Biology subjects

Foote, K.

Publications and source records attributed to Foote, K..

6 recordsLinked to original sources

bioRxiv2026

Investigating biotic, chemical, and physical drivers of periphyton and invertebrate biomass in boreal streams supporting juvenile Atlantic salmon

1. Atlantic salmon (Salmo salar) are an anadromous fish with a broad distribution from eastern North America to western Europe, with ecological, economic, and cultural significance. Despite their expansive range, wild populations across the North Atlantic have experienced decline. Survival to reproductive age is a management concern, with a focus on identifying factors affecting the juvenile freshwater life stage. Specifically, research is needed to identify potential bottlenecks limiting freshwater productivity. 2. We addressed this research gap with a case study on the Exploits River, Newfoundland - a watershed that receives one of the largest anadromous Atlantic salmon returns in North America. We aimed to identify biotic, chemical, and physical predictors of food resources for juvenile salmon (i.e., invertebrates) and food resources for invertebrates (i.e., periphyton). To test our hypotheses, we collected data on a suite of biotic (e.g., invertebrates and periphyton), chemical (e.g., total dissolved N), and physical (e.g., wetted width) variables at 42 sites within and around this watershed. 3. We observed evidence for relationships between invertebrate biomass and biotic and temporal variables. Specifically, invertebrate biomass was higher at sites with high periphyton biomass that were sampled later in the season. In addition, we observed that periphyton biomass was related to biotic, chemical, and physical variables. Here, we present evidence for bottom-up control, with increased periphyton biomass supporting increased invertebrate biomass. 4. We expect knock-on effects where increased invertebrate biomass results in increased juvenile Atlantic salmon biomass. Our large sample size revealed some predictors of invertebrate biomass and periphyton biomass. However, we found no evidence of correlation between invertebrate biomass and chemical or physical variables. The low productivity of our maritime boreal forest system could be an outlier in expected biotic, chemical, and physical relationships in streams. 5. Our findings provide an important step forward in furthering boreal stream ecology, producing novel invertebrate and periphyton knowledge for watershed managers.

ecology↗

bioRxiv2026

Identification of osteopontin as a positional and functional candidate gene for cardiac hypertrophy in the SHRSP rat

Left ventricular hypertrophy, common in cardiometabolic and renal disease, is a major risk factor for cardiovascular morbidity and mortality. Left ventricular mass is a highly heritable, polygenic trait. Linkage studies in WKY and SHRSP rats have identified a quantitative trait locus for left ventricular mass index on chromosome 14. Congenic strains, where trait-associated genetic loci are introduced into a control strain, can identify causal genetic mediators relevant to human disease. Chromosome 14 congenic (WKY.SPGla14a), WKY, and SHRSP strains underwent cardiac phenotyping and transcriptome profiling at; 1-3 days (neonate), 5 weeks, and 16-weeks. Compared to WKY, LVMI was significantly increased in SHRSP and WKY.SPGla14a at 5 weeks (LVMISHRSP-WKY=0.26g/kg, LVMIWKY.SPGla14a-WKY=0.30g/kg), prior to measured hypertension in this model. SHRSP blood pressure was significantly greater than WKY.SPGla14a, and WKY from 12-20 weeks (AUCdiff=497 vs WKY, AUCdiff=412 vs WKY.SPGla14a). Cardiac transcriptome analysis of neonate, 5-week, and 16-week hearts identified significantly increased expression of secreted phosphoprotein 1 (Spp1/osteopontin) in SHRSP and WKY.SPGla14a compared to WKY, which is positioned within the transferred congenic region. Overexpression of Spp1 mRNA significantly increased H9c2 cell size and was shown to be transferred in small extracellular vesicles (sEV). Overexpression of Spp1 in neonatal chromosome 14 congenic and SHRSP strains preceded development of increased cardiac mass and onset of hypertension. The congenic strategy identified Spp1 as a positional and functional candidate gene determining increased LVMI in the SHRSP model of human cardiovascular disease.

genetics↗

bioRxiv2025

Wide-ranging behavioral dysfunction in two mouse models of pathological human variants in the GRIK2 kainate receptor gene

De novo variants in a subset of ionotropic glutamate receptor (iGluR) genes cause nonsyndromic neurodevelopmental disorders (NDDs) in individuals. Two recurrent variants in the kainate receptor (KAR) gene GRIK2 result in the gain-of-function (GoF) substitutions p.Ala657Thr and p.Thr660Lys in a critical pore-forming domain of the GluK2 subunit. Disorders in individuals with these variants manifest as intellectual disability, developmental delay, motor impairments, and, in the case of p.Thr660Lys, epilepsy. To explore their pathogenicity and phenotypic consequences in vivo, we generated knock-in mouse models harboring orthologous Grik2 mutations. Behavioral analyses revealed a range of developmental, motor, cognitive, and naturalistic behavior impairments in both lines, with T660K mice typically exhibiting more severe phenotypes, consistent with clinical observations in humans. GluK2(T660K) mice also display interictal EEG abnormalities and handling-induced seizures. These models establish the first in vivo platforms for dissecting the underlying mechanisms of NDDs caused by a GoF mutation in the GluK2 KAR subunit and represent crucial tools for therapeutic development. HighlightsO_LIDe novo variants in the GRIK2 kainate receptor gene cause developmental disorders C_LIO_LIWe studied knockin mouse models of pathogenic p.Ala657Thr and p.Thr660Lys variants C_LIO_LIGluK2(A657T) and GluK2(T660K) mice have deficits analogous to human disorder symptoms C_LIO_LILike their human counterparts, GluK2(T660K) but not GluK2(A657T) mice have seizures C_LIO_LIGrik2 knockin mice are key tools for interrogating underlying causes of dysfunction C_LI

neuroscience↗

bioRxiv2024

Delineation of a thrombin receptor-stimulated vascular smooth muscle cell transition generating cells in the plaque-stabilising fibrous cap

AimsVascular smooth muscle cells (VSMCs) accumulate in atherosclerotic plaques and exhibit remarkable phenotypic plasticity, contributing to both plaque growth and stability. The plaque-stabilising fibrous cap is rich in VSMC-derived cells, yet the cellular transitions and regulatory mechanisms governing fibrous cap formation remain unclear. We aimed to delineate the VSMC phenotypic transitions associated with this critical process. Methods and ResultsMapping of lineage-traced VSMCs during plaque development revealed investment of VSMCs prior to fibrous cap formation. Using single-cell RNA-sequencing (scRNA-seq) profiles of lineage-traced VSMCs from atherosclerotic and acutely injured mouse arteries, we identified a disease-specific VSMC state co-expressing contractile genes with extracellular matrix (ECM) components (including fibrillar collagens and elastin) and NOTCH3, which are associated with fibrous cap formation. Computational trajectory analysis predicted that this proposed fibrous cap-related VSMC (fcVSMC) state arises from a previously described plastic, intermediate VSMC population expressing SCA1 and VCAM1. Clonal analysis further showed that NOTCH3+ fcVSMCs derive from intermediate VSMCs in both atherosclerosis and an acute vascular injury model, suggesting a conserved disease-relevant mechanism. The fcVSMCs were enriched in plaque fibrous caps compared to lesion cores, consistent with a role in fibrous cap formation. By combining scRNA-seq trajectory analysis and spatial transcriptomics of human atherosclerotic plaques, we identified protease-activated receptor-1 (PAR1) as a candidate regulator of fcVSMC generation. PAR1 was expressed by VSMCs in human plaque fibrous caps and, PAR1 activation by thrombin induced expression of contractile genes and ECM components associated with the fcVSMC state in human VSMCs. ConclusionsOur findings identify a VSMC transition linked to fibrous cap formation in atherosclerosis and show this is modelled by vascular injury. We identify VSMC-expressed PAR1 as a potential therapeutic target for promoting plaque stability by driving the transition to the matrix-producing, fibrous cap-associated VSMC state.

molecular biology↗

bioRxiv2023

Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease

Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation are hallmarks of vascular diseases causing heart attack and stroke. To elucidate molecular determinants governing VSMC proliferation, we reconstructed gene regulatory networks from single cell transcriptomics and epigenetic profiling. We find progressive activation of enhancers at disease-relevant loci in VSMCs that dont respond to injury and proliferation-predisposed cells. Our analysis suggests that while many transcription factors are shared, their target loci differ between VSMC states. Comparison of rewiring between VSMC subsets and in silico perturbation analysis prioritised novel regulators, including RUNX1 and the network target TIMP1. We experimentally validated that the pioneer factor RUNX1 increased VSMC responsiveness and show that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signalling. Both RUNX1 and the TIMP1-CD74 axis were expressed in hVSMCs, at low frequency in normal arteries and increased in disease, suggesting clinical significance and potential as novel vascular disease targets.

molecular biology↗

bioRxiv2020

Primed smooth muscle cells acting as first responder cells in disease

RationaleVascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype of proliferating VSMCs are unknown. ObjectiveTo understand the cellular mechanisms underlying clonal VSMC expansion in disease. Methods and ResultsHere we analyse clonal dynamics in multi-color lineage-traced animals over time after vessel injury. We demonstrate that VSMC proliferation is initiated in a small fraction of VSMCs that initially expand clonally in the medial layer and then migrate to form the oligoclonal neointima. Selective activation of VSMC proliferation also occurs in vitro, suggesting that this is a cell-autonomous feature. Mapping of VSMC trajectories using single-cell RNA-sequencing reveals a continuum of cellular states after injury and suggests that VSMC proliferation initiates in cells that have downregulated the contractile phenotype and show evidence of pronounced phenotypic switching. We show that proliferation is associated with induced expression of stem cell antigen 1 (SCA1) and the expression signature previously identified in SCA1+ VSMCs in healthy arteries. A remarkably increased proliferation of SCA1+ VSMCs, directly validated in functional assays, indicates that SCA1+ VSMCs act as "first responders" in vascular injury. Early atherosclerotic lesions also had clonal VSMC contribution and we show that the proliferation-associated injury response is conserved in plaque VSMCs, extending these findings to atherosclerosis. Finally, we identify VSMCs in healthy human arteries that correspond to the SCA1+ state in mouse VSMCs and show that genes identified as differentially expressed in this human VSMC subpopulation are enriched for genes showing genetic association with cardiovascular disease. ConclusionsWe show that cell-intrinsic, selective VSMC activation drives clonal proliferation after injury and in atherosclerosis. Our study suggests that healthy mouse and human arteries contain VSMCs characterised by expression of disease-associated genes that are predisposed for proliferation. Targeting such "first responder" cells in patients undergoing vascular surgery could effectively prevent injury-associated VSMC activation and neoatherosclerosis.

cell biology↗