including clonal BCR expansion, enrichment of IGHV1 B cell receptor variants, and increased expression of activation markers (CD69 and Nur77). Intercellular communication analyses revealed enhanced antigen-presentation signalling between MZB and CD8+ T cells in hypertensive mice. Activated MZB-like memory B cells also accumulated in the kidneys of hypertensive mice. Consistent with these findings, multiomic analysis of kidneys from patients with hypertensive chronic kidney disease (CKD) demonstrated an increase in memory B cells with a MZB phenotype and enrichment of antigen-presentation-linked communication with CD8+ T cells. Importantly, hypertensive responses to angiotensin II infusion were significantly blunted in mice lacking MZB cells (BAFF-R-/-). ConclusionOur findings identify MZB cells as a selectively activated, antigen-responsive B cell subset that amplified pathogenic immune responses in murine and human hypertension. By linking subset-specific BCR activation to immune cross-talk and disease causality, this study identifies MZB cells - and the (auto)antigens that activate them - as promising targets for precision immunomodulatory strategies in hypertension.

physiology↗

bioRxiv2025

High-resolution transcriptomic profiling of the aortic cellular landscape during hypertension reveals novel drivers of vascular fibrosis

BackgroundAortic stiffening is a consequence of hypertension and a major contributor to end organ damage. A key driver of aortic stiffening is fibrosis involving the excess production of extracellular matrix (ECM) proteins such as collagen, fibronectin and laminin. The present study aimed to identify the cell types and signalling mechanisms that contribute to aortic fibrosis in hypertension. Methods and ResultsMale C57BL/6 mice (10-12-week-old) were randomly assigned to a 28-day angiotensin II (0.7 mg/kg/day) or vehicle (saline) infusion via osmotic minipump (s.c.). At endpoint, scRNA-seq analysis of 26,196 cells recovered all major aortic cell populations. Among these, fibroblasts exhibited the greatest heterogeneity and shift in gene expression after angiotensin II compared to all other cell types. Gene ontology analyses revealed that after angiotensin II treatment, a particular subcluster of fibroblasts (Fibro-Cthrc1) - characterised by its high expression of Cthrc1 - was especially fibrogenic. Fibro-Cthrc1 cells were nearly undetectable in aortas from vehicle-infused mice. Transcripts relating to ECM remodelling (Thbs2, Cdh11 and Postn) and collagen production (specifically collagen type I, III and V) were more highly enriched in Fibro-Cthrc1 compared to other fibroblasts within hypertensive aortas. Moreover, GO terms corresponding to profibrotic signalling pathways (i.e., cell adhesion, extracellular matrix organisation and collagen fibril organisation) were significantly enriched in Fibro-Cthrc1. Spatial transcriptomics and immunohistochemistry confirmed the presence of Fibro-Cthrc1 in the adventitial layer of angiotensin II-infused but not vehicle-infused mice. Finally, analysis of plasma analytes in approximately 24,000 participants of the UK Biobank collection revealed CTHRC1 to be strongly associated with raised systolic blood pressure and pulse pressure, and a strong predictor of the risk of developing hypertension over a 15-year follow-up. ConclusionOur study identifies a novel fibroblast subcluster, Fibro-Cthrc1, as a potential driver of aortic fibrosis and stiffening in hypertension. This cluster is absent in normotensive aortas, suggesting that targeting Fibro-Cthrc1 therapeutically could prevent aortic fibrosis and its associated hypertensive end-organ damage. Notably, such an approach may avoid compromising physiological extracellular matrix production and vessel integrity. Translational perspectiveAortic stiffening is a hallmark of hypertension resulting from functional (vasoconstriction) and structural (extracellular matrix remodelling) alterations of the vessel wall. While several antihypertensive medications address functional changes, no therapies directly target the causes of the structural remodelling. The therapeutic challenge is to distinguish between physiological and pathological extracellular matrix remodelling. This study identifies a novel highly profibrotic fibroblast cell population (Fibro-Cthrc1) present in aortas from hypertensive, but not normotensive mice. This raises the possibility that Fibro-Cthrc1 may be a key driver of aortic stiffening and a promising future therapeutic target.

physiology↗

bioRxiv2024

Impact of Parental Time-Restricted Feeding on Offspring Metabolic Phenotypic Traits

A substantial body of research elucidates the mechanisms and health advantages associated with intermittent fasting (IF). However, the impact of parental IF on offspring remains unclear. Through an investigation involving four IF and ad libitum combinations of parental mating groups, we demonstrate that parental IF (daily time-restricted feeding) influences offsprings metabolic health indicators in male and female offspring in distinct ways. We found that when both parents are on IF their offspring exhibit protection against the adverse effects of a high-fat, high-sugar, and high-salt diet in a sex-specific manner. This study underscores the potential significance of parental lifestyle modifications involving dietary restriction for the metabolic status of their children and their risk for obesity and diabetes.

genetics↗

bioRxiv2023

Experimental Factors Influence Diversity Metrics of the Gut Microbiome in Laboratory Mice

IntroductionAnimal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external factors not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations. Methods and ResultsWe conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomised into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced -diversity (P=0.0137) and {beta}-diversity (i.e., composition of the microbiome, P<0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid-producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both - and {beta}-diversity (all P<0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%). ConclusionsOur large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.

microbiology↗

bioRxiv2022

Intermittent Fasting Mitigates Vascular and Neuronal Pathologies in a Mouse Model of Vascular Dementia

Chronic cerebral hypoperfusion (CCH) is an important pathophysiological mechanism of vascular cognitive impairment (VCI). The heterogeneous effects of CCH complicate establishing single target therapies against VCI and its more severe form, vascular dementia (VaD). Intermittent fasting (IF) has multiple targets and is neuroprotective across a range of disease conditions including stroke, but its effects against CCH-induced neurovascular pathologies remain to be elucidated. We therefore assessed the effect of IF against CCH-associated neurovascular pathologies and investigated underlying mechanisms. Male C57BL/6 mice were subjected to either ad libitum feeding (AL) or IF (16 hours of fasting per day) for 4 months. In both groups, CCH was experimentally induced by the bilateral common carotid artery stenosis (BCAS) method. Sham operated groups were used as controls. Measures of leaky microvessels, blood brain barrier (BBB) permeability, protein expression of tight junctions, extracellular matrix components and white matter changes were determined to investigate the effect of IF against CCH-induced neurovascular pathologies. IF alleviated CCH-induced neurovascular pathologies by reducing the number of leaky microvessels, BBB breakdown, loss of tight junctional proteins and vascular endothelial growth factors. In addition, IF mitigated the severity of white matter lesions, maintained myelin basic protein levels, while concurrently reducing hippocampal neuronal cell death. Furthermore, IF reduced CCH-induced increase in levels of matrix metalloproteinase (MMP)-2 and its upstream activator MT1-MMP, which are involved in the breakdown of the extracellular matrix that is a core component of the BBB. Additionally, we observed that IF reduced CCH-induced increase in the oxidative stress marker malondialdehyde, and increased antioxidant markers glutathione and superoxide dismutase. Combined, our data suggests that IF attenuates neurovascular damage, metalloproteinase and oxidative stress-associated pathways, and cell death in the brain following CCH in a mouse model of VCI. Although IF has yet to be assessed in human patients with VaD, our data suggest that IF may be an effective means of preventing the onset or suppressing the development of neurovascular pathologies in VCI and VaD.

neuroscience↗

bioRxiv2021

Self-renewing tissue-resident endothelial-macrophage progenitor cells originate from yolk sac and are a local source of inflammation and neovascularization in postnatal aorta

Converging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX3CR1+ and CSF1R+ source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and forming perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally.

cell biology↗

bioRxiv2021

Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting

AimsIntermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular and cellular adaptations of the heart to IF, we carried out system-wide comprehensive analyses of proteome and phosphoproteome, complemented with transcriptome profiling, followed by functional analysis. Methods and resultsIn order to understand molecular and cellular remodeling of the heart during IF, we employed advanced mass spectrometry for system-wide profiling of the proteome and phosphoproteome of heart tissues obtained from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. We also performed transcriptome analyses using RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed the higher correlation of pathway alternation in short IF regimen but the inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. In addition, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. ConclusionOur systematic multi-omics study elucidates a molecular framework for understanding how IF impacts the hearts function and its vulnerability to injury and disease. Translational perspectiveIntermittent fasting is emerging as a desirable lifestyle adaptation to impact cardiovascular health through the modulation of molecular and cellular mechanisms, and by acting on disease risk factors. Evidence from numerous studies indicates that the fasting cycles are highly and consistently effective in protecting against cardiovascular diseases and improving cardiac health in animals and human. Using multi-omics, here we dissect distinct molecular adaptations of the heart to different intermittent fasting regimens. Our results unveil novel cardioprotective mechanisms and open up new avenues for innovative pharmacological approaches to prevent and treat cardiovascular diseases.

systems biology↗

bioRxiv2020

Hippocampal Transcriptome Profiling Reveals Common Disease Pathways in Chronic Hypoperfusion and Ageing

Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected due to rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice show the normal age-associated decline in cerebral blood flow and differential gene expression. BCAS and ageing caused broadly similar effects, however, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those present in sham aged mice. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for chronic hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.

neuroscience↗

bioRxiv2020

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response - particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1{beta} and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

neuroscience↗

bioRxiv2020

Integrative Epigenomic and Transcriptomic Analysis Reveals Robust Metabolic Switching in the Brain During Intermittent Fasting

Intermittent fasting (IF) is a lifestyle intervention comprising a dietary regimen in which energy intake is restricted via alternating periods of fasting and ad libitum food consumption, without compromising nutritional composition. While epigenetic modifications can mediate effects of environmental factors on gene expression, no information is yet available on potential effects of IF on the epigenome. In this study, we found that IF causes modulation of histone H3 lysine 9 trimethylation (H3K9me3) epigenetic mark in the cerebellum of male C57/BL6 mice, which in turn orchestrates a plethora of transcriptomic changes involved in the robust metabolic switching processes commonly observed during IF. Interestingly, both epigenomic and transcriptomic modulation continued to be observed after refeeding, suggesting that memory of the IF-induced epigenetic change is maintained at the locus. Notably though, we found that termination of IF results in a loss of H3K9me3 regulation of the transcriptome. Collectively, our study characterizes a novel mechanism of IF in the epigenetic-transcriptomic axis, which controls myriad metabolic process changes. In addition to providing a valuable and innovative resource, our systemic analyses reveal molecular framework for understanding how IF impacts the metaboloepigenetics axis of the brain. Highlights{circ} Intermittent fasting (IF) and refeeding modifies epigenome in the cerebellum {circ}Integrative epigenomic and transcriptomic analyses revealed metabolic switching {circ}IF affects the metaboloepigenetics axis in regulating metabolic processes {circ}Integrative analyses revealed a loss of epigenetic reprogramme following refeeding

neuroscience↗