Biology subjects

Russell, M.

Publications and source records attributed to Russell, M..

9 recordsLinked to original sources

bioRxiv2025

Rapid and Consistent Genome Clustering for Navigating Bacterial Diversity with Millions of MAGs and Isolates

Bacterial genome and metagenome databases collectively contain over 5 million high-quality assemblies. However, the redundancy of these databases and the limited scalability of existing tools create bottlenecks for fully comprehensive, tree-of-life-scale genomic analyses. A fundamental task is to first break this data into smaller chunks, guided by their genome similarity. However, alignment-based comparative methods struggle to handle more than a few tens of thousands of genomes at a time, making the global organisation computationally complex and expensive. Here, we present gemsparcl (https://github.com/johannahelene/gemsparcl), a tool that clusters bacterial genomes into genomic cohesive units (GCUs), at approximately species-level resolution, over 500 times faster than existing methods. As part of developing gemsparcl, we developed sketchlib.rust, a one-permutation MinHash approach that implements an auxiliary inverted index to further accelerate all-versus-all comparisons. We added a statistical correction for incomplete metagenome-assembled genomes (MAGs) to enable accurate distance estimation and network-based edge quality filtering. After genome completeness quality control, we clustered 5.6 million high-quality bacterial genomes (2.88 million isolates and 2.77 million MAGs) into 92,954 GCUs in [~]14 hours using 48 CPU threads and less than 16.5 GB of memory. Using taxonomic validation of the GCUs, the method achieves very high (99.76%) cluster purity (meaning only one species label occurs per GCU). We demonstrate that the clustering also highlights cases where taxonomic naming can be potentially harmonised or improved. Furthermore, we identify the most frequently reconstructed MAGs that lack a corresponding isolate genome and are thus priorities for culturing. The enhanced speed of gemsparcl enables routine database updates to incorporate the latest genomes. It also makes reference-free microbiome analysis across millions of genomes computationally tractable for the first time.

bioinformatics↗

bioRxiv2025

A Fourfold Male-Specific Lifespan Extension via Canonical Insulin/IGF-1 Signaling

Aging is a universal biological process driven by conserved genetic networks that balance somatic maintenance with growth and reproduction. The insulin/insulin-like growth factor I signaling pathway is a central architect of this balance, and inhibiting its activity has long been established as a primary mechanism to extend lifespan across diverse species. However, our understanding of this pathways limits has been constrained by a historical focus on hermaphroditic models, which inherently link longevity extensions to a rigid trade-off involving immense reproductive costs and restricted somatic growth. Here we show that the latent potential of this canonical aging pathway is profoundly amplified by male-specific biology. We demonstrate that a classic insulin receptor mutation extends male survival to an unprecedented extreme, vastly surpassing the established benchmarks of the field. We reveal that this extraordinary lifespan expansion remains strictly dependent on the canonical FOXO transcription factor, yet it fuels a male-specific metabolic reprogramming that uncouples aging from stunted growth--massively accumulating neutral lipids to support sustained somatic preservation. These findings establish biological sex as a primary determinant of longevity potential and provide a new framework for identifying hidden, sex-specific mechanisms capable of promoting extreme healthy longevity.

physiology↗

bioRxiv2025

The effects of morning priming exercise on afternoon physical and cognitive performance in male rugby union players

ObjectiveTo assess the effect of morning resistance exercise on afternoon physical and cognitive performance in male rugby union players. MethodsOn two occasions (randomised, crossover design), 25 male rugby union players completed morning physical (countermovement jump, 40 m linear sprint) and cognitive (rapid visual information processing; spatial working memory; paired associates of learning) assessments. Control (passive rest) or intervention (barbell back squat, 3 x 3 repetitions at 85% of one repetition maximum and barbell squat jump, 5 x 3 repetitions at 40% one repetition maximum) trials were implemented 5.5 h before afternoon assessments. ResultsDifferences between morning and afternoon assessments were found in sprinting performance following intervention for 30 m fly (-0.08 {+/-} 0.13 s, P = 0.001, ES: -0.75) and 40 m (-0.12 {+/-} 0.17 s, P = 0.004, ES: -0.62) relative to control (0.03 {+/-} 0.07 s, 0.01 {+/-} 0.09 s, 30 m fly and 40 m, respectively). Afternoon countermovement jump flight time improved following intervention compared to control (2% vs. 0%, p = 0.012). Delta analysis discovered significant differences from morning to afternoon in intervention (0.385 ms {+/-} 0.053) but not control (0.405 ms {+/-} 0.057). No changes were found for cognitive assessments (P > 0.05). ConclusionMorning lower body resistance exercise, incorporating a combination of high intensity and ballistic exercises, was an effective morning strategy to improve afternoon markers of physical but not cognitive performance in male rugby union players.

physiology↗

bioRxiv2024

Semi-automated navigation for efficient targeting of electron tomography to regions of interest in volume correlative light and electron microscopy

Electron microscopy is essential for the quantitative study of synaptic ultrastructure. At present, the correlation of functional and structural properties of the same synapse is extremely challenging. We introduce a novel integrated workflow designed to simplify sample navigation across spatial scales, allowing the identification of individual synapses from optical microscopy mouse brain image stacks that can be targeted for analysis using electron tomography imaging. We developed a software which has a function to register multimodal images using a novel segmentation-based image registration algorithm as well as a function to visualize all the registration results. Using our newly designed software we streamline mapping of high-resolution optical imaging onto reference maps using blood vessels as endogenous fiducial marks. Further we demonstrate significant improvements on the ultramicrotomy stage of volume Correlative Light and Electron Microscopy (vCLEM) workflows, providing real time guidance to targeted trimming to match previously acquired Regions Of Interest (ROIs), and reliable estimates of cutting depth relative to ROI, based on fluorescence imaging of TEM ready ultrathin sections. Using this workflow, we successfully targeted TEM tomography to the proximal axonal region containing the Axon Initial Segment identified using fluorescent light microscopy.

neuroscience↗

bioRxiv2024

Sex differences in oxycodone-taking behaviors are linked to disruptions in reward-guided, decision-making functions

Problematic opioid use that emerges in a subset of individuals may be due to pre-existing disruptions in the biobehavioral mechanisms that regulate drug use. The identity of these mechanisms is not known, but emerging evidence suggests that suboptimal decision-making that is observable prior to drug use may contribute to the pathology of addiction and, notably, serve as a powerful phenotype for interrogating biologically based differences in opiate-taking behaviors. The current study investigated the relationship between decision-making phenotypes and opioid-taking behaviors in male and female Long Evans rats. Adaptive decision-making processes were assessed using a probabilistic reversal-learning task and oxycodone- (or vehicle, as a control) taking behaviors assessed for 32 days using a saccharin fading procedure that promoted dynamic intake of oxycodone. Tests of motivation, extinction, and reinstatement were also performed. Computational analyses of decision-making and opioid-taking behaviors revealed that attenuated reward-guided decision-making was associated with greater self-administration of oxycodone and addiction-relevant behaviors. Moreover, pre-existing impairments in reward-guided decision-making observed in female rats was associated with greater oxycodone use and addiction-relevant behaviors when compared to males. These results provide new insights into the biobehavioral mechanisms that regulate opiate-taking behaviors and offer a novel phenotypic approach for interrogating sex differences in addiction susceptibility and opioid use disorders.

neuroscience↗

bioRxiv2023

Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious virus production

Oncogenic virus infections are estimated to cause [~]15% of all cancers. Two prevalent human oncogenic viruses are members of the gammaherpesvirus family: Epstein Barr Virus (EBV) and Kaposis Sarcoma Herpesvirus (KSHV). We use murine herpesvirus 68 (MHV-68), which shares significant homology with KSHV and EBV, as a model system to study gammaherpesvirus lytic replication. Viruses implement distinct metabolic programs to support their life cycle, such as increasing the supply of lipids, amino acids, and nucleotide materials necessary to replicate. Our data define the global changes in the host cell metabolome and lipidome during gammaherpesvirus lytic replication. Our metabolomics analysis found that MHV-68 lytic infection induces glycolysis, glutaminolysis, lipid metabolism, and nucleotide metabolism. We additionally observed an increase in glutamine consumption and glutamine dehydrogenase protein expression. While both glucose and glutamine starvation of host cells decreased viral titers, glutamine starvation led to a greater loss in virion production. Our lipidomics analysis revealed a peak in triacylglycerides early during infection and an increase in free fatty acids and diacylglyceride later in the viral life cycle. Furthermore, we observed an increase in the protein expression of multiple lipogenic enzymes during infection. Interestingly, pharmacological inhibitors of glycolysis or lipogenesis resulted in decreased infectious virus production. Taken together, these results illustrate the global alterations in host cell metabolism during lytic gammaherpesvirus infection, establish essential pathways for viral production, and recommend targeted mechanisms to block viral spread and treat viral induced tumors. IMPORTANCEViruses are intracellular parasites which lack their own metabolism, so they must hijack host cell metabolic machinery in order to increase the production of energy, proteins, fats, and genetic material necessary to replicate. Using murine herpesvirus 68 (MHV-68) as a model system to understand how similar human gammaherpesviruses cause cancer, we profiled the metabolic changes that occur during lytic MHV-68 infection and replication. We found MHV-68 infection of host cells increases glucose, glutamine, lipid, and nucleotide metabolic pathways. We also showed inhibition or starvation of glucose, glutamine or lipid metabolic pathways results in an inhibition of virus production. Ultimately, targeting changes in host cell metabolism due to viral infection can be used to treat gammaherpesvirus induced cancers and infections in humans.

microbiology↗

bioRxiv2022

Toxoplasma gondii ROP1 subverts murine and human innate immune restriction

Toxoplasma gondii is an intracellular parasite that can infect many different host species and is a cause of significant human morbidity worldwide. T. gondii secretes a diverse array of effector proteins into the host cell which are critical for infection; however, the vast majority of these secreted proteins are uncharacterised. Here, we carried out a pooled CRISPR knockout screen in the T. gondii Prugniaud strain in vivo to identify secreted proteins that contribute to parasite immune evasion in the host. We identify 22 putative virulence factors and demonstrate that ROP1, the first-identified rhoptry protein of T. gondii, has a previously unrecognised role in parasite resistance to interferon gamma-mediated innate immune restriction. This function is conserved in the highly virulent RH strain of T. gondii and contributes to parasite growth in both murine and human macrophages. While ROP1 affects the morphology of rhoptries, from where the protein is secreted, it does not affect rhoptry secretion. ROP1 interacts with the host cell protein C1QBP, which appears to facilitate parasite immune evasion. In summary, we identify 22 secreted proteins which contribute to parasite growth in vivo and show that ROP1 is an important and previously overlooked effector in counteracting both murine and human innate immunity.

microbiology↗

bioRxiv2019

Differential requirements of cyclase associated protein (CAP) for actin turnover during the lytic cycle of Toxoplasma gondii

Toxoplasma gondii contains a limited subset of actin binding proteins. Here we show that ablation of the putative actin regulator cyclase-associated protein (TgCAP) leads to significant defects in some but not all actin dependent processes, including a defect in cell-cell communication, but surprisingly not synchronicity of division. Two CAP isoforms originate from alternative translational start sites and are beneficial for parasite fitness while a single isoform is sufficient for virulence in mice. Examination of the mutant parasites by 3D electron microscopy reveals that loss of CAP results in a defect to form a normal residual body, but all parasites remain connected within the vacuole. This dissociates synchronicity of division and parasite rosetting and reveals that establishment and maintenance of the residual body may be more complex than previously thought. These results highlight the different spatial requirements for actin turnover in Toxoplasma, controlled by a reduced subset of actin binding proteins.

microbiology↗

bioRxiv2018

Identification and Characterisation of the CD40-Ligand of Sigmodon hispidus

Cotton rats are an important animal model to study infectious diseases. They have demonstrated higher susceptibility to a wider variety of human pathogens than other rodents and are also the animal model of choice for pre-clinical evaluations of some vaccine candidates. However, the genome of cotton rats remains to be fully sequenced, with much fewer genes cloned and characterised compared to other rodent species. Here we report the cloning and characterization of CD40 ligand, whose human and murine counterparts are known to be expressed on a range of cell types including activated T cells and B cells, dendritic cells, granulocytes, macrophages and platelets and exerts a broad array of immune responses. The cDNA for cotton rat CD40L we isolated is comprised of 1104 nucleotides with an open reading frame (ORF) of 783bp coding for a 260 amino acid protein. The recombinant cotton rat CD40L protein was recognized by an antibody against mouse CD40L. Moreover, it demonstrated functional activities on immature bone marrow dendritic cells by upregulating surface maturation markers (CD40, CD54, CD80, and CD86), and increasing IL-6 gene and protein expression. The availability of CD40L gene identity could greatly facilitate mechanistic research on pathogen-induced-immunopathogenesis and vaccine-elicited immune responses.

immunology↗