Biology subjects

Hope, J.

Publications and source records attributed to Hope, J..

8 recordsLinked to original sources

bioRxiv2026

Coordinated Representational Drift Across the Mouse Cortex

Cortical neurons continuously change their spatial tuning properties over days and weeks, yet how this representational drift is coordinated across distributed cortical networks remains unknown. Using a robotic cranial exoskeleton for chronic widefield calcium imaging with cellular resolution, we tracked over 110,000 unique layer 2/3 neurons across retrosplenial, visual, somatosensory, and motor cortices in mice navigating a figure-8 maze spanning 47 days. Single-neuron spatial tuning properties followed a posterior-to-anterior gradient, with retros-plenial and visual cortices containing the highest proportions of spatially tuned neurons. This was dissociated from local functional coupling, which was strongest in somatosensory cortex. Population activity formed a low-dimensional manifold whose geometry mirrored the structure of the maze. Despite these regional differences, all four regions decorrelated with similar exponential timescales, and session-specific deviations from each regions decay trajectory were correlated across all pairwise region combinations, suggesting that drift was coordinated rather than independent across the dorsal cortex. This coordination persisted after controlling for shared behavioral fluctuations. Furthermore, drift was consistent with an orthogonal transformation of the population code that preserved the geometric relationships between spatial representations across sessions despite continuous drift in single-neuron tuning.

neuroscience↗

bioRxiv2026

Integrating temporal genomic and transcriptomic analyses to decipher genetic basis of feed intake in dairy cattle

BackgroundFood intake is a complex trait in living organisms, where the genetics of food intake have been widely studied in humans, mice, Drosophila, cattle, pigs, chicken, and fish. In dairy cattle, intake of feed is highly linked to individuals energy balance, health, production, efficiency, and the environmental footprint of the individual to the society. Recent studies have provided solid evidence of the genetic variation of feed intake (FI) in dairy cattle population, but the genetic basis and molecular mechanism of dairy feed intake is still far from clear especially considering the lactation cycles of dairy cattle. This study aims to integrate stage-dependent genome-wide association (GWA) analyses, regional heritability mapping (RHM), and RNA-seq gene expression analyses to identify temporal functional variants associated with cattle dry matter intake (DMI) across multiple stages in lactation cycles. A total of 750,000 daily DMI records from 7,500 lactations of 2,300 cows were available with animals genotype and pedigree information. Total RNA-seq from blood were generated for 121 individuals in this population from 2 lactation stages. Data were split into multiple lactations stages for GWA, RHM, and transcriptomic analyses. ResultsStage-dependent GWAS and RHM identified 21 significant loci associated with DMI across multiple lactation stages. A total of 45 candidate genes were identified from GWA and RHM. Among all the 45 genes, six genes were later found significantly differently expressed between high and low feed intake animal groups using gene expression information from RNA-seq data. These genes show links to sugar and adipose metabolism, milk production, body weight, dopamine-reward pathways and immune functions. ConclusionsOur multi-omics analyses provide molecular evidence that the genetic basis of cattle DMI across lactation is not static. Temporal genomic variants associated with FI were identified with their transcriptomic patterns investigated, decoding the molecular mechanisms underlying DMI. Overall, the associated variants and candidate genes uncovered herein decoded genetic architecture of dairy feed intake on a temporal and multi-omics basis, enhancing the understanding of basic biology of dairy feed intake and informing breeding strategies aimed at improving dairy feed efficiency.

genomics↗

bioRxiv2024

Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1

Immunological determinants favouring emergence of broadly neutralising antibodies are crucial to the development of HIV-1 vaccination strategies. Here, we combined RNAseq and B cell cloning approaches to isolate a broadly neutralising antibody (bnAb) ELC07 from an individual living with untreated HIV-1. Using single particle cryogenic electron microscopy (cryo-EM), we show that the antibody recognises a conformational epitope at the gp120-gp41 interface. ELC07 binds the closed state of the viral glycoprotein causing considerable perturbations to the gp41 trimer core structure. Phenotypic analysis of memory B cell subsets from the ELC07 bnAb donor revealed a lack of expected HIV-1-associated dysfunction, specifically no increase in CD21-/CD27- cells was observed whilst the resting memory (CD21+/CD27+) population appeared preserved despite uncontrolled HIV-1 viraemia. Moreover, single cell transcriptomes of memory B cells from this bnAb donor showed a resting memory phenotype irrespective of the epitope they targeted or their ability to neutralise diverse strains of HIV-1. Strikingly, single memory B cells from the ELC07 bnAb donor were transcriptionally similar to memory B cells from HIV-negative individuals. Our results demonstrate that potent bnAbs can arise without the HIV-1-induced dysregulation of the memory B cell compartment and suggest that sufficient levels of antigenic stimulation with a strategically designed immunogen could be effective in HIV-negative vaccine recipients.

microbiology↗

bioRxiv2023

Investigating the role of Mce proteins in Mycobacterium avium paratuberculosis infection

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johnes Disease, a chronic granulomatous enteritis of ruminants. MAP establishes an infection in the host via the small intestine. This requires the bacteria to adhere to and be internalised by cells of the intestinal tract. The effector molecules expressed by MAP for this remain to be fully identified and understood. The mammalian cell entry (Mce) proteins play an essential role for other Mycobacterial species to facilitate the attachment and invasion of host epithelial cells. Here, we have expressed Mce1A, Mce1D, Mce3C and Mce4A proteins derived from MAP on the surface of a non-invasive E. coli host to characterise their role in the initial interaction between MAP and the host. To this end, mce1A was found to significantly increase the ability of the E. coli to attach and survive intracellularly in THP-1 cells, and mce1D was found to significantly increase attachment and invasion of MDBK cells. Both genes were implicated in the increased ability of E. coli to infect 3D bovine basal-out enteroids. Together, these results have identified two effector molecules used by MAP with a degree of cell-type specificity.

microbiology↗

bioRxiv2022

The immune response to lumpy skin disease virus in cattle is influenced by inoculation route

Lumpy skin disease virus (LSDV) causes severe disease in cattle and water buffalo and is transmitted by hematophagous arthropod vectors. Detailed information of the adaptive and innate immune response to LSDV is limited, hampering the development of tools to control the disease. This study provides an in-depth analysis of the immune responses of calves experimentally inoculated with LSDV via either needle-inoculation or arthropod-inoculation using virus-positive Stomoxys calcitrans and Aedes aegypti vectors. Seven out of seventeen needle-inoculated calves (41%) developed clinical disease characterised by multifocal necrotic cutaneous nodules. In comparison 8/10 (80%) of the arthropod-inoculated calves developed clinical disease. A variable LSDV-specific IFN-{gamma} immune response was detected in the needle-inoculated calves from 5 days post inoculation (dpi) onwards, with no difference between clinical calves (developed cutaneous lesions) and nonclinical calves (did not develop cutaneous lesions). In contrast a robust and uniform cell-mediated immune response was detected in all eight clinical arthropod-inoculated calves, with little response detected in the two nonclinical arthropod-inoculated calves. Neutralising antibodies against LSDV were detected in all inoculated cattle from 5-7 dpi. Comparison of the production of anti-LSDV IgM and IgG antibodies revealed no difference between clinical and nonclinical needle-inoculated calves, however a strong IgM response was evident in the nonclinical arthropod-inoculated calves but absent in the clinical arthropod-inoculated calves. This suggests that early IgM production is a correlate of protection in LSD. This study presents the first evidence of differences in the immune response between clinical and nonclinical cattle and highlights the importance of using a relevant transmission model when studying LSD.

immunology↗

bioRxiv2022

Development of 3D bovine intestinal organoid derived models to investigate Mycobacterium avium ssp paratuberculosis pathogenesis

Mycobacterium avium subspecies paratuberculosis (MAP) is the etiologic agent of Johnes Disease, a chronic enteritis of ruminants prevalent across the world. It is estimated that approximately 50% of UK dairy herds are infected with MAP, but this is likely an underestimate of the true prevalence. Infection can result in reduced milk yield, infertility and premature culling of the animal, leading to significant losses to the farming economy and negatively affecting animal welfare. Understanding the initial interaction between MAP and the host is critical to develop improved diagnostic tools and novel vaccines. Here we describe the characterisation of three different multicellular in vitro models derived from bovine intestinal tissue, and their use for the study of cellular interactions with MAP. In addition to the previously described basal-out 3D bovine enteroids, we have established viable 2D monolayers and 3D apical-out organoids. The apical-out enteroids differ from previously described bovine enteroids as the apical surface is exposed on the exterior surface of the 3D structure, enabling study of host-pathogen interactions at the epithelial surface without the need for microinjection. We have characterised the cell types present in each model system using RT-qPCR to detect predicted cell type-specific gene expression and confocal microscopy for cell type-specific protein expression. Each model contained the cells present in the bovine ileum and were therefore representative of the bovine gut. Exposure of the three model systems to the reference strain MAP K10, and a recent Scottish isolate referred to as C49, led to the observation of intracellular bacteria by confocal microscopy. Enumeration of the bacteria by genome copy number quantification, indicated that K10 was less invasive than C49 at early time points in infection in all model systems. This study shows that bovine enteroid-based models are permissive to infection with MAP and that these models may be useful in investigating early stages of MAP pathogenesis in a physiologically relevant in vitro system, whilst reducing the use of animals in scientific research.

microbiology↗

bioRxiv2021

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

immunology↗

bioRxiv2020

Functional Predictors of Causative Cis-Regulatory Mutations in Mendelian Disease

Undiagnosed neurodevelopmental disease is significantly associated with rare variants in cis-regulatory elements (CRE) but demonstrating causality is challenging as target gene consequences may differ from a causative variant affecting the coding region. Here, we address this challenge by applying a procedure to discriminate likely diagnostic regulatory variants from those of neutral/low-penetrant effect. We identified six rare CRE variants using targeted and whole genome sequencing in 48 unrelated males with apparent X-linked intellectual disability (XLID) but without detectable coding region variants. These variants segregated appropriately in families and altered conserved bases in predicted CRE targeting known XLID genes. Three were unique and three were rare but too common to be plausibly causative for XLID. We compared the cis-regulatory activity of wild-type and mutant alleles in zebrafish embryos using dual-color fluorescent reporters. Two variants showed striking changes: one plausibly causative (FMR1CRE) and the other likely neutral/low-penetrant (TENM1CRE). These variants were "knocked-in" to mice and both altered embryonic neural expression of their target gene. Only Fmr1CRE mice showed disease-relevant behavioral defects. FMR1CRE is plausibly disease-associated resulting in complex misregulation of Fmr1/FMRP rather than loss-of-function. This is consistent both with absence of Fragile X syndrome in the probands and the observed electrophysiological anomalies in the FMR1CRE mouse brain. Although disruption of in vivo patterns of endogenous gene expression in disease-relevant tissues by CRE variants cannot be used as strong evidence for Mendelian disease association, in conjunction with extreme rarity in human populations and with relevant knock-in mouse phenotypes, such variants can become likely pathogenic.

genetics↗