Biology subjects

Jones, S. T.

Publications and source records attributed to Jones, S. T..

9 recordsLinked to original sources

bioRxiv2026

Unmasking Supervillin: SVIL haploinsufficiency causes hypertrophic cardiomyopathy by impairing mechanotransduction and cellular energetics

BackgroundRare heterozygous loss-of-function (LoF) variants in SVIL, encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. MethodsUsing CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVILQ255X/+ and homozygous SVILQ255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. ResultsThe Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVILQ255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVILQ255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVILQ255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVILQ255X/+ cells but did not rescue energetic compromise. ConclusionsPathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL-associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LISVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. C_LIO_LIHeterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. C_LIO_LIMavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. C_LI What Are the Clinical Implications?O_LIOur findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. C_LIO_LIThese findings establish SVIL-associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM C_LIO_LIThe persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL-associated cardiomyopathy. C_LI

cell biology↗

bioRxiv2026

Microglial and Neuronal Cross-talk in the Nucleus Accumbens

Microglia are the brain's resident immune cells and rapidly migrate toward sites of neuronal stress and neurotransmitter imbalance. The molecular cues directing microglia movement remain poorly understood, particularly in brain regions involved in reward processing, including the nucleus accumbens (NAc). Dopamine (DA) dysregulation and production of reactive oxygen species (ROS) are hallmarks of substance use disorders and neurodegenerative diseases. Dopamine and adenosine triphosphate (ATP) are co-released in the NAc, but the effects of ROS on ATP/DA co-transmission and microglia surveillance remain unknown. Using multiphoton imaging in brain slices with GFP-labeled microglia, we found that ATP consistently and non-selectively drives microglia chemoattraction, whereas DA chemoattraction only occurs in a subset of microglia through D1 but not D2 receptor activation. Microglia enter a reactive state via LPS, and LPS results in enhanced DA/ATP release measured via fast scan cyclic voltammetry. ROS production also transitions microglia to a reactive state, but inhibits DA release, with mixed effects on ATP release. These findings identify ATP- and DA-mediated mechanisms for NAc microglia chemoattraction and opposing immune dysregulation (via LPS or ROS) of DA terminal function.

neuroscience↗

bioRxiv2025

A broad-spectrum, biocompatible, virucidal polymer reduces chikungunya virus in murine models

Autochthonous transmission of arboviruses poses significant threats to global health and economies. Yet, no effective antivirals exist. Building on our previous antiviral star-polymer, we designed zwitterionic star-polymers for efficacy in high protein environments. A polymer with 12% positively charged monomer (Zwitterionic Polymer-ZP12) exhibited broad-spectrum, biocompatible antiviral activity against Alphaviridae, Flaviviridae, Herpesviridae, and Picornaviridae. Using murine models for Chikungunya virus (CHIKV) infection, ZP12 treatment (10 mg/kg every 24 hours for 7 days) reduced tissue viral load by 90% 3 days post-infection and significantly alleviated CHIKV-induced joint swelling. Mechanistically, ZP12 downregulated CHIKV-driven immunopathogenesis by reducing viral load and dampening CD4+ T cell and macrophage activation in virus-infected joints. With no current antiviral interventions for these arboviruses, ZP12 represents a promising intervention for combating future pandemics.

microbiology↗

bioRxiv2025

Connexin 36-mediated gap junctions contribute to fine odor discrimination and excitation of mitral cells in the mouse olfactory bulb

Key PointsO_LIThe output MCs of the olfactory bulb (OB) engage in strong electrical coupling via connexin 36 (Cx36)-mediated gap junctions. However, the behavioral and physiological relevance of these gap junctions is not well understood. C_LIO_LIIn studies conducted in Cx36 knock-out (KO) mice, we found that the mice displayed reduced fine odor discrimination capabilities versus wild-type mice in a go/no-go associative learning task. These results provide the first evidence to date of olfactory behavioral deficits in Cx36 KO mice. C_LIO_LIIn OB slices, Cx36 KO reduced excitatory responses in MCs to electrical stimulation of sensory afferents, especially during latter stages of the response. C_LIO_LIWe suggest that KO-induced impairments in fine odor discrimination are linked to reduced late MC excitation due to the longer time that mice require to make difficult odor discriminations. C_LI The output mitral cells (MCs) and tufted cells (TCs) of the mammalian olfactory bulb (OB) are coupled through both chemical mechanisms as well as gap junctions that are mediated by connexin 36 (Cx36). Here we tested both behavioral and physiological effects of eliminating gap junctions in knockout (KO) mice with homozygous deletions of Cx36. In a go/no-go associative learning task, Cx36 KO mice were found to display reduced discrimination capabilities when presented with pairs of stimuli that included a monomolecular odor and mixtures that had the same monomolecular odor and a small amount of a structurally similar odor. The impairments did not occur for less similar odor pairs, suggesting that Cx36 KO mice have olfactory processing deficits that are specific to fine odor discrimination. In physiological recordings in OB slices from Cx36 KO mice, MCs displayed reduced excitation in response to electrical stimulation of sensory afferents, both single stimulus pulses as well as a theta burst pattern designed to mimic sniffing. The reduction in MC excitatory current was most prominent for late portions of their response, 300 ms after single stimulus pulses or following all theta bursts that came after the first. More global local field potentials recorded in OB glomeruli were largely unaffected by Cx36 KO. We suggest that the KO-induced impairments in fine odor discrimination are linked to reduced late MC excitation due to the longer time that mice require to make difficult odor discriminations.

neuroscience↗

bioRxiv2025

SLFN11 restricts escape from telomere crisis to prevent alternative lengthening of telomeres

The tRNA nuclease SLFN11 is epigenetically silenced in [~]50% of treatment-naive tumours and is the strongest predictor of chemoresistance but why it is frequently inactivated in cancer is unknown. To acquire immortality, cancer cells can activate alternative lengthening of telomeres (ALT), typically accompanied by ATRX loss. Here, we implicate SLFN11 in sensing telomere replication stress, triggering eradication of ATRX deficient cells prior to ALT establishment. Whereas progressive telomere shortening of cells lacking telomerase and ATRX leads to telomere crisis and cell death, SLFN11 loss confers tolerance to PML-BLM dependent ALT intermediates, permitting emergence of ALT survivors. We propose that during tumorigenesis SLFN11 inactivation is selected as means to tolerate endogenous replication stress following telomere crisis, leading to the development of therapy resistant tumours before treatment.

molecular biology↗

bioRxiv2025

Prevalence and modulation of rat off-track head-scanning on linear tracks: possible implications for representational and dynamical properties of hippocampal place cells

(Re)mapping of different environments by hippocampal place cells is thought to reflect incidental learning. Rat "head scanning" is a spontaneous and presumed investigatory behavior that can trigger the onset of firing locations in place cells. This behavior was studied on (quasi-)circular tracks, and it was speculated that off-track head scans might have been overlooked or inadvertently discouraged in studies employing more common apparatus. To better understand the general prevalence and significance of off-track scanning, we investigated it in rats running laps on linear tracks in rooms featuring visual landmarks. Scanning spanned the length of the track, even in highly familiar conditions and in rats rewarded only at the two ends of the track. Thus, co-localized rewards are not necessary for the occurrence of this behavior. Scanning rate increased markedly in a novel room and then declined steeply during each daily session in this room over 3 days. Transient increases at the beginning of each daily session partially counteracted this decline, producing a "seesaw" profile that is reminiscent of previous observations on place cell plasticity. Therefore, the remapping that place cells are known to undergo in similar contextual changes could conceivably be facilitated by the putative surge of new place fields induced by increased scanning. Investigatory behaviors could thus be causally involved in the representational and dynamic properties of hippocampal representations. Addressing these possibilities offers insight into the incidental creation and update of a cognitive map. HIGHLIGHTSO_LIRat head scanning is known to trigger the onset of firing locations in place cells C_LIO_LIOff-track scanning occurs on linear tracks in familiar and novel conditions C_LIO_LICo-localized rewards are not necessary for scanning events C_LIO_LIResponse to a novel room resembles that seen in place cell dynamics C_LIO_LIRelationships between head scanning and place field formation could help uncover the incidental process of map making C_LI

neuroscience↗

bioRxiv2024

Star-polymers as potent broad-spectrum extracellular virucidal antivirals

Viruses pose a significant threat to both global health and the global economy. It is clear that novel antiviral strategies are urgently needed, with a broad-spectrum approach being most desired. We have discovered a broad-spectrum, non-toxic polymer virucide that can tackle the viral threat. This polymeric virucide is effective at nanomolar concentrations, against a broad-spectrum of viruses and, demonstrated using an intranasal respiratory syncytial virus (RSV) murine model, has excellent efficacy, low anti-coagulant properties and low toxicity in vivo. Molecular dynamic simulations show that this polymer achieves its virucidal antiviral effect via self-assembly of viral-receptors leading to increased envelope forces and viral disassembly. The discovery of this cheap and readily produced polymer marks the start of a new type of receptor-crosslinking broad-spectrum antiviral that has significant potential to combat the global threat posed by viruses.

microbiology↗

bioRxiv2023

Hyperexcitability in the olfactory bulb and impaired fine odor discrimination in the Fmr1 KO mouse model of fragile X syndrome

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type and Fmr1 KO (Fmr1-/y) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of LLDs did not appear to reflect changes in inhibitory connections onto MCs but rather enhanced spontaneous excitation of external tufted cells (eTCs) that provide feedforward excitation onto MCs within glomeruli. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the higher excitability of MCs in Fmr1 KO mice may impair fine odor discrimination by broadening odor tuning curves of MCs and/or altering synchronized oscillations through changes in transient inhibition. Significance StatementFragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used Fmr1 knockout (KO) mouse model of FXS. Our studies indicate that Fmr1 KO alters the local excitation/inhibition balance in the bulb - similar to what Fmr1 KO does in other brain circuits - but through a novel mechanism that involves enhanced feedforward excitatory drive. Furthermore, Fmr1 KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by enhanced neural excitability.

neuroscience↗

bioRxiv2022

Broad-spectrum extracellular antiviral properties of Cucurbiturils

Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortality and morbidity worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a macrocycle chemical compound existing as a range of homologues; due to their structure they can bind to biological materials, acting as supramolecular "hosts" to "guests", such as amino acids. Due to the increasing need for a non-toxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including RSV and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n] mixtures, having an antiviral effect against enveloped and non-enveloped species. High levels of efficacy were observed with five-minute contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalisation or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals) demonstrating the potential of supramolecular interactions for future antiviral disinfectants.

microbiology↗