Biology subjects

Cox, M.

Publications and source records attributed to Cox, M..

17 recordsLinked to original sources

bioRxiv2026

Feasibility study of fluid-structure-growth modelling in the context of endogenous tissue restoration

In situ tissue engineering exploits natural inflammatory responses to turn a synthetic vascular graft into a regenerated, functioning, and living vessel through endogenous tissue restoration. Despite promising preclinical results, challenges remain, especially in high-pressure regimes. To better understand the underlying biological processes and predict long-term outcomes of graft implantation, we propose an in silico approach. We account for the solid mechanics of conduit grafts in high and low pressure regimes, the wall shear stresses, and long-term growth and remodeling through two reduced-order fluid-structure-growth models. The first employs an artificial neural network surrogate model to compute the time-averaged wall shear stress at every growth step, whereas the second evaluates a fully-coupled fluid-structure interaction model every 60 time steps. We thoroughly verify both models and confirm acceptable model-form errors, then calibrate them against data from animal experiments. A validation study comparing in silico predictions with unseen animal data of carotid and pulmonary conduit grafts confirms that the model remains reliable up to at least one month of prediction time, hence in the future enabling in silico optimization of short-term endogenous tissue restoration in tissue engineering vascular grafts.

bioengineering↗

bioRxiv2026

A dependency-free, streamable format and cross-language toolkit for scalable LC-MS feature detection: reading only what you need

Mass spectrometry generates data faster than it can be read, and the exchange standard, mzML, is text-based and must be parsed in full before any spectrum is accessible. Binary alternatives are smaller but depend on storage engines such as HDF5, so access is dictated by the engine, not the file. We present Ionic (.ion), an open-source, compact, streamable binary format, and Quant{middle dot}ion, a processing toolkit built on the former. Ionic stores spectra, chromatograms and metadata as independently compressed, indexed blocks, so a reader retrieves only the bytes it needs, even inside a web browser, and converts losslessly to and from mzML. Ionic was smaller than compressed mzMLb on every acquisition type tested, and extracting one compound took under 40 ms, 35 to 90 times faster than an mzML reader. Quant{middle dot}ion exposes one core to R, Python, and JavaScript with identical results, and recovered 97% of true features on a ground-truth benchmark.

bioinformatics↗

bioRxiv2026

Sexually Dimorphic Response to Dietary Restriction-induced Longevity and Muscle Rejuvenation in Nothobranchius furzeri.

Age-related skeletal muscle decline (sarcopenia) is a major contributor to frailty and mortality during aging, yet the extent to which sex shapes muscle aging and its response to dietary interventions remains poorly understood. Here, we use the short-lived vertebrate Nothobranchius furzeri (African turquoise killifish; ATK) to investigate how sex and intermittent fasting (IF) interact to regulate lifespan and skeletal-muscle aging. We establish and optimize an IF regimen that significantly extends lifespan in both male and female killifish, albeit with classical trade-offs including reduced growth and reproductive output. Despite these costs, IF markedly improves swimming performance in aged animals of both sexes. Structural analyses of killifish on a normal diet reveal pronounced sexual dimorphism in muscle aging. Males exhibit age-associated myofiber hyperplasia, whereas females maintain fiber number but undergo hypertrophic remodeling. IF partially reverses both phenotypes, restoring a more youthful fiber size distribution in both males and females. Single-nucleus RNA sequencing uncovers sex-specific remodeling of muscle-fiber composition in killifish on a normal diet, with females displaying an age-associated shift toward oxidative slow-twitch fibers that is reversed by IF, while males show relatively stable fiber-type proportions under normal and IF feeding regimens. Cell-cell communication analyses further reveal a global decline in intercellular signaling with age, alongside sex-specific restoration of distinct pathways under IF, including axon guidance and IGF signaling in females and metabolic ANGPTL signaling in males. Finally, bulk transcriptomic profiling demonstrates that aging follows largely sexually dimorphic molecular trajectories, whereas IF induces both sex-specific and shared responses. Notably, under IF, both sexes exhibit upregulation of ribosome biogenesis and genes supporting myofibrillar organization and contraction, likely underlying preserved muscle function. Together, these findings demonstrate that IF promotes longevity and muscle health through conserved anabolic mechanisms alongside sex-specific cellular and molecular rejuvenation strategies. Our work highlights the importance of incorporating sex as a biological variable when designing dietary interventions to promote healthy aging.

physiology↗

bioRxiv2025

JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones

Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2-mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNF mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.

cancer biology↗

bioRxiv2025

A global map for introgressed structural variation and selection in humans

Genetic introgression from Neanderthals and Denisovan has shaped modern human genomes; however, introgressed structural variants (SVs [≥]50 base pairs) remain challenging to discover. We integrated high-quality phased assemblies from four new Papua New Guinea (PNG) genomes with 94 published assemblies of diverse ancestry to infer an archaic introgressed SV map. Introgressed SVs are overall enriched in genes (44%, n=1,592), including critical genomic disorder regions, and most abundant in PNG. We identify 11 centromeres likely derived from archaic hominins, adding unexplored diversity to centromere genomics. Pangenome genotyping across 1,363 samples reveals 16 candidate adaptive SVs, many associated with immune-related genes and their expression, in the PNG. We hypothesize that archaic SV introgression contributed to reproductive success, underscoring introgression as a significant force in human adaptive evolution.

evolutionary biology↗

bioRxiv2025

Resolving the evolutionary history of bighorn sheep to inform future management

Although translocations can be effective for augmenting and restoring wild populations, they can disrupt native patterns of genetic structure, diversity, and local adaptation, thereby hampering conservation efforts. Managers must weigh potential costs and benefits of choosing well-differentiated donor individuals that could confer a boost to genetic diversity while avoiding outbreeding depression or ecological mismatch. This decision is more daunting when taxonomy is unclear or debated. For example, bighorn sheep (Ovis canadensis) populations in the United States that have been managed as the "California" lineage (part of the formerly recognized subspecies O. c. californiana) originate from serial translocations sourced from populations in British Columbia, resulting in reduced genetic diversity and elevated risk of inbreeding. After research on skull shape and RFLP analysis of mtDNA failed to find support for that subspecies, some jurisdictions treated the California lineage as part of the Rocky Mountain subspecies (O. c. canadensis) and mixed individuals in subsequent translocations, in part to increase genetic diversity of bottlenecked populations. Yet detailed genetic data addressing validity of those putative lineages were lacking. We reconstructed the genetic history of bighorn sheep by sampling the major putative subspecies or lineages, focusing on native (remnant) genetic variation, and generating high-throughput DNA sequencing data ([~]15,000-25,000 SNPs). Complementary phylogenetic and population genetic analyses supported the distinctiveness of four bighorn lineages at levels corresponding to subspecies. Our results confirm the genetic identity of the no longer putative California bighorn lineage, answering a question that puzzled geneticists and managers for decades. Moving forward, we recommend that managers 1) maintain the natural variation held in native populations by protecting them from intentional translocations or unintentional mixing with nearby populations; 2) prioritize withinlineage translocations for population augmentation or repatriation to previously occupied regions; and 3) cautiously consider any translocations that would lead to mixing of distinct evolutionary lineages.

evolutionary biology↗

bioRxiv2024

Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR

BackgroundThe ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation. MethodsThis study uses genetic tools (transgenic C. elegans, RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions. ResultsWe use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans. Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1. ConclusionLow translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

genetics↗

bioRxiv2024

Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis in C. elegans

Dietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimers disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide (flp) genes and the neuroprotective growth factor progranulin gene prgn-1 under dietary restriction in C. elegans. Here, we tested the effects of flp-5, flp-14, flp-15 and pgrn-1 on lifespan and proteostasis under both standard and dietary restriction conditions. We also tested and distinguished function based on their expression in either neuronal or non-neuronal tissue. Lowering the expression of pgrn-1 and flp genes selectively in neural tissue showed no difference in survival under normal feeding conditions nor under DR in two out of three experiments performed. Reduced expression of flp-14 in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of the eat-2 gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown of pgrn-1 or flp genes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown of pgrn-1 and flp genes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targeting flp-14 increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi of pgrn-1 decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show that pgrn-1, flp-5, flp-14, and flp-15 do not have major roles in diet-related changes in longevity or whole-body proteostasis. However, reduced expression of these genes in neurons increases motility early in life in a neural-specific model of proteotoxicity, whereas knockdown of non-neuronal expression mostly increases motility in mid-life under the same conditions.

molecular biology↗

bioRxiv2022

High-resolution eye-tracking via digital imaging of Purkinje reflections

Reliably measuring eye movements and determining where the observer looks are fundamental needs in vision science. A classical approach to achieve high-resolution oculomotor measurements is the so-called Dual-Purkinje-Image (DPI) method, a technique that relies on the relative motion of the reflections generated by two distinct surfaces in the eye, the cornea and the back of the lens. This technique has been traditionally implemented in fragile and difficult to operate analog devices, which have remained exclusive use of specialized oculomotor laboratories. Here we describe progress on the development of a digital DPI, a system that builds on recent advances in digital imaging to enable fast, highly precise eye-tracking without the complications of previous analog devices. This system integrates an optical setup with no moving components with a digital imaging module and dedicated software on a fast processing unit. Data from both artificial and human eyes demonstrate sub-arcminute resolution at 1 Khz. Furthermore, when coupled with previously developed gaze-contingent calibration methods, this system enables localization of the line of sight within a few arcminutes.

neuroscience↗

bioRxiv2022

FPGA Acceleration of GWAS Permutation Testing

MotivationGenome-wide association studies (GWASs) analyse genetic variation over the genomes of many individuals in an attempt to identify single nucleotide polymorphisms (SNPs) associated with complex phenotypes. To capture a large amount of genetic variation and increase the chance of detecting associated SNPs, modern GWASs include millions of SNPs sampled from thousands of individuals. The cumulative probability of false associations increases with the number of SNPs included in the analysis. A GWAS, therefore, needs to control the number of false associations. Permutation testing is a straightforward and accurate method of controlling the false positive rate, but it is very computationally expensive (and slow) so there is a need for a permutation testing accelerator that can process modern GWAS datasets in reasonable time. ResultsFPGAs (Field-Programmable Gate Arrays) are reconfigurable integrated circuits which provide a high level of parallelisation that can be harnessed to accelerate GWAS permutation testing. This work presents an accessible FPGA-based tool (designed to run on a cloud-based AWS EC2 FPGA instance) that accelerates GWAS permutation testing for continuous phenotypes. The tool implements two known GWAS permutation testing algorithms: maxT permutation testing and adaptive permutation testing. The speed of the FPGA-based tool was compared to the speed of PLINK (a popular CPU-based tool) running on 40 Intel Xeon 4114 CPU cores using an imputed breast cancer dataset of 13.7 million SNPs sampled from 3652 individuals. For 1000 maxT permutations, the FPGA-based algorithms run time was 22 minutes while PLINKs run time was almost 7 days; for 100 million adaptive permutations, the FPGA-based algorithms run time was 325 minutes and PLINKs run time was about 8.5 days. For 700 million adaptive permutations of the same dataset (an almost unfeasible workload for PLINK running on a 40-core CPU) the run time of the FPGA-accelerated algorithm was 33 hours. AvailabilityAn EC2 AMI (FPGA_perm) in the us-east-1 region is available. Instructions, source code and sample data are available at https://github.com/witseie/fpgaperm.

bioinformatics↗

bioRxiv2021

An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza-targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.

microbiology↗

bioRxiv2021

Self-organization and information transfer in Antarctic krill swarms

Antarctic krill swarms are one of the largest known animal aggregations. However, despite being the keystone species of the Southern Ocean, little is known about how swarms are formed and maintained, and we lack a detailed understanding of the local interactions between individuals that provide the basis for these swarms. Here we analyzed the trajectories of captive, wild-caught krill in 3D to determine individual level interaction rules and quantify patterns of information flow. Our results suggest krill operate a novel form of collective organization, with measures of information flow and individual movement adjustments expressed most strongly in the vertical dimension, a finding not seen in other swarming species. In addition, local directional alignment with near neighbors, and strong regulation of both direction and speed relative to the positions of groupmates suggest social factors are vital to the formation and maintenance of swarms. This research represents a first step in understanding the fundamentally important swarming behavior of krill.

animal behavior and cognition↗

bioRxiv2020

Host infection by the grass-symbiotic fungus Epichloë festucaerequires catalytically active H3K9 and H3K36 methyl transferases

Recent studies have identified key genes in Epichloe festucae that control the symbiotic interaction of this filamentous fungus with its grass host. Here we report on the identification of specific fungal genes that determine its ability to infect and colonize the host. Deletion of setB, which encodes a homolog of the H3K36 histone methyltransferase Set2/KMT3, specifically reduced histone H3K36 trimethylation and led to severe defects in colony growth and hyphal development. The E. festucae {Delta}clrD mutant, which lacks the gene encoding the homolog of the H3K9 methyltransferase KMT1, displays similar developmental defects. Both mutants are completely defective in their ability to infect the host grass, and mutational studies of key residues in the catalytic SET domains from these proteins show that these phenotypes are dependent on the methyltransferase activities of SetB and ClrD. A comparison of the differences in the host transcriptome between seedlings inoculated with wild-type versus mutants suggests that the inability of these mutants to infect the host was not due to an aberrant host defense response. Co-inoculation of either {Delta}setB or {Delta}clrD with the wild-type strain enables these mutants to colonize the host. However, successful colonization by the mutants resulted in death or stunting of the host plant. Transcriptome analysis at the early infection stage identified four fungal candidate genes, three of which encode small-secreted proteins, that are differentially regulated in these mutants compared to wild-type. Deletion of crbA, which encodes a putative carbohydrate binding protein, resulted in significantly reduced host infection rates by E. festucae. Author SummaryThe filamentous fungus Epichloe festucae is an endophyte that forms highly regulated symbiotic interactions with the perennial ryegrass. Proper maintenance of such interactions is known to involve several signalling pathways, but much less is understood about the infection capability of this fungus in the host. In this study, we uncovered two epigenetic marks and their respective histone methyltransferases that are required for E. festucae to infect perennial ryegrass. Null mutants of the histone H3 lysine 9 and lysine 36 methyltransferases are completely defective in colonizing the host intercellular space, and these defects are dependent on the methyltransferase activities of these enzymes. Importantly, we observed no evidence for increased host defense response to these mutants that can account for their non-infection. Rather, these infection defects can be rescued by the wild-type strain in co-inoculation experiments, suggesting that failure of the mutants to infect is due to altered expression of genes encoding infection factors that are under the control of the above epigenetic marks that can be supplied by the wild-type strain. Among genes differentially expressed in the mutants at the early infection stage is a putative small-secreted protein with a carbohydrate binding function, which deletion in E. festucae severely reduced infection efficiency.

genetics↗

bioRxiv2020

Ancient human genomes reveal a hidden history of strong selection in Eurasia

The role of natural selection in shaping biological diversity is an area of intense interest in modern biology. To date, studies of positive selection have primarily relied upon genomic datasets from contemporary populations, which are susceptible to confounding factors associated with complex and often unknown aspects of population history. In particular, admixture between diverged populations can distort or hide prior selection events in modern genomes, though this process is not explicitly accounted for in most selection studies despite its apparent ubiquity in humans and other species. Through analyses of ancient and modern human genomes, we show that previously reported Holocene-era admixture has masked more than 50 historic hard sweeps in modern European genomes. Our results imply that this canonical mode of selection has likely been underappreciated in the evolutionary history of humans and suggests that our current understanding of the tempo and mode of selection in natural populations may be quite inaccurate.

genomics↗

bioRxiv2019

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

Indonesia is the worlds fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10% of tested genes are differentially expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating with nearby CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by very local environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.

genomics↗

bioRxiv2019

Respiratory viral infection alters the gut microbiota by inducing inappetence

The gut microbiota has an important role in health and disease. Respiratory viral infections are extremely common but their impact on the composition and function of the gut microbiota is poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here we show that weight loss during Respiratory Syncytial Virus (RSV) or influenza virus infection was due to decreased food consumption, and that fasting mice independently of infection altered gut microbiota composition. While the acute phase TNF- response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, depleting CD8+ cells increased food intake and prevented weight loss resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the faecal gut metabolome during RSV infection, with a significant shift in lipid metabolism. Sphingolipids, poly-unsaturated fatty acids (PUFAs) and the short-chain fatty acid (SCFA) valerate all increased in abundance in the faecal metabolome following RSV infection. Whether this, and the impact of infection-induced anorexia on the gut microbiota, are part of a protective, anti-inflammatory response during respiratory viral infections remains to be determined.

immunology↗

bioRxiv2018

Repeat elements organize 3D genome structure and mediate transcription in the filamentous fungus Epichloë festucae

Structural features of genomes, including the three-dimensional arrangement of DNA in the nucleus, are increasingly seen as key contributors to the regulation of gene expression. However, studies on how genome structure and nuclear organization influence transcription have so far been limited to a handful of model species. This narrow focus limits our ability to draw general conclusions about the ways in which three-dimensional structures are encoded, and to integrate information from three-dimensional data to address a broader gamut of biological questions. Here, we generate a complete and gapless genome sequence for the filamentous fungus, Epichloe festucae. Coupling it with RNAseq and HiC data, we investigate how the structure of the genome contributes to the suite of transcriptional changes that an Epichloe species needs to maintain symbiotic relationships with its grass host. Our results reveal a unique \"patchwork\" genome, in which repeat-rich blocks of DNA with discrete boundaries are interspersed by gene-rich sequences. In contrast to other species, the three-dimensional structure of the genome is anchored by these repeat blocks, which act to isolate transcription in neighbouring gene-rich regions. Genes that are differentially expressed in planta are enriched near the boundaries of these repeat-rich blocks, suggesting that their three-dimensional orientation partly encodes and regulates the symbiotic relationship formed by this organism.

genomics↗