Biology subjects

Russell, K.

Publications and source records attributed to Russell, K..

12 recordsLinked to original sources

bioRxiv2026

A Spectrum of Free Energy Landscape Topologies Encodes Chromatin Polymorphism and Phase Separation

Chromatin exhibits structural polymorphism, yet how such substantial structural heterogeneity is encoded in its underlying free-energy landscape remains unknown. Here we map the folding landscapes of tetra-nucleosome arrays using adaptive Markov state models constructed from near-atomistic coarse-grained simulations. We find that chromatin is not governed by a single folding funnel analogous to those of many globular proteins. Instead, it spans a continuum of free-energy landscape topologies, ranging from funnelled to rugged to flat. Remarkably, phase separation reshapes chromatins free-energy landscape by stabilising conformations that maximise intermolecular connectivity, demonstrating that the landscape is determined not only by intrinsic molecular parameters but also by the environment and intermolecular interactions. Linker DNA geometry selects among landscape regimes through geometric frustration of zig-zag nucleosome stacking. At short and intermediate linker lengths, canonical 10N bp linkers produce funnelled landscapes dominated by compact zig-zag structures, whereas 10N +5 bp linkers generate rugged landscapes with multiple competing minima. Long linkers relieve frustration and flatten the landscape into a broad entropic basin. This control operates with single-base-pair precision, such that changing linker length by one base pair is sufficient to reorganise both the thermodynamics and kinetics of chromatin folding. DNA sequence provides a second level of control by modulating linker deformability, but only when zig-zag geometric frustration is present. These results establish free-energy landscapes as a framework for understanding the physical origin of chromatin polymorphism and its coupling to phase separation.

biophysics↗

bioRxiv2025

Near-atomistic simulations reveal the molecular principles that control chromatin structure and phase separation

Understanding how chromatins physicochemical properties shape its emergent organisation is central to deciphering genome function. To address this, we present OpenCGChromatin, a high-performance coarse-grained model that achieves near-atomistic simulations of chromatin systems an order of magnitude larger than previously possible, spanning biomolecular condensates and fibers tens of kilobases in length. OpenCGChromatin simulations independently predict, from physicochemical principles, the linker-DNA-dependent chromatin structures observed by cryo-ET and the relative thermodynamic stability of condensates inferred from biochemical assays. Crucially, OpenCGChromatin resolves histone-tail dynamics and interaction networks that remain inaccessible experimentally, explaining how linker-DNA length controls histone tail accessibility and the resulting multiscale structure of chromatin condensates. Extending simulations to 108-nucleosome fibers shows that acetylation disrupts chromatin compaction in a pattern-specific manner by weakening key tail-mediated interactions, with H4K16 and H3K9 emerging as the most energetically disruptive modifications. These results position OpenCGChromatin as a powerful framework for linking molecular detail to emergent chromatin organization.

biophysics↗

bioRxiv2025

Distinct druggable biological processes in early-onset prostate cancer

Despite advances in understanding and treating Prostate Cancer (PCa), there has been little effort to systematically map the biology distinguishing Early-(EOPCa) and Late-(LOPCa) onset PCa. Around 25% of EOPCa cases present with metastatic spread or aggressive disease with earlier metastatic development. Some available lines of therapy are extending treatment trajectories and prolonging lives. However, there remains a critical clinical need to identify new therapeutic targets for EOPCa where life expectancy necessitates safer, more targeted treatment options. To our knowledge, here we present the largest systematic analysis of molecular profiles in EOPCa versus LOPCa, employing machine-learning-enabled algorithms to identify distinguishing biology and druggable targets for each age group. Distinct stromal signatures are uncovered in EOPCa, which are used to propose therapeutic opportunities herein. Moreover, our analysis identifies 50 druggable targets, 11 of which we confirm in PCa cell line genetic/pharmacological perturbation data. These findings provide the first specific, testable hypotheses in EOPCa, offering avenues for experimental validation and potential therapeutic exploitation, and, more generally, shed light on the intricate and distinguished molecular profile of this aggressive, poorly understood disease. One Sentence SummaryMachine learning-enabled algorithms were utilized to identify distinguishing biology and associated druggable targets for early-onset prostate cancers.

cancer biology↗

bioRxiv2025

Bdnf-Ntrk2 Signaling Promotes but is not Essential for Spinal Cord Myelination in Larval Zebrafish

Myelin, a specialized membrane produced by oligodendroglial cells in the central nervous system, wraps axons to enhance conduction velocity and maintain axon health. Not all axons are myelinated, and not all myelinated axons are uniformly wrapped along their lengths. Several lines of evidence indicate that neuronal activity can influence myelination, however, the cellular and molecular mechanisms that mediate communication between axons and oligodendrocytes remain poorly understood. Prior research showed that the neurotrophic growth factor Bdnf and its receptor Ntrk2 promote myelination in rodents, raising the possibility that Bdnf and Ntrk2 convey myelin-promoting signals from neurons to oligodendrocytes. We explored this possibility using a combination of gene expression analyses, gene function tests, and myelin sheath formation assays in zebrafish larvae. Altogether, our data indicate that, although not essential for myelination, Bdnf-Ntrk2 signaling contributes to the timely formation of myelin in the developing zebrafish spinal cord.

developmental biology↗

bioRxiv2025

Multi-scale structure of chromatin condensates rationalizes phase separation and material properties

Biomolecular condensates, compartments that concentrate molecules without surrounding membranes, are integral to numerous cellular processes. The structure and interaction networks of molecules within condensates remain poorly understood. Using cryo-electron tomography and molecular dynamics simulations we elucidated the structure of phase separated chromatin condensates across scales, from individual amino acids to network architecture. We found that internucleosomal DNA linker length controls nucleosome arrangement and histone tail interactions, shaping the structure of individual chromatin molecules both within and outside condensates. This structural modulation determines the balance between intra- and intermolecular interactions, which in turn governs the molecular network, thermodynamic stability, and material properties of chromatin condensates. Mammalian nuclei contain dense clusters of nucleosomes whose non-random organization is mirrored by the reconstituted condensates. Our work explains how the structure of individual chromatin molecules ultimately determines physical properties of chromatin condensates, with implications for cellular chromatin organization.

biophysics↗

bioRxiv2024

A Randomized, Controlled Clinical Trial Demonstrates Improved Cognitive Function in Senior Dogs Supplemented with a Senolytic and NAD+ Precursor Combination.

Age-related decline in mobility and cognition are associated with cellular senescence and NAD+ depletion in dogs and people. A combination of a novel NAD+ precursor and senolytic, LY-D6/2 was examined in this randomized controlled trial. Seventy dogs were enrolled and allocated into placebo, low or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors. Fifty-nine dogs completed evaluations at the three-month primary endpoint, and 51 reached the six-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p=0.02) with the largest decrease in the full dose group. There were no significant differences between groups in changes in measured activity. However, the proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups. Adverse events occurred equally across groups. All groups showed improvement in cognition, frailty, and activity suggesting placebo effect and benefits of trial participation. We conclude that LY-D6/2 significantly improves owner-assessed cognitive function and may have broader effects on frailty, activity and happiness as reported by owners.

animal behavior and cognition↗

bioRxiv2022

Radioactive Contamination in Feral Dogs in the Chernobyl Exclusion Zone: Population Body-Burden Survey and Implications for Human Radiation Exposure

This report describes a two-year effort to survey the internal 137Cs and external {beta}-emitter contamination present in the feral dog population near the Chernobyl nuclear power plant (ChNPP) site, and to quantify the potential for human radiation exposure from this contamination. This work was performed as an integral part of the radiation safety and control procedures of an animal welfare oriented trap-neuter-release (TNR) program. The measurement program employed handheld {beta}-sensitive probes, and a simple whole-body counter to measure internal 137Cs burden during post-surgical observation and recovery. External {beta} contamination surveys performed during intake showed that 21/288 animals had significant, removable external contamination. Measurements with the whole-body counter indicated internal 137Cs body burdens ranging from undetectable (minimum detection level [~]100 Bq/kg in 2017, [~] 30 Bq/kg in 2018) to approximately 30,000 Bq/kg. A total of 33 animals had 137Cs body-burdens above 1 kBq/kg. We observe that internal contamination levels are positively correlated with capture locations within ChNPP boundaries. The large variation in the 137Cs concentration in these animals is not well-understood, could be due to prey selection, access to human food scraps, or extended residence in highly contaminated areas. These internally-contaminated animals are unlikely to pose an exposure hazard despite their large body-burdens due to their limited exposure to humans. However, the small minority of animals with external contamination may pose a contamination hazard to workers, tourists, and others interacting with the dogs, as evidenced by total quantity of removable activity and incidents of transfer to materials used in animal capture.

zoology↗

bioRxiv2021

MFN2 Influences Amyotrophic Lateral Sclerosis Pathology

ObjectiveTo better understand the pathology of amyotrophic lateral sclerosis, we used sequence data from patients seen at the University of Utah to identify novel disease-associated loci. We utilized both in vitro and in vivo studies to determine the biological effect of patient mutations in MFN2. MethodSequence data for a total of 140 patients were run through VAAST and Phevor to determine genes that were more burdened with rare, nonsynonymous variants compared to control longevity cohort. Variants identified in MFN2 were expressed in Mfn2 knockout cells to determine if mutant MFN2 could rescue mitochondrial morphology defects. We identified additional rare, nonsynonymous variants in MFN2 in ALSdb that were expressed in knockout mouse embryonic fibroblasts (MEFs). Membrane potential was measured to quantify mitochondrial health upon mutant MFN2 expression. mfn2 knockout zebrafish were used to examine movement compared to wildtype and protein aggregation in brain. ResultsMFN2 mutations identified in ALS patients from our University of Utah cohort and ALSdb were defective in rescuing morphological defects in Mfn2 knockout MEFs. Selected mutants showed decreased membrane potential compared to wildtype MFN2 expression. Zebrafish heterozygous and homozygous for loss of mfn2 showed increased TDP-43 levels in their hindbrain and cerebellum. ConclusionIn total, 21 rare, deleterious mutations in MFN2 were tested in Mfn2 knockout MEFs. Mutant MFN2 expression was not able to rescue the knockout phenotype, though at differing degrees of severity. Decreased membrane potential also argues for inhibited mitochondrial function. Increased TDP-43 levels in mutant zebrafish illustrates MFN2s function in ALS pathology. MFN2 variants influence ALS pathology and highlight the importance of mitochondria in neurodegeneration.

genetics↗

bioRxiv2020

Genetic control of Campylobacter colonisation in broiler chickens: genomic and transcriptomic characterisation

Campylobacter is the leading cause of bacterial foodborne gastroenteritis in many countries. Source attribution studies unequivocally identify the handling or consumption of contaminated poultry meat as the primary risk factor. One potential strategy to control Campylobacter is to select poultry with increased resistance to colonisation. We conducted genomic and transcriptomic analyses of commercial pedigree broilers exposed to Campylobacter to examine persistent colonisation of the caecum as a quantitative trait. 3,000 broilers were genotyped using a 50K single nucleotide polymorphism (SNP) array and imputed to 600K SNPs. Genotypes were analysed for associations with the number of viable Campylobacter in the caeca. Heritability of the trait was modest but significantly greater than zero (h2=0.11 {+/-} 0.03). Genome-wide association analyses confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified using the progeny of crosses of inbred lines differing in resistance, and detected two additional genome-wide significant QTLs on chromosomes 19 and 26. RNA-Seq analysis of the transcriptome of caecal tonsils from birds at the low and high extremes of C. jejuni colonisation phenotype identified differentially transcribed genes, mainly located within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We also identified strong cis-QTLs located within the MHC suggesting the presence of cis-acting variation in both MHC class I, class II and BG genes. Multiple other cis-acting variants were identified in association with key immune genes (COPS3, CCL4, CR1L, C4BP, PLGR) in the other QTLs. Pathway and network analysis implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin-angiotensin signalling. While co-selection for enhanced resistance and other breeding goal traits is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influence Campylobacter colonisation in poultry. Author summaryCampylobacter infection is estimated to cause 95 million illnesses in people worldwide each year. Human infections mostly involve gastroenteritis, but can have severe complications. The handling or consumption of contaminated poultry meat is a key risk factor for human campylobacteriosis. The bacteria reach high numbers in the intestines of chickens reared for meat (broilers) and are frequently found on carcasses after slaughter. Effective vaccines against Campylobacter are not yet available, and treatments to reduce carcass contamination (e.g. chlorination) are not acceptable in some markets. One alternative is to breed for chickens with improved resistance to Campylobacter colonisation. To test the feasibility of this option in commercial birds, we analysed the genetic make-up of 3,000 pedigree broilers and determined the number of Campylobacter in their gut. There were associations between specific regions of the chicken genome and resistance to Campylobacter. Within some of these regions, expression of certain genes differed between birds at the low and high extremes of Campylobacter colonisation, providing a potential explanation for genetic variation in resistance. Selection of poultry with increased resistance to Campylobacter colonisation may be a complementary strategy to improved biosecurity, management, handling and processing procedures to reduce the burden of Campylobacter on human health.

genomics↗

bioRxiv2019

Insights from two decades of the Student Conference on Conservation Science

Conservation science is a crisis-oriented discipline focused on delivering robust answers to reducing human impacts on nature. To explore how the field might have changed during the past two decades, we analyzed 3,245 applications for oral presentations submitted to the Student Conference on Conservation Science (SCCS) in Cambridge, UK. SCCS has been running every year since 2000, aims for global representation by providing bursaries to early-career conservationists from lower-income countries, and has never had a thematic focus, beyond conservation in the broadest sense. We found that the majority of submissions to SCCS were based on primary biological data collection from local scale field studies in the tropics, contrary to established literature which highlights gaps in tropical research. Our results showed a small increase over time in submissions framed around how nature benefits people as well as a small increase in submissions integrating social science. Our findings also suggest that students and early-career conservationists could provide pathways to increased availability of data from the tropics and for addressing well-known biases in the published literature towards wealthier countries. We hope this research will motivate efforts to support student projects, ensuring data and results are published and made publicly available.

ecology↗

bioRxiv2019

Monocarboxylate transporter 1 in Schwann cells is critical for maintenance of sensory nerve myelination during aging

Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/-, MCT1f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, enlarged node length and reduced mechanical sensitivity were evident in aged P0-Cre+/-, MCT1f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein (MAG), and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the essential role of SC MCT1 in both SC metabolism and peripheral nerve maturation and aging.\n\nMain PointsO_LISC MCT1 deficiency causes hypomyelination of sensory, but not motor, axons during aging\nC_LIO_LIEnlarged node length of sensory axons is evident in mutant mouse with SC-specific MCT1 deletion\nC_LIO_LISelective ablation of MCT1 within SCs impairs glycolytic and mitochondrial functions\nC_LIO_LISC-specific MCT1 deficiency impairs proteins that regulate myelin and lipid metabolism in peripheral nerves\nC_LI

neuroscience↗

bioRxiv2017

Best Practice Data Life Cycle Approaches for the Life Sciences

Throughout history, the life sciences have been revolutionised by technological advances; in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a life cycle view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain.\n\nHere we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on omics datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.

bioinformatics↗