Biology subjects

Palmer, C. D.

Publications and source records attributed to Palmer, C. D..

4 recordsLinked to original sources

bioRxiv2025

Prokaryotic mechanosensitive channels mediate copper influx

Copper is an essential micronutrient in all kingdoms of life, requiring a meticulous balance between acquisition and toxic overload. While copper import in eukaryotes has been investigated extensively, few prokaryotic copper importers have been identified, leading to the notion that cytoplasmic copper uptake is unnecessary in prokaryotes. Here we report that mechanosensitive channels are key players in prokaryotic copper import. Deletion of the gene encoding the E. coli small mechanosensitive channel, EcMscS, leads to significantly reduced copper influx. Conversely, overexpression of EcMscS leads to increased copper influx, elevated intracellular copper content, and renders cells hypersensitive to copper. Furthermore, specific channel blockers and competing permeating ions inhibit EcMscS copper conductance, lowering intracellular copper accumulation and alleviating copper hypersensitivity. These findings extend beyond E. coli, as other prokaryotic small mechanosensitive channels of bacterial and archaeal origin also facilitate copper influx. Taken together, these results uncover a previously unknown moonlighting function for mechanosensitive channels as a pathway for prokaryotic copper uptake.

microbiology↗

bioRxiv2024

A novel HLA Class II presentation prediction algorithm deciphers immunogenic CD4 epitopes specific to KRAS G12C

Accurate prediction of peptide presentation by HLA molecules is important for generation of effective individualized cancer vaccines and immunotherapies. While presentation prediction algorithms for HLA class I have been successfully applied in the context of such therapies, improved prediction algorithms for class II are needed. EDGE-II is a novel algorithm based on a protein large language model that has a learned allele deconvolution network trained on existing and new immunopeptidomics data. It delivers state-of-the-art performance on prediction of peptide presentation by HLA class II and immunogenicity elicited by CD4+ T-cell epitopes. In a patient with a KRAS G12C positive tumor treated with a KRAS G12C targeting immunotherapy, EDGE-II identified KRAS G12C class II neoantigens that elicited clonally expanded CD4+ T cells with cytotoxic transcriptional profiles post-vaccination. EDGE-II could play an important role in the development of effective cancer immunotherapies by elucidating an enriched understanding of the immunopeptidome.

bioinformatics↗

bioRxiv2019

A schizophrenia risk locus alters brain metal transport and plasma glycosylation

A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease. SummaryA common variant in the manganese transporter SLC39A8 is associated with numerous phenotypes including schizophrenia. Mealer et. al. presents an in-depth analysis of brain MRI and plasma glycomics in human carriers of the common variant, identifying several manganese-related changes with potential for diagnostic and therapeutic biomarker development.

biochemistry↗

bioRxiv2019

Conjunctival microbiome-host responses are associated with impaired epithelial cell health in both early and late stages of trachoma

BackgroundTrachoma, a neglected tropical disease, is the leading infectious cause of blindness and visual impairment worldwide. Host responses to ocular chlamydial infection resulting in chronic inflammation and expansion of non-chlamydial bacteria are hypothesised risk factors for development of active trachoma and conjunctival scarring\n\nMethodsOcular swabs from trachoma endemic populations in The Gambia were selected from archived samples for 16S sequencing and host conjunctival gene expression. We recruited children with active trachoma and adults with conjunctival scarring, alongside corresponding matched controls.\n\nFindingsIn children, active trachoma was not associated with significant changes in the ocular microbiome. Haemophilus enrichment was associated with antimicrobial responses but not linked to active trachoma. Adults with scarring trachoma had a reduced ocular bacterial diversity compared to controls, with increased relative abundance of Corynebacterium. Increased abundance of Corynebacterium in scarring disease was associated with innate immune responses to the microbiota, dominated by altered mucin expression and increased matrix adhesion.\n\nInterpretationIn the absence of current C. trachomatis infection, changes in the ocular microbiome associate with antimicrobial and inflammatory responses that impair epithelial cell health. In scarring trachoma, expansion of non-pathogenic bacteria such as Corynebacterium and innate responses are coincident, warranting further investigation of this relationship. Comparisons between active and scarring trachoma supported the relative absence of type-1 interferon responses in scarring, whilst highlighting a common suppression of re-epithelialisation with altered epithelial and bacterial adhesion, likely contributing to development of scarring pathology.

microbiology↗