Biology subjects

Evans, N. J.

Publications and source records attributed to Evans, N. J..

5 recordsLinked to original sources

bioRxiv2025

GlpR Regulates Motility and Viscoelasticity Properties of Pseudomonas aeruginosa

Despite the onset of highly effective modulator therapies people with Cystic Fibrosis continue to experience recurrent microbial lung infections. Many of these individuals will have at least one positive culture per year for Pseudomonas aeruginosa, a bacterium that readily adapts to chronic CF airway disease. Of these adaptations, the formation of a protective biofilm and changes in motility are hallmarks of established infections. We have shown previous evidence that glycerol metabolism and the P. aeruginosa glycerol regulon repressor, GlpR, is linked to enhanced biofilm production and reduced susceptibility to tobramycin. In the current study, we report that loss of GlpR contributes to higher viscosity and elasticity in synthetic cystic fibrosis sputum media. Further, we show that the loss of the glycerol repressor GlpR, or growth on glycerol, both resulting in derepression of the GlpR/glycerol regulon, cause decreased motility in both acute and chronic CF-adapted lab strains. RNA sequencing analysis indicated that loss of GlpR altered the expression of genes involved in motility, iron scavenging, transport, metabolism, and virulence. An in silico search of P. aeruginosas genome using GlpRs previously determined binding consensus site identified potential bindings sites in genes related to biofilm development, motility, antibiotic resistance, and metabolism, and these binding sites were confirmed using chromatin immunoprecipitation sequencing. Collectively, our results indicate that GlpR regulates P. aeruginosa phenotypes that facilitate persistence in the CF airway and we provide evidence that GlpR regulates genes outside of the canonical glp regulon. IMPORTANCEPseudomonas aeruginosa continues to persist in the airways of individuals with cystic fibrosis (CF), even with modulator therapy. The nutritional environment of the CF airway has been shown to trigger the microevolution of P. aeruginosa to assist this bacterium in adaptation and persistence. P. aeruginosa can liberate glycerol from lung surfactant to use as a nutritional source. Previous studies have shown that glycerol metabolic genes are constitutively expressed in P. aeruginosa isolates recovered from CF sputum, highlighting the importance of the glp (glycerol) regulon, which is regulated by the transcriptional repressor, GlpR. Since glycerol is a critical nutritional source for P. aeruginosa adaptation, it is essential to understand the regulatory network controlled by GlpR.

microbiology↗

bioRxiv2025

Shotgun metagenomic analysis of the oral microbiomes of children with noma reveals a novel disease-associated organism

Noma is a rapidly progressive orofacial gangrene that predominantly affects children living in extreme poverty. Despite its documentation since antiquity and its designation as a World Health Organisation Neglected Tropical Disease in 2023, the microbiological cause of noma remains poorly understood, with no specific organisms confidently identified as definitive aetiological agents. Here, we present the first deep shotgun metagenomic profiling of oral saliva microbiomes from 19 Nigerian children with acute noma. Our analyses reveal marked microbial dysbiosis in noma microbiomes, with machine learning and multivariate statistical analyses indicating significant enrichment of Treponema, Porphyromonas, and Bacteroides, alongside depletion of Streptococcus and Rothia, as key microbial signatures of noma disease. From the dataset we recovered 40 high-quality Treponema metagenome-assembled genomes (MAGs) spanning 19 species, 14 of which were novel. Notably, a novel species designated Treponema sp. A was detected in 15 of the 19 noma participants and was entirely absent from global healthy saliva metagenomes. Re-analysis of previously published 16S rRNA datasets from children with noma in Niger also revealed Treponema sp. A to be highly prevalent in noma cases but rare in controls. This study identifies Treponema--particularly Treponema sp. A--as a strong candidate organism associated with noma pathogenesis. Additionally, analysis of antimicrobial resistance determinants detected in noma metagenomes revealed concerning levels of resistance to antibiotics commonly used in noma treatment, particularly {beta}-lactams and metronidazole, especially among Prevotella species. These findings provide the first high-resolution microbial framework for noma and offer a foundation for future research into its pathogenesis and the development of novel diagnostics, therapeutics, and preventive strategies in endemic settings.

pathology↗

bioRxiv2025

Activation of the Pseudomonas aeruginosa Glycerol Regulon Promotes Antibiotic Persistence and Modulates Virulence Phenotypes

Chronic infections with Pseudomonas aeruginosa are a major contributor of lung decline in persons with cystic fibrosis (pwCF). P. aeruginosa establishes life-long infections in the CF airway by utilizing various adaptation strategies to persist, including altering the expression of metabolic genes to acquire nutrients that are abundant in the CF airway. Glycerol, which is readily available in the airway, is imported and metabolized by genes in the glp regulon, which is under the control of the GlpR repressor. Previously, it has been shown that the loss of GlpR results in increased biofilm development in a CF-adapted isolate of P. aeruginosa compared to a wound isolate. Based on the increased biofilm phenotype previously observed and because biofilms are associated with increased antibiotic tolerance, we questioned whether GlpR plays a role in mediating antibiotic resistance of P. aeruginosa. In this report, we show that loss of GlpR increases tobramycin resistance of a CF-adapted isolate in synthetic sputum and in airway epithelial cell and Drosophila melanogaster colonization models. Further, transcriptomics analysis revealed that CF-adapted mutants of glpR overexpresses genes involved in multidrug tolerance and chronic infection phenotypes such as alginate. In summary, our study illustrates that activation of the glycerol (glp) regulon may promote P. aeruginosa persistence in the CF airway.

microbiology↗

bioRxiv2024

Graph Structured Neural Networks for Perturbation Biology

1Computational modeling of perturbation biology identifies relationships between molecular elements and cellular response, and an accurate understanding of these systems will support the full realization of precision medicine. Traditional deep learning, while often accurate in predicting response, is unlikely to capture the true sequence of involved molecular interactions. Our work is motivated by two assumptions: 1) Methods that encourage mechanistic prediction logic are likely to be more trustworthy, and 2) problem-specific algorithms are likely to outperform generic algorithms. We present an alternative to Graph Neural Networks (GNNs) termed Graph Structured Neural Networks (GSNN), which uses cell signaling knowledge, encoded as a graph data structure, to add inductive biases to deep learning. We apply our method to perturbation biology using the LINCS L1000 dataset and literature-curated molecular interactions. We demonstrate that GSNNs outperform baseline algorithms in several prediction tasks, including 1) perturbed expression, 2) cell viability of drug combinations, and 3) disease-specific drug prioritization. We also present a method called GSNNExplainer to explain GSNN predictions in a biologically interpretable form. This work has broad application in basic biological research and pre-clincal drug repurposing. Further refinement of these methods may produce trustworthy models of drug response suitable for use as clinical decision aids. Availability and implementationOur implementation of the GSNN method is available at https://github.com/nathanieljevans/GSNN. All data used in this work is publicly available.

bioinformatics↗

bioRxiv2022

Imputed genomes and haplotype-based analyses of the Picts of early medieval Scotland reveal fine-scale relatedness between Iron Age, early medieval and the modern people of the UK.

The origins and ancestry of the Picts of early medieval Scotland (ca. AD 300-900) has been traditionally seen as a problem, prompted in part by exotic medieval origin myths, their enigmatic symbols and inscriptions, and the meagre textual evidence. The Picts, first mentioned in the late 3rd century AD resisted the Romans and went on to form a powerful kingdom that ruled over a large territory in northern Britain. In the 9th and 10th centuries Gaelic language, culture and identity became dominant, transforming the Pictish realm into Alba, the precursor to the medieval kingdom of Scotland. To date, no comprehensive analysis of Pictish genomes has been published, and questions about their biological relationships to other cultural groups living in Britain remain unanswered. Here we present two high-quality Pictish genomes (2.4 and 16.5X coverage) from central and northern Scotland dated from the 5th-7th century which we impute and co-analyse with >8,300 previously published ancient and modern genomes. Using allele frequency and haplotype-based approaches, we can firmly place the Pictish genomes within the Iron Age gene pool in Britain and demonstrate local biological affinity. We also demonstrate the presence of population structure within Pictish groups, with Orcadian Picts being genetically distinct from their mainland contemporaries. When investigating Identity-By-Descent (IBD) with present-day genomes, we observe broad affinities between the mainland Pictish genomes and the present-day people living in western Scotland, Wales, Northern Ireland and Northumbria, but less with the rest of England, the Orkney islands and eastern Scotland - where the political centres of Pictland were located. The pre-Viking Age Orcadian Picts evidence a high degree of IBD sharing across modern Scotland, Wales, Northern Ireland, and the Orkney islands, demonstrating substantial genetic continuity in the Orkney for the last ~2,000 years. Analysis of mitochondrial DNA diversity at the Pictish cemetery of Lundin Links (n = 7) reveals absence of female endogamy, with implications for broader social organisation. Overall, our study provides novel insights into the genetic affinities and population structure of the Picts and direct relationships between ancient and present-day groups of the UK.

genomics↗