Biology subjects

Matthews, S.

Publications and source records attributed to Matthews, S..

13 recordsLinked to original sources

bioRxiv2026

A gene-centric analysis of copy number variation reveals tumour suppressor modulation of cancer risk and novel associations with common diseases

Copy number variants (CNVs) are a significant source of genomic variation in humans. They can span large genomic regions that encompass whole genes and their flanking regions, having the potential to alter the number of functional copies in an individual. Typically, CNVs are analysed individually or combined into regions without regard to the genes they span. Here, we employ a gene-centric approach to link changes in whole-gene copy number to phenotype. We first examined the relationship between CNVs spanning whole genes and gene expression using data from GTEx and found that predicted effects on gene expression are often realised. Applying this method, we identified 34 gene deletions associated with cancer incidence, including several novel candidate associations. Most notably, we discovered that gene deletions in the 13q14 region are linked to increased cancer risk, a novel extension of a known somatic association to the germline, which we did not find using region-based methods. Statistical associations were found between whole-gene loss of tumour suppressor genes and overall cancer risk, as hypothesized. It was additionally found that the total number of whole-gene losses was strongly associated with increased cancer risk, even when known cancer-related genes are not included in the count. Finally, we extended these methods to non-cancer phenotypes, uncovering significant associations with common diseases, including asthma and heart attack.

genomics↗

bioRxiv2026

CoralBlox: A computationally efficient coral model for decision support

Coral reef management under climate change is challenging due to data sparsity and high uncertainty, yet it is essential for informing conservation strategies. We present CoralBlox, a mechanistic discrete time coral ecology model with the explicit aim of supporting rapid scenario exploration and decision making. The model represents discretized distributions of five coral functional groups across configurable spatial scales while incorporating key ecological processes, including coral growth, reproduction, thermal adaptation, and responses to disturbances. Validation against observed data demonstrates that CoralBlox effectively captures major trends in coral cover dynamics across the Great Barrier Reef, particularly for bleaching-driven mortality and recovery patterns. While simplifying ecological complexities, the model maintains sufficient ecological realism to evaluate and compare the result of distinct management strategies. CoralBlox enables comprehensive assessment of potential management interventions with high computational efficiency and interoperability. The model's flexible architecture makes it extensible to coral ecosystems worldwide, providing valuable exploratory capability for reef management.

ecology↗

bioRxiv2026

Long-range PCR amplification and nanopore sequencing of 8-10 kb mitochondrial fragments from environmental DNA

O_LILong-read sequencing data can provide increased taxonomic resolution and genomic linkage information that is otherwise impossible to obtain from short-read amplicon or shotgun sequencing. However, the use of long-read sequencing for environmental DNA (eDNA) analysis has thus far been limited by both the apparent rarity of long DNA molecules in eDNA samples and the lack of established bioinformatics workflows for long-read metabarcoding, particularly from mixed template samples. C_LIO_LIHere, we report nanopore sequencing of 8.0 - 9.5 kb mitochondrial fragments obtained from mesocosm and field eDNA samples, amplified with long-range PCR (LR-PCR) using primers designed to preferentially amplify teleost mitogenomes. C_LIO_LIWe recovered half-mitochondria from 13 fish species in field-collected samples (Puget Sound in Washington State, USA), as well as from approximately half of the fish species inhabiting the positive control mesocosm (the Seattle Aquarium). Among biological replicates, we observed consistent detection of read-abundant species, while there was greater stochasticity in the presence of rarer species. C_LIO_LIWe demonstrate that long fragments can be obtained from standard eDNA samples and successfully amplified and sequenced to obtain species identifications despite higher error rates characteristic of nanopore sequencing. We present both laboratory methods and an accessible bioinformatic pipeline for obtaining and analyzing LR-PCR amplified fragments from eDNA, providing a framework for future long-read metabarcoding studies. C_LI

bioinformatics↗

bioRxiv2025

MsyB-HU Interaction Modulates a Two-Tiered Bacterial Stress Response by Regulating DNA Supercoiling

Bacteria respond to stressful conditions through multiple pathways, including changes in gene expression patterns and mutations for adaptation. DNA supercoiling is a fundamental regulatory principle of bacterial gene expression, controlled antagonistically by DNA gyrase and topoisomerase I. Nucleoid-associated proteins, such as HU, also regulate supercoiling through interactions with DNA. Here, we identify Escherichia coli protein MsyB as a HU inhibitor and a {beta}-clamp binder. MsyB is fine-tuned under various stressful conditions, where it modulates the population of DNA-bound HU by forming a HU-MsyB complex. Consequently, the balance between DNA-bound HU and MsyB-bound HU adjusts the DNA supercoiling state, thereby influencing transcription for adaptation. Additionally, under prolonged starvation during the stationary phase, sustained high level of MsyB increases DNA exposure to damaging factors, acting as a damage inducer. The HU/MsyB/{beta}-clamp interaction suggests a model in which MsyB coordinates with HU and the {beta}-clamp to facilitate damage acquisition and error-prone DNA repair. Thus, MsyB-dependent supercoiling regulation represents a novel two-tiered bacterial stress response mechanism in gene expression and adaptive mutation. Our findings reveal a previously unrecognized regulatory mechanism of bacterial supercoiling, positioning HU as a promising antibiotic target.

microbiology↗

bioRxiv2024

Enhanced antifungal activity of NK-92 cells against Candida albicans mediated by a mannan-specific chimeric antigen receptor

Chimeric antigen receptors (CARs) offer promising prospects for innovative cell-based therapies against invasive fungal infections such as invasive candidiasis. Here, we have developed four CARs targeting Candida albicans with distinct single-chain variable fragments (scFvs): scFv3-CAR, scFv5-CAR, scFv12-CAR, and scFv{kappa}3-1-CAR. In T cells, scFv5-CAR induced IL-2 expression in response to C. albicans hyphae, while scFv3-CAR and scFv12-CAR did not mediate cell activation against C. albicans. Notably, scFv{kappa}3-1-CAR mediated the strongest cell activation against C. albicans yeast, hyphae, and other clinically relevant Candida species. scFv{kappa}3-1-CAR-NK-92 cells exhibited elevated IFN-{gamma} and CD107a expression, reducing C. albicans viability. NOD scid gamma (NSG) mice treated with scFv{kappa}3-1-CAR-NK-92 cells had reduced C. albicans burden in the kidney 24 hours postinfection. We showed that scFv{kappa}3-1-CAR targets C. albicans mannan but no other glycans in glycan microarray screening analyses. These findings reveal the scFv{kappa}3-1-CAR potential as a therapeutic strategy for treating Candida spp. by modifying peripheral blood mononuclear cells. ImportanceRecent studies on novel immunotherapies, including chimeric antigen receptor (CAR)-T cells, have shown promising results in preclinical models against invasive fungal infections (IFIs). However, the application of CAR technology in natural killer (NK) cells for treating IFIs remains unexplored. NK cells play a key role in early fungal clearance due to their antifungal activity mediated by granzymes, perforins, and the secretion of proinflammatory cytokines. This study is the first to demonstrate the feasibility and efficacy of CAR-modified NK cells targeting Candida spp. We provided proof-of-concept data showing that CAR-expressing NK cells exhibit enhanced activation and antifungal effects against clinically relevant Candida species by targeting mannan in the fungal cell wall. These findings are significant as they open new avenues for developing CAR-NK-based therapies to treat invasive candidiasis - a severe infection with limited treatment options and high mortality rates, particularly in immunocompromised patients.

bioengineering↗

bioRxiv2024

Risk-free polio vaccine: Recombinant expression systems for production of stabilised virus-like particles

Polioviruses have caused crippling disease in humans for centuries, prior to the successful development of vaccines in the mid-1900s, which dramatically reduced disease prevalence. Continued use of these vaccines, however, threatens ultimate disease eradication and achievement of a polio-free world. Virus-like particles (VLPs) that lack a viral genome represent a safer potential vaccine, although they require particle stabilization. Using our previously established genetic techniques to stabilize the structural capsid proteins, we demonstrate production of poliovirus VLPs of all three serotypes, from four different recombinant expression systems. We compare the antigenicity, thermostability and immunogenicity of these stabilized VLPs against the current inactivated polio vaccine, demonstrating equivalent or superior immunogenicity. Structural analyses of these recombinant VLPs provide a rational understanding of the stabilizing mutations and the role of potential excipients. Collectively, we have established these poliovirus stabilized VLPs as viable next-generation vaccine candidates for the future.

microbiology↗

bioRxiv2023

Structural and regulatory insights into the glideosome-associated connector from Toxoplasma gondii

The phylum of Apicomplexa groups intracellular parasites that employ substratedependent gliding motility to invade host cells, egress from the infected cells and cross biological barriers. The glideosome associated connector (GAC) is a conserved protein essential to this process. GAC facilitates the association of actin filaments with surface transmembrane adhesins and the efficient transmission of the force generated by myosin translocation of actin to the cell surface substrate. Here, we present the crystal structure of Toxoplasma gondii GAC and reveal a unique, supercoiled armadillo repeat region that adopts a closed ring conformation. Characterisation of the membrane binding interface within the C-terminal PH domain as well as an N-terminal fragment necessary for association with F-actin suggest that GAC adopts multiple conformations. A multi-conformational model for assembly of GAC within the glideosome is proposed.

biochemistry↗

bioRxiv2022

Uncovering the universality of self-replication in protein aggregation and its link to disease.

Fibrillar protein aggregates are a hallmark of the pathology of a range of human disorders, from prion diseases to dementias. Yet, the same aggregated structures that are formed in disease are also encountered in several functional contexts. The fundamental properties that determine whether these protein assembly processes are functional or, by contrast, pathological, have remained elusive. Here, we address this question by analysing the aggregation kinetics of a large set of self-assembling proteins, from those associated with disease, over those whose aggregates fulfil functional roles in biology, to those that aggregate only under artificial conditions. Remarkably, we find that essentially all systems that assemble by a nucleated-growth mechanism are capable of significant self-replication on experimentally accessible timescales. However, comparing the intrinsic timescales of self-replication with the timescales over which the corresponding aggregates form in a biological context yields a clear distinction; for aggregates which have evolved to fulfil a structural role, the rate of self-replication is too low to be significant on the biologically relevant timescale. By contrast, all analysed proteins that aggregate in the context of disease are able to self-replicate quickly compared to the timescale of the associated disease. Our findings establish the ability to self-replicate as both a ubiquitous property of protein aggregates and one that has the potential to be a key process across aggregation-related disorders.

biophysics↗

bioRxiv2022

Toxoflavin secreted by Pseudomonas alcaliphila inhibits growth of Legionella pneumophila and its host Vermamoeba vermiformis

Legionella pneumophila is a natural inhabitant of water systems. From there, it can be transmitted to humans by aerosolization resulting in severe pneumonia. Most large outbreaks are caused by cooling towers contaminated with L. pneumophila. The resident microbiota of the cooling tower is a key determinant for the colonization and growth of L. pneumophila. The genus Pseudomonas correlates negatively with the presence of L. pneumophila, but it is not clear which species is responsible. Therefore, we identified the Pseudomonas species inhabiting 14 cooling towers using a Pseudomonas-specific 16S rRNA amplicon sequencing strategy. Cooling towers free of L. pneumophila contained a high relative abundance of members from the Pseudomonas alcaliphila/oleovorans phylogenetic cluster. In vitro, P. alcaliphila JCM 10630 inhibited the growth of L. pneumophila on agar plates. Analysis of the P. alcaliphila genome revealed the presence of a genes cluster predicted to produce toxoflavin. L. pneumophila growth was inhibited by pure toxoflavin and by extract from P. alcaliphila culture found to contain toxoflavin by LC-ESI-MS. In addition, toxoflavin inhibits growth of Vermameoba vermiformis, a host cell of L. pneumophila. Our study indicates that P. alcaliphila may be important to restrict growth of L. pneumophila in water systems through the production of toxoflavin. A sufficiently high concentration is likely not achieved in the bulk water but might have a local inhibitory effect such as in biofilm.

microbiology↗

bioRxiv2021

On the genetic architecture of rapidly adapting and convergent life history traits in guppies

The genetic basis of traits can shape and constrain how adaptation proceeds in nature; rapid adaptation can be facilitated by polygenic traits, whereas polygenic traits may restrict re-use of the same genes in adaptation (genetic convergence). The rapidly evolving life histories of guppies in response to predation risk provide an opportunity to test this proposition. Guppies adapted to high- (HP) and low-predation (LP) environments in northern Trinidad evolve rapidly and convergently among natural populations. This system has been studied extensively at the phenotypic level, but little is known about the underlying genetic architecture. Here, we use an F2 QTL design to examine the genetic basis of seven (five female, two male) guppy life history phenotypes. We use RAD-sequencing data (16,539 SNPs) from 370 male and 267 female F2 individuals. We perform linkage mapping, estimates of genome-wide and per-chromosome heritability (multi-locus associations), and QTL mapping (single-locus associations). Our results are consistent with architectures of many-loci of small effect for male age and size at maturity and female interbrood period. Male trait associations are clustered on specific chromosomes, but female interbrood period exhibits a weak genome-wide signal suggesting a potentially highly polygenic component. Offspring weight and female size at maturity are also associated with a single significant QTL each. These results suggest rapid phenotypic evolution of guppies may be facilitated by polygenic trait architectures, but these may restrict gene-reuse across populations, in agreement with an absence of strong signatures of genetic convergence from recent population genomic analyses of wild HP-LP guppies.

evolutionary biology↗

bioRxiv2020

Effect of sub-lethal prenatal endotoxemia on murine placental transport systems and lipid homeostasis

Infection alters the expression of transporters that mediate the placental exchange of xenobiotics, lipids and cytokines. We hypothesized that lipopolysaccharide (LPS) modifies the expression of placental transport systems and lipid homeostasis. LPS (150 g/kg; i.p.) treatments were administered for 4 h or 24 h, animals were euthanized at gestational days (GD) 15.5 or 18.5, and maternal blood, foetuses and placentae were collected. Increased rates of foetal demise were observed at GD15.5 following LPS treatment, whereas at GD18.5, high rates of early labour occurred and were associated with distinct proinflammatory responses. LPS did not alter ABC transporter mRNA expression but decreased Fabppm at GD15.5 (LPS-4 h) and increased Fat/Cd36 lipid transporter mRNA at GD18.5 (LPS-4 h). At the protein level, breast cancer-related protein (BCRP) and Abcg1 levels were decreased in the placental labyrinth zone (Lz) at GD15.5, whereas P-glycoprotein (P-gp) and Bcrp Lz-immunostaining was decreased at GD18.5. In the placental junctional zone (Jz), P-gp, Bcrp and Abcg1 levels were higher at GD18.5. Specific maternal plasma and placental changes in triacylglycerol, free fatty acid, cholesterol, cholesterol ester and monoacylglycerol levels were detected in a gestational age-dependent manner. In conclusion, LPS-induced foetal death and early labour were associated with altered placental ABC and lipid transporter expression and deranged maternal plasma and placental lipid homeostasis. These changes likely modify foetal xenobiotic exposure and placental lipid exchange in cases of bacterial infection.

physiology↗

bioRxiv2020

Thermogenic hydrocarbons sustain diverse subseafloor microbial communities in deep sea cold seep sediments

At marine cold seeps, gaseous and liquid hydrocarbons migrate from deep subsurface origins to the sediment-water interface. Cold seep sediments are known to host taxonomically diverse microorganisms, but little is known about their metabolic potential and depth distribution in relation to hydrocarbon and electron acceptor availability. In this work, we combined geochemical, metagenomic and metabolomic measurements in distinct sediment redox regimes to profile microbial activities within the uppermost 350 cm of a newly discovered cold seep in the NW Atlantic deep sea (2.3 km water depth). Depth-resolved metagenomic profiling revealed compositional and functional differentiation between near-surface sediments (dominated by Proteobacteria) and deeper subsurface layers (dominated by Atribacteria, Chloroflexi, Euryarchaeota and Lokiarchaeota). Metabolic capabilities of community members were inferred from 376 metagenome-assembled genomes spanning 46 phyla (including five novel candidate phyla). In deeper sulfate-reducing and methanogenic sediments, various community members are capable of anaerobically oxidizing short-chain alkanes (alkyl-CoM reductase pathway), longer-chain alkanes (fumarate addition pathway), and aromatic hydrocarbons (fumarate addition and subsequent benzoyl-CoA pathways). Geochemical profiling demonstrated that hydrocarbon substrates are abundant in this location, thermogenic in origin, and subject to biodegradation. The detection of alkyl-/arylalkylsuccinate metabolites, together with carbon isotopic signatures of ethane, propane and carbon dioxide, support that microorganisms are actively degrading hydrocarbons in these sediments. Hydrocarbon oxidation pathways operate alongside other deep seabed metabolisms such as sulfide oxidation, hydrogen oxidation, carbon fixation, fermentation and reductive dehalogenation. Upward migrated thermogenic hydrocarbons thus sustain diverse microbial communities with activities that affect subseafloor biogeochemical processes across the redox spectrum in deep sea cold seeps.

microbiology↗

bioRxiv2018

A T7 phage factor required for managing RpoS in Escherichia coli

T7 development in Escherichia coli requires the inhibition of the housekeeping form of the bacterial RNA polymerase (RNAP), E{sigma}70, by two T7 proteins: Gp2 and Gp5.7. While the biological role of Gp2 is well understood, that of Gp5.7 remains to be fully deciphered. Here, we present results from functional and structural analyses to reveal that Gp5.7 primarily serves to inhibit E{sigma}S, the predominant form of the RNAP in the stationary phase of growth, which accumulates in exponentially growing E. coli as a consequence of buildup of guanosine pentaphosphate ((p)ppGpp) during T7 development. We further demonstrate a requirement of Gp5.7 for T7 development in E. coli cells in the stationary phase of growth. Our finding represents a paradigm for how some lytic phages have evolved distinct mechanisms to inhibit the bacterial transcription machinery to facilitate phage development in bacteria in the exponential and stationary phases of growth.\n\nSignificance statementVirus that infect bacteria (phages) represent the most abundant living entities on the planet and many aspects of our fundamental knowledge of phage-bacteria relationships have been derived in the context of exponentially growing bacteria. In the case of the prototypical Escherichia coli phage T7, specific inhibition of the housekeeping form of the RNA polymerase (E{sigma}70) by a T7 protein, called Gp2, is essential for the development of viral progeny. We now reveal that T7 uses a second specific inhibitor that selectively inhibits the stationary phase RNAP (E{sigma}S), which enables T7 to develop well in exponentially growing and stationary phase bacteria. The results have broad implications for our understanding of phage-bacteria relationships and therapeutic application of phages.

microbiology↗