Biology subjects

Field, C.

Publications and source records attributed to Field, C..

8 recordsLinked to original sources

bioRxiv2026

iPSC-Derived Myotubes from ME/CFS Patients Reveal Signature Genes, Isoforms and Pathways with Drug Repurposing Potential

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disorder. Its hallmark feature, post-exertional malaise (PEM), is a delayed and prolonged worsening of symptoms following even minor exertion. As PEM commonly includes muscle pain, weakness, exercise intolerance and impaired recovery, skeletal muscle dysfunction may contribute to its pathophysiology, but the underlying molecular processes remain poorly understood. We generated induced pluripotent stem cell-derived skeletal muscle myotubes from individuals with ME/CFS (n = 6) and healthy controls (n = 7) to investigate disease-associated transcriptomic alterations and identify potential therapeutic candidates. Myogenic progenitor cells from both groups differentiated into elongated, multinucleated myotubes expressing titin and myosin heavy chain, while qPCR profiling of myogenic differentiation markers further supported successful differentiation. Gene-level analysis identified three differentially expressed genes at an FDR-adjusted p < 0.05: ERVH48-1, CDX4 and SLC2A14. Isoform-switching analysis identified 16 genes with significant differential isoform usage, including CACNA1H, MIEF2, SMAD2 and CHD4. Gene set enrichment analysis identified broader pathway-level alterations involving RNA processing, protein synthesis, proteostasis, mitochondrial quality control, metabolism and muscle-related processes. Library of Integrated Network-based Cellular Signatures Phase 2 (LINCS2) analysis further prioritised 14 compounds associated with mitochondrial metabolism, glucose and lipid regulation, PPAR signalling, calcium and excitatory signalling, neuroimmune activity and cellular stress responses. Overall, ME/CFS iPSC-derived myotubes showed modest gene-level differences alongside broader isoform- and pathway-level alterations, supporting their use for investigating skeletal muscle biology and prioritising candidates for functional validation.

cell biology↗

bioRxiv2026

A DNA foundation model predicts osteoporosis risk genes without proximity bias

Targets supported by human genetic associations are more than twice as likely to progress from clinical development to approval. Genome-wide association studies are the largest source of genetic evidence for disease risk but linking non-coding variants to effector genes remains a significant barrier to identifying causal targets. Current gene-mapping approaches suffer from proximity bias, largely ignoring distal genes. Here we introduce Rosalind, a DNA foundation model fine-tuned on human genetic variation from GTEx, that directly predicts variant-gene regulatory relationships from sequence without relying on nearest-gene heuristics. We demonstrate Rosalinds accuracy through extensive benchmarking, apply it to multiple complex traits to establish broad utility, and provide experimental validation in osteoporosis using a translational osteoblast assay. We demonstrate that genes distal to osteoporosis risk variants were significantly more likely to alter a bone formation phenotype than nearest genes. Together, these results highlight deep learning-based regulatory models as a general and scalable framework for translating novel genetic insights to drug discovery.

genetics↗

bioRxiv2026

Maximum Unified Fatty Acid Signature Analysis: a new approach to QFASA

Accurately estimating predator diets is crucial for understanding and predicting ecosystem changes. The desire for non-lethal but accurate diet estimation techniques has led to new approaches such as quantitative fatty acid signature analysis (QFASA), a now widely accepted method for estimating the diets of marine predators. We propose a novel alternative to QFASA, namely maximum unified fatty acid signature analysis (MUFASA), to estimate dietary proportions using fatty acid signatures. MUFASA is based on maximum likelihood estimation principles and consequently offers several theoretical advantages over QFASA, including estimates that possess desirable properties when model assumptions hold. In addition, the availability of a likelihood function enables the use of a broad range of existing methodologies that may have the capacity to address current well-known challenges associated with diet estimation via fatty acids. MUFASA and QFASA are compared using simulations based on wide-ranging diets, as well as real-life data from a captive study of harbour seals, for which diets are known. Estimates derived from QFASA and MUFASA are similar, suggesting that diet estimation in this context can potentially be viewed through an MLE framework. While not the primary focus of this work, bootstrap confidence intervals are also developed and preliminary results yield high coverage probabilities when the diet proportions are not near 0 or 1.

ecology↗

bioRxiv2024

Episodic Transport of Protein Aggregates Achieves a Positive Size Selectivity in Aggresome Formation

Eukaryotic cells direct toxic misfolded proteins to various protein quality control pathways based on their chemical features and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the "aggresome," a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selectively sequestering protein aggregates into the aggresome remains unclear. To investigate aggresome formation, we reconstituted MTOC-directed aggregate transport in Xenopus laevis egg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking revealed that dynein-mediated transport of aggregates was highly episodic, with average velocity positively correlated with aggregate size. Our mechanistic model suggests that the recurrent formation of the dynein transport complex biases larger aggregates towards the active transport state, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are specifically associated with aggresome-dynein adaptors. Coupling conventional dynein-activating adaptors to the aggregates perturbs aggresome formation and reverses size selectivity.

cell biology↗

bioRxiv2024

Step selection analysis with non-linear and random effects in mgcv

Step selection analysis is used to jointly describe animal movement patterns and habitat preferences. Recent work has extended this framework to model inter-individual differences, account for unexplained structure in animals space use, and capture temporally-varying patterns of movement and habitat selection.In this paper, we formulate step selection functions with penalised smooths (similar to generalised additive models) to unify new and existing extensions, and conveniently implement the models in the popular, open-source mgcv R package. We explore non-linear patterns of movement and habitat selection, and use the equivalence between penalised smoothing splines and random effects to implement individual-level and spatial random effects. This framework can also be used to fit varying-coefficient models to account for temporally or spatially-heterogeneous patterns of selection (e.g., resulting from behavioural variation), or any other non-linear interactions between drivers of the animals movement decisions. We provide the necessary technical details to understand several key special cases of smooths and their implementation in mgcv, showcase the ecological relevance using two illustrative examples, and provide R code (available at https://github.com/NJKlappstein/smoothSSF) to facilitate the adoption of these methods. This paper is a broad overview of how smooth effects can be applied to increase the flexibility and biological realism of step selection analysis.

ecology↗

bioRxiv2020

An MRI protocol for anatomical and functional evaluation of the California sea lion brain

We describe a research MRI protocol for in vivo evaluation of pinniped brains using standard human clinical MRI hardware and pulse sequences. Our intended application is to study development of California sea lions (Zalophus californianus) exposed in utero to domoic acid (DOM) produced by harmful algae blooms in the coastal Pacific Ocean. In cases where the fetus survives to birth, exposure to the toxin in utero could result in developmental abnormalities leading to neurological and behavioral deficits. Prior studies on sea lions naturally exposed to DOM as adults have demonstrated hippocampal atrophy and altered mesial temporal connectivity. This MRI protocol is therefore intended to depict the hippocampal formation as the primary region of interest, and to provide longitudinal measures of brain functional and structural connectivity as well as quantitative anatomical evaluations. Scan quality and utility are assessed by comparison with prior studies in live and post mortem sea lion brains. We include the first determination of cerebral blood flow mapping using MRI, and also the first fiber tractography using diffusion-weighted imaging from a live sea lion brain. The protocol also facilitates screening for common neurological pathologies, including tumors, trauma and hemorrhages. We believe the protocol would be suitable for any pinniped that can fit inside a human MRI scanner.

neuroscience↗

bioRxiv2019

Unconventional cell division cycles from marine-derived yeasts

Fungi have been found in every marine habitat that has been explored, however, the diversity and functions of fungi in the ocean are poorly understood. In this study, fungi were cultured from the marine environment in the vicinity of Woods Hole, MA, USA including from plankton, sponge and coral. Our sampling resulted in 36 unique species across 20 genera. We observed many isolates by time-lapse differential interference contrast (DIC) microscopy and analyzed modes of growth and division. Several black yeasts displayed highly unconventional cell division cycles compared to those of traditional model yeast systems. Black yeasts have been found in habitats inhospitable to other life and are known for halotolerance, virulence, and stress-resistance. We find that this group of yeasts also shows remarkable plasticity in terms of cell size control, modes of cell division, and cell polarity. Unexpected behaviors include division through a combination of fission and budding, production of multiple simultaneous buds, and cell division by sequential orthogonal septations. These marine-derived yeasts reveal alternative mechanisms for cell division cycles that seem likely to expand the repertoire of rules established from classic model system yeasts.

cell biology↗

bioRxiv2019

Whole genome phylogenies reflect long-tailed distributions of recombination rates in many bacterial species

Although homologous recombination is accepted to be common in bacteria, so far it has been challenging to accurately quantify its impact on genome evolution within bacterial species. We here introduce methods that use the statistics of single-nucleotide polymorphism (SNP) splits in the core genome alignment of a set of strains to show that, for many bacterial species, recombination dominates genome evolution. Each genomic locus has been overwritten so many times by recombination that it is impossible to reconstruct the clonal phylogeny and, instead of a consensus phylogeny, the phylogeny typically changes many thousands of times along the core genome alignment. We also show how SNP splits can be used to quantify the relative rates with which different subsets of strains have recombined in the past. We find that virtually every strain has a unique pattern of frequencies with which its lineages have recombined with those of other strains, and that the relative rates with which different subsets of strains share SNPs follow long-tailed distributions. Our findings show that bacterial populations are neither clonal nor freely recombining, but structured such that recombination rates between different lineages vary along a continuum spanning several orders of magnitude, with a unique pattern of rates for each lineage. Thus, rather than reflecting clonal ancestry, whole genome phylogenies reflect these long-tailed distributions of recombination rates.

evolutionary biology↗