Biology subjects

Chambers, M.

Publications and source records attributed to Chambers, M..

9 recordsLinked to original sources

bioRxiv2026

A genome-wide catalog of sites where peripheral DNA methylation reflects the brain

Epigenetic studies of psychiatric and neurological disorders rely largely on peripheral tissues, yet where peripheral DNA methylation (DNAm) reflects the brain remains unclear. We generated a paired brain and peripheral DNAm dataset from 148 donors in three cohorts and combined it with five published cohorts for consensus brain-peripheral correlations. By cross-validation across cohorts, we defined brain epigenome shared sites (BrESS), more than 100,000 CpGs per tissue at which peripheral DNAm reproducibly predicts brain DNAm. BrESS lay at promoters active in both brain and periphery and in housekeeping genes, and most were not explained by genetic effects. BrESS did not contribute to the heritability of seven disorders, and CpGs from epigenome-wide association studies of these disorders were not enriched at BrESS. Peripheral DNAm reflects the brain mainly in a regulatory compartment shared across tissues, outside which disease signals largely lie, and BrESS separate peripheral signals attributable to the brain from others.

neuroscience↗

bioRxiv2026

Isolation of postnatal human neural stem cells

While it was once thought that neurogenesis is complete by birth, it is now apparent that the human brain continues to generate new neurons postnatally, at least into childhood. While much attention has been focused on postnatally-born neurons, their presumed progenitor - the postnatal neural stem cell (NSC) - remains poorly characterized. Using index sorting, we identify and prospectively isolate two subsets of NSCs from the postnatal human brain, and describe their differentiation dynamics using clonal barcoding and in vivo xenotransplantation. We demonstrate an A2B5+EGFR+ population biased towards interneuron and oligodendrocyte fates (NINO), and an A2B5-EGFRhi population biased towards an astrocyte fate (NAC). Profiling of human brains across lifespan shows that the frequency of NSCs declined exponentially across the first two decades of life, but stabilized thereafter, still present in the brains of donors as old as 90 years. Our study provides a framework for the functional study of postnatal human NSCs and their potential roles in development, aging, and disease.

neuroscience↗

bioRxiv2025

Data-driven Analysis of Fine-Scale Badger Movement in the UK

Understanding animal movements at different spatial scales presents a significant challenge as their patterns can vary widely from daily foraging behaviours to broader migration or territorial movements. This challenge is of general interest because it impacts the ability to manage wildlife populations effectively. In this study, we conduct diffusion analysis based on European badger (Meles meles) movement data obtained from three different regions in the UK (Gloucestershire, Cornwall, and Northern Ireland) and fit a generalised linear mixed-effects model to examine the relationship between variables. We also feature a novel application of extended dynamic mode decomposition (EDMD) to uncover patterns relating to badger social organisation. By applying our approach to these different populations, we were able to assess its performance across a range of badger densities. A key result was that in some areas, EDMD clusters matched observed group home ranges, whilst in others, discrepancies likely arose because of population management interventions, such as badger culling. The methods presented offer a promising approach for studying territoriality and the impacts of management strategies on animal movement behaviour. Author summaryWild animals move for many reasons, such as searching for food, finding mates, or maintaining territories, and these movements can be affected by changes in their environment. In this comparative study, we focused on European badgers, a social species whose movements are important for understanding behaviour and disease spread. Using GPS data from different locations around the UK, we explore how badger movement patterns vary both from day to day and over longer periods, revealing differences by sex, season, and region. The core contribution of this study lies in the novel application of extended dynamic mode decomposition (EDMD) alongside a more established generalised linear mixed-effects model (GLMM), together capturing movement dynamics across multiple timescales. These tools offer a new way to interpret animal behaviour including territoriality, and can be adapted to other species and ecological contexts. While dependent on tracking data, this approach lays the groundwork for future tools that may inform wildlife management and policy in conservation and disease control.

ecology↗

bioRxiv2024

Koina: Democratizing machine learning for proteomics research

Recent developments in machine-learning (ML) and deep-learning (DL) have immense potential for applications in proteomics, such as generating spectral libraries, improving peptide identification, and optimizing targeted acquisition modes. Although new ML/DL models for various applications and peptide properties are frequently published, the rate at which these models are adopted by the community is slow, which is mostly due to technical challenges. We believe that, for the community to make better use of state-of-the-art models, more attention should be spent on making models easy to use and accessible by the community. To facilitate this, we developed Koina, an open-source containerized, decentralized and online-accessible high-performance prediction service that enables ML/DL model usage in any pipeline. Using the widely used FragPipe computational platform as example, we show how Koina can be easily integrated with existing proteomics software tools and how these integrations improve data analysis.

bioinformatics↗

bioRxiv2024

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identified pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protected against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.

cell biology↗

bioRxiv2024

Variation in drug penetration does not account for the natural resistance of Mycobacterium abscessus biofilms to antibiotic

Mycobacterium abscessus, an inherently drug-resistant, opportunistic, nontuberculous mycobacterium (NTM) predominantly causes pulmonary infections in immunocompromised patients, notably those with cystic fibrosis. M. abscessus subspecies display distinct colony morphologies (rough and smooth), with the prevalent view that M. abscessus (smooth) is a persistent, biofilm-forming phenotype, whilst M. abscessus (rough) is unable to form biofilms. Biofilm formation contributes to persistent infections and exhibits increased antibiotic resistance. We used the chemical mapping technique, nanoscale secondary ion spectrometry (NanoSIMS), to investigate if variations in the biofilm morphology and antibiotic penetration account for the antibiotic susceptibility amongst M. abscessus subspecies, contributing to increased antimicrobial resistance (AMR) and potentially explaining the protracted treatment duration. The susceptibility to bedaquiline (BDQ) of M. abscessus grown as planktonic bacilli and biofilms was measured. The minimum biofilm eradication concentration (MBEC) of BDQ was 8-16 times higher (2-4{micro}g/ml) compared with the minimum inhibitory concentration (MIC) (0.25{micro}g/ml), indicating reduced efficacy against biofilms. Correlative imaging with electron microscopy revealed that M. abscessus (irrespective of the colony morphotype) formed biofilms and that BDQ treatment influenced biofilm morphology. We determined that M. abscessus morphotypes exhibit differential uptake of the antibiotic BDQ in biofilms. M. abscessus subsp. abscessus (smooth) biofilms exhibited the least uptake of BDQ, whereas M. abscessus subsp. bolletii biofilms showed the greatest antibiotic penetration. NanoSIMS analysis revealed no correlation between antibiotic penetration and drug efficacy within the biofilm. This challenges the previous assumption linking biofilm architecture to drug efficacy. Investigating other biofilm characteristics like antibiotic persistence could lead to enhanced treatment approaches. Significance StatementMycobacterium abscessus is an increasingly prevalent pathogen, most often causing lung infections in immunocompromised individuals. Their distinct morphotypes and biofilm-forming capabilities contribute to persistent infections, rendering them challenging to treat with increased antibiotic resistance. This research demonstrates that the antibiotic, bedaquiline exhibits significantly reduced efficacy against M. abscessus growing as a biofilm compared to planktonic growth, but that the efficiency of antibiotic penetration was not the main explanation for the different susceptibilities of MABC biofilms to treatment.

microbiology↗

bioRxiv2020

Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria and produce parasite inhibitory IgM

IgG antibodies are known to play a central role in naturally acquired immunity to blood-stage malaria in humans, but little is known about the IgM response to blood-stage malaria, the mechanisms by which IgM may protect, or the underlying biology of Plasmodium falciparum (Pf)-specific IgM B cells. In a Mali cohort spanning infants to adults we conducted a longitudinal analysis of B cells specific for the Pf blood-stage antigens AMA1 and MSP1, as well as the comparator antigen influenza hemagglutinin (HA). At the uninfected baseline, before the malaria season, Pf-specific memory B cells (MBCs) in children are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to HA-specific MBCs that are predominantly IgG+ from infancy to adulthood. In response to acute febrile malaria, Pf-specific IgM B cells increase in frequency and upregulate activation and co-stimulatory markers. B cell receptor (BCR) analysis showed that Pf-specific IgM B cells are somatically hypermutated at levels comparable to HA-specific IgG B cells. Finally, IgM antibodies from the plasma of malaria-exposed individuals were comparable to IgG in inhibiting Pf blood-stage growth in vitro, and significantly better at enhancing phagocytosis of Pf merozoites, suggesting that IgM may protect through both direct neutralization and opsonization. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in early life, are activated and expand during acute malaria and are associated with plasma IgM that inhibits parasite growth in vitro.

immunology↗

bioRxiv2018

Outflanking Immunodominance to Target Subdominant Broadly Neutralizing Epitopes

A major obstacle to vaccination to antigenically variable viruses is skewing of antibody responses to immunodominant epitopes. For influenza virus hemagglutinin (HA), the immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem only-constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, co-immunization of HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming immunodominance with important implications for human vaccination.

immunology↗

bioRxiv2018

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

A central goal of HIV-1-vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion-stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryo-electron microscopy structures of these antibodies revealed fusion peptide-conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses suggesting translatability. The N terminus of the HIV-1-fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

immunology↗