Biology subjects

Mason, J.

Publications and source records attributed to Mason, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Stabilizing gas in aqueous liquids with metal-organic frameworks for persistent acoustic transduction

Gas is the most efficient mediator of acoustic energy owing to its high compressibility, yet its thermodynamic instability in aqueous environments makes it inherently transient, limiting sustained ultrasound-biological interfacing. Here, we show that gas can be stabilized, confined, and manipulated in the liquid phase to function as a persistent acoustic transducer. By trapping gas within designed microporous metal-organic framework (MOF) nanocrystals, interfacial forces establish a stable ternary-phase equilibrium that suppresses water intrusion and prevents gas collapse, enabling reversible, non-destructive oscillations under ultrasound stimulation and providing design principles for stabilizing gas in liquid environments. By leveraging high-resolution ultra-high-speed digital image correlation (DIC), we unveil the previously inaccessible spatiotemporal dynamics of confined gas oscillations within these nanotransducers under ultrasound stimulation, revealing localized amplification of the surrounding acoustic field and establishing a quantitative structure-function relationship for programmable acoustic transduction. These aqueous-phase gas nanotransducers exhibit sustained acoustic amplification over millions of excitation cycles and remain functional after prolonged storage (>2 years) under physiological conditions. In vitro and in vivo, this platform enables long-term ultrasound imaging and sustained, non-invasive neuromodulation by converting confined gas oscillations into persistent and amplified mechanical actuation. Our findings establish a generalizable design framework for stabilizing gas in liquid environments to achieve persistent and programmable acoustic transduction, thereby enabling sustained ultrasound-biological interfacing and opening opportunities for gas-based therapeutics.

bioengineering↗

bioRxiv2026

Systematic exploration of predicted quaternary structures within pandemic-relevant viral proteomes

Mechanistic understanding of viral protein-protein interactions enables global health security and pandemic preparedness, yet experimental characterisation remains difficult, costly, and often restricted to specialised laboratories. Here, we describe an in silico campaign using AlphaFold2 and AlphaFold-Multimer to predict monomers and dimer structures within 2,812 viral proteomes from 23 viral families relevant to human health. We report high-confidence predicted structures of 5,279 hetero-, and 2,749 homo-dimers. Structural clustering of interfaces reduces the set fivefold to 1,598 consolidated by form and function, of which 471 (29.5%) lacked detectable similarity to experimentally determined interfaces in the PDB. These clusters yielded two notable findings: new data on vaccinology-relevant glycoproteins, and accurate prediction of the specificity and cleavage-site recognition of viral proteases, which are targets for anti-viral development. Viral monomers and high-confidence dimers are available for interactive browsing in the Pandemic Preparedness Portal of the AlphaFold Database (https://alphafold.ebi.ac.uk/), and the full dataset is available for bulk download.

bioinformatics↗

bioRxiv2026

Supershoes or Superhumans? A controlled analysis of sex-specific road-running performance evolution in the era of advanced footwear technology

Advanced footwear technology (AFT) improves running economy and is widely credited with recent performance improvements in road running, with observational analyses consistently demonstrating that women have improved more than men. In contrast, laboratory studies generally report similar running economy responses to AFT in both sexes, leaving the observational-experimental divergence unresolved. A fundamental limitation of observational work is the absence of a control condition, making it impossible to separate AFT-related gains from concurrent performance trends. We addressed this by comparing performances between pre-AFT (2009-2015) and AFT (2017-2024) eras across road-running events (10km, half marathon, marathon) and throwing events (shot put, discus, javelin, hammer), the latter serving as an active control condition subject to the same broad athletic trends but unaffected by footwear technology. The top 50 performances per event, era, and sex were converted to World Athletics points and analysed using linear mixed-effects models. Performances improved significantly between eras ({beta} = 0.294, p < .001), with gains substantially larger in road running than in throwing ({beta} = 0.731, p < .001). The sex-specific pattern of improvement also differed between event categories (era x event type x sex interaction, {beta} = 0.786, p < .001): road-running improvements were greater in women than men (4.51% vs 2.62%), whereas throwing improvements did not differ by sex (0.93% vs 1.14%). These findings suggest that AFT benefits women more than men in competition, whether through a greater physiological response or more effective translation of economy gains to race performance, and suggest current laboratory protocols may be insufficiently sensitive to detect potential sex-specific effects.

physiology↗

bioRxiv2025

Phosphoinositide lipids have bidirectional and spatially distinct roles in filopodial dynamics

Neural circuits are assembled by filopodia, dynamic actin-rich protrusions that connect environment sensing with structural changes. Using rapid timelapse imaging and acute pharmacological perturbation in Xenopus laevis retinal ganglion cells, we reveal that phosphoinositide lipid conversions impose spatially distinct control over filopodial dynamics. The class I phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and Oculocerebrorenal syndrome of Lowe protein/Inositol polyphosphate 5-phosphatase inhibitor YU142670 markedly reduced filopodial tip motility. Class II PI3K inhibitor PITCOIN4 and YU142670 curtailed base dynamics, indicating location-specific lipid requirements. Despite no detectable change in PI(4,5)P2, both alpelisib and YU142670 depleted PI(3,4)P2 at filopodial tips. Their co-application was non-additive, with partial alleviation of YU142670-induced stalling by alpelisib, consistent with networked control of lipid conversion and actin remodelling. Live imaging with a TAPP1-3xcPH probe combined with quantitative cross-correlation and Granger causality analysis showed that PI(3,4)P2 at filopodial tips both generates tip extension and responds to forward filopodial movement. Disrupting actin polymerisation rapidly erased tip PI(3,4)P2 prior to filopodial stalling. These findings define a vulnerable node with implications for neurodevelopmental miswiring.

cell biology↗

bioRxiv2025

PRIMPOL promotes replication fork progression but not double strand break formation in FBH1-deficient cells in response to hydroxyurea

In response to stress, stalled replication forks undergo fork reversal converting replication forks into a 4-way junction. FBH1 is a DNA helicase that promotes replication fork reversal. After prolonged replication stress, FBH1 promotes double strand break accumulation and cell death. One of the hallmarks of loss of fork reversal is unrestrained replication in the presence of DNA damage, but how FBH1 restrains replication at stalled forks is not known. Here, we show that FBH1 limits replication fork progression by PRIMPOL in response to hydroxyurea. However, PRIMPOL is not preventing double strand break formation in FBH1 knockout cells. Finally, we demonstrate that increased resistance of FBH1-deficient cells to hydroxyurea treatment is not due to unrestrained replication by PRIMPOL. Our results indicate FBH1 restrains PRIMPOL-mediated DNA synthesis at stalled replication forks and promoting double strand break accumulation occur by distinct mechanisms.

molecular biology↗

bioRxiv2025

Cerebral Organoids with Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis

Cerebral organoids (COs) are multicellular, self-organized, in vitro, 3D brain-like tissues used for developmental biology, disease modelling and drug screening. However, their lack of vascularity renders them less physiologically accurate. Vascularization of COs remains challenging due to the different requirements between COs and vascular cells, limited vascular network penetration within the organoid, and the absence of luminal perfusion. Here, we devised an encapsulation approach in which human brain microvascular endothelial cells (HBMVECs) were delivered to developing COs from progressively degrading extracellular matrix (ECM)-based hydrogel droplets. By tuning this hydrogel concentration and media composition, we observed enhanced vascular-like network formation that expanded within the organoid tissue. Using pathway inhibitors, we showed that a subset of the endothelial cells (ECs) originated from the CO itself, promoting network integration. Endothelial networks displayed blood-brain barrier (BBB) features, including astrocytic end-footlike interactions, pericyte wrapping, and collagen-laminin basal lamina. Vascularized COs exhibited greater media internalization and up to three-fold lower apoptosis than non-vascularized COs. This comprehensive 3D neurovascular model is a promising platform for cerebrovascular research and drug testing applications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/650161v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@175edb7org.highwire.dtl.DTLVardef@1499b91org.highwire.dtl.DTLVardef@184567borg.highwire.dtl.DTLVardef@149c8e4_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG HighlightsO_LIAddition and angiogenic stimulation of human brain microvascular endothelial cells (HBMVECs) co-cultured with cerebral organoids (COs) generate multicellular vascular-like networks C_LIO_LIVascularization induces changes in organoid morphology but not on tissue stiffness C_LIO_LIEndothelial networks morphological features are correlated with the concentration of the supporting matrix C_LIO_LIA number of the endothelial cells (ECs) in the networks originate from the organoid itself C_LIO_LIEndothelial networks integrate within the organoid tissue interacting with astrocytes and pericyte-like cells, and are surrounded by basement membrane-like depositions C_LIO_LIVascularized COs exhibit higher media diffusion, and a reduced necrotic core compared to non-vascularized COs C_LI

bioengineering↗

bioRxiv2025

Unsupervised Detection of Rare Events in Liquid Biopsy Assays

The use of liquid biopsies in the detection, diagnosis and treatment monitoring of different types of cancers and other diseases often requires identifying and enumerating instances of analytes that are rare. Most current techniques that aim to computationally isolate these rare instances or events first learn the signature of the event, and then scan the appropriate biological assay for this signature. While such techniques have proven to be very useful, they are limited because they must first establish what signature to look for, and only then identify events that are consistent with this signature. In contrast to this, in this study, we present an automated approach that does not require the knowledge of the signature of the rare event. It works by breaking the assay into a sequence of components, learning the probability distribution of these components, and then isolating those that are rare. This is done with the help of deep generative algorithms in an unsupervised manner, meaning without a-priori knowledge of the rare event associated with an analyte. In this study, this approach is applied to immunofluorescence microscopy images of peripheral blood, where it is shown that it successfully isolates biologically relevant events in blood from normal donors spiked with cancer-related cells and in blood from patients with late-stage breast cancer.

bioinformatics↗

bioRxiv2024

EXOSOMES FROM CYCLIC MICE MODULATE LIVER TRANSCRIPTOME IN ESTROUPAUSE MICE INDEPENDENT OF AGE

BackgroundExosomes are extracellular vesicles secreted by cells that contain microRNAs (miRNAs). These miRNAs can induce changes in gene expression and function of recipient cells. In different cells exosome content can change with age and physiological state affecting tissues function and health. AimsTherefore, the aim of this study was to characterize the miRNA content and role of exosomes from cyclic female mice in the modulation of liver transcriptome in estropausal mice. Main MethodsTwo-month-old female mice were induced to estropause using 4-vinylcyclohexene diepoxide (VCD). At six months of age VCD-treated mice were divided in control group (VCD) and exosome treated group (VCD+EXO), which received 10 injections at 3-day intervals of exosomes extracted from serum of cyclic female mice (CTL). Key findingsExosome injection in estropausal mice had no effect on body mass, insulin sensitivity or organ weight. We observed ten miRNAs differentially regulated in serum exosomes of VCD compared to CTL mice. In the liver we observed 931 genes differentially expressed in VCD+EXO compared to VCD mice. Interestingly, eight pathways were up-regulated in liver by VCD treatment and down-regulated by exosome treatment, indicating that exosomes from cyclic mice can reverse changes promoted by estropause in liver. Cyp4a12a expression which is male-specific was increased in VCD females and not reversed by exosome treatment. SignificanceOur findings indicate that miRNAs content in exosomes is regulated by estropause in mice independent of age. Additionally, treatment of estropausal mice with exosomes from cyclic mice can partially reverse changes in liver transcriptome.

physiology↗

bioRxiv2024

Membrane composition and curvature in SNX9-mediated actin polymerization

Membrane-binding adaptor protein Sorting nexin 9 (SNX9) contributes to viral uptake and inflammation and is associated with worse outcomes in several cancers. It is involved in endocytosis of epidermal growth factor receptors, {beta}1-integrin and membrane type 1 matrix metalloprotease and in mitochondrial-derived vesicles. Its BAR-PX domain binds phosphatidylinositol phosphates (PIPs) and its SH3 domain interacts with dynamin and N-WASP to stimulate Arp2/3 complex actin polymerization during vesicle scission. Recent complexities have arisen in SNX9s lipid specificity and its involvement both endocytic and filopodial membrane topologies. Here we use biolayer interferometry, cell-free reconstitution and superresolution microscopy to analyse the activities of SNX9. We find that more SNX9 binds membranes that contain PI(4,5)P2 and PI(3)P compared with PI(3,4)P2, despite having similar affinity, suggesting SNX9 can assemble into different macromolecular arrangements depending on the composition. Actin assembly requires the wider protein and lipid network provided by PX-BAR and SH3 interactions. 3D direct stochastic optical reconstruction microscopy on filopodia-like reconstitutions shows that SNX9 and related protein Transducer of Cdc42 activation-1 (TOCA-1) are competent to form both tubular and plaque-like organizations with the actin machinery. Finally, using cryo-electron tomography we show that SNX9 assembles both branched and bundled actin filaments demonstrating its multifunctional nature.

cell biology↗

bioRxiv2024

The open to closed D-loop conformational switch determines length in filopodia-like actin bundles

Filopodia, microspikes and cytonemes are implicated in sensing the environment and in dissemination of morphogens, organelles and pathogens across tissues. Their major structural component is parallel bundles of actin filaments that assemble from the cell membrane. Whilst the length of filopodia is central to their function, it is not known how their lengths are determined by actin bundle dynamics. Here, we identified a set of monoclonal antibodies that lengthen filopodia-like structures formed in a cell-free reconstitution system, and used them to uncover a key molecular switch governing length regulation. Using immunolabelling, enzyme-linked immunosorbent assays, immunoprecipitation and immunoblock experiments, we identified four antibodies that lengthen actin bundles by selectively binding the open DNase 1-binding loop (D-loop) of actin filaments. The antibodies inhibit actin disassembly and their effects can be alleviated by providing additional actin or cofilin. This work indicates that maintaining an open state of the actin filament D-loop is a mechanism of generating the long projections of filopodia-like actin bundles.

biochemistry↗

bioRxiv2024

A Human iPSC-derived Organoid System to Model Myelin Destruction and Repair

We engineered a novel human iPSC-derived organoid system enriched with mature, myelinating oligodendrocytes and functionally reactive microglia. This model enables the study of human CNS remyelination following a demyelinating insult, encapsulating: myelin fragmentation, microglial clearance of myelin debris and oligodendrocyte genesis, differentiation, and axon ensheathment. This system provides a powerful and unparalleled capacity to interrogate complex human cell behaviour, relevant to those studying glial biology and neurological disease mechanisms.

neuroscience↗

bioRxiv2023

Fecal microbial transfer and complex carbohydrates mediate protection against COPD

ObjectiveChronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DesignUsing an in vivo mouse model of cigarette smoke-induced COPD and fecal microbial transfer (FMT), we characterized the fecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology, and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in sixteen COPD patients using a randomized, double-blind, placebo-controlled pilot study of inulin supplementation. ResultsFMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in cigarette smoke-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. ConclusionThe gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically. What is already known on this topicO_LIChanges in gut microbiota are associated with COPD but the underlying host and microbial mechanisms are unclear, limiting the therapeutic applications. C_LI What this study addsO_LIMicrobiome composition and metabolism is reproducibly correlated with lung and gastrointestinal pathology in experimental COPD. C_LIO_LIMicrobiome modifying interventions effectively alleviate disease, including protective effects supplementing smoking cessation. C_LIO_LINutritional interventions targeting the microbiome in COPD patients demonstrate efficacy in a small pilot study. C_LI How this study might affect research, practice or policyO_LIMicrobiome-targeting therapeutics and nutritional interventions may be developed for COPD, including as supplements to smoking cessation. C_LI

physiology↗

bioRxiv2023

FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe

WEE1 kinase phosphorylates CDK1 and CDK2 to regulate origin firing and mitotic entry. Inhibition of WEE1 has become an attractive target for cancer therapy due to the simultaneous induction of replication stress and inhibition of the G2/M checkpoint. WEE1 inhibition in cancer cells with high levels of replication stress results in induction of replication catastrophe and mitotic catastrophe. To increase potential as a single agent chemotherapeutic, a better understanding of genetic alterations that impact cellular responses to WEE1 inhibition is warranted. Here, we investigate the impact of loss of the helicase, FBH1, on the cellular response to WEE1 inhibition. FBH1-deficient cells have a reduction in ssDNA and double strand break signaling indicating FBH1 is required for induction of replication stress response in cells treated with WEE1 inhibitors. Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.

cell biology↗

bioRxiv2023

Filopodial protrusion driven by density-dependent Ena-TOCA-1 interactions

Filopodia are narrow actin-rich protrusions with important roles in neuronal development. The neuronally-enriched TOCA-1/CIP4 family of F-BAR and SH3 domain adaptor proteins have emerged as upstream regulators that link membrane interactions to actin binding proteins in lamellipodia and filopodia, including WAVE and N-WASP nucleation promoting factors and formins. Here, we demonstrate a direct interaction between TOCA-1 and Ena/VASP actin filament elongators that is mediated by clustered SH3 domain interactions. Using Xenopus retinal ganglion cell axonal growth cones, where Ena/VASP proteins have a native role in filopodia extension, we show that TOCA-1 localises to filopodia and lamellipodia, with a retrograde flow of puncta, and correlates with filopodial protrusion. Two-colour single molecule localization microscopy of TOCA-1 and Ena supports their nanoscale association. TOCA-1 clusters coalesce at advancing lamellipodia and filopodia and operate synergistically with Ena to promote filopodial protrusion dependent on a functional SH3 domain. In analogous yet distinct ways to lamellipodin and IRSp53, we propose that transient TOCA-1 clusters recruit and promote Ena activity to orchestrate filopodial protrusion.

cell biology↗

bioRxiv2022

Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Cerebral organoids show great promise as tools to unravel the complex mechanisms by which the mammalian brain develops during embryogenesis. We generated mouse cerebral organoids harbouring constitutive or conditional mutations in Pax6, which encodes a transcription factor with multiple important roles in brain development. By comparing the phenotypes of mutant organoids with the well-described phenotypes of Pax6 mutant mouse embryos, we evaluated the extent to which cerebral organoids reproduce phenotypes previously described in vivo. Organoids lacking Pax6 showed multiple phenotypes associated with its activity in mice, including precocious neural differentiation, altered cell cycle and an increase in abventricular mitoses. Neural progenitors in both Pax6 mutant and wild type control organoids cycled more slowly than their in vivo counterparts, but nonetheless we were able to identify clear changes to cell cycle attributable to the absence of Pax6. Our findings support the value of cerebral organoids as tools to explore mechanisms of brain development, complementing the use of mouse models.

developmental biology↗

bioRxiv2022

Sex differences in allometry for phenotypic traits indicate that females are not scaled males

Sex differences in the lifetime risk and expression of disease are well-known. Preclinical research targeted at improving treatment, increasing health span, and reducing the financial burden of health care, has mostly been conducted on male animals and cells. The extent to which sex differences in phenotypic traits are explained by sex differences in body weight remains unclear. We quantify sex differences in the allometric relationship between trait value and body weight for 375 phenotypic traits in male and female mice, recorded in >2.1 million measurements from the International Mouse Phenotyping Consortium. We find sex differences in allometric parameters (slope, intercept, residual SD) are common (76% traits). Body weight differences do not explain all sex differences in trait values but scaling by weight may be useful for some traits. Our results support a trait-specific patterning of sex differences in phenotypic traits, promoting case-specific approaches to drug dosage scaled by body weight.

evolutionary biology↗

bioRxiv2022

PAX6 LIMITS THE COMPETENCE OF DEVELOPING CEREBRAL CORTICAL CELLS

The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence of cells to respond to such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being exposed to signals with the potential to initiate the production of other neuronal types, suggesting that their competence is limited. Here we tested the hypothesis that this limitation is due to their expression of transcription factor Pax6. We used bulk and single cell RNAseq to show that conditional cortex-specific Pax6 deletion from the onset of cortical neurogenesis allowed some progenitors to generate abnormal lineages resembling those normally found outside the cortex. Analysis of selected gene expression showed that the changes occurred in specific spatiotemporal patterns. We then compared the responses of control and Pax6-deleted cortical cells to in vivo and in vitro manipulations of extracellular signals. We found that Pax6 loss increased cortical progenitors competence to generate inappropriate lineages in response to extracellular factors normally present in developing cortex, including the morphogens Shh and Bmp4. Regional variation in the levels of these factors could explain spatiotemporal patterns of fate change following Pax6 deletion in vivo. We propose that Pax6s main role in developing cortical cells is to minimize the risk of their development being derailed by the potential side-effects of morphogens engaged contemporaneously in other essential functions.

neuroscience↗

bioRxiv2021

A thermodynamic model for interpreting tryptophan excitation-energy-dependent fluorescence spectra provides insight into protein conformational sampling and stability

It is now over thirty years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. Whilst there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the protein REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides to multi-tryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibody in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating bimolecular simulation with experimental data to yield novel insights.

biophysics↗