Biology subjects

Stride, E.

Publications and source records attributed to Stride, E..

6 recordsLinked to original sources

bioRxiv2026

Ultrasound-mediated focal serotonin delivery causally modulates motivation in primates

Causal manipulation of neuromodulatory systems has been constrained by a trade-off between spatial precision and translational relevance: circuit-specific techniques are invasive, whereas systemic pharmacology lacks anatomical specificity. Here, we establish ultrasound-mediated neuromodulator delivery as a non-invasive, spatially precise approach for causal neuropharmacology in awake, behaving primates. By transiently opening the blood-brain barrier, we delivered systemically administered serotonin to the perigenual anterior cingulate cortex (pgACC) during a decision-making task. Combining computational modelling with multimodal imaging, pupillometry and histology, we show that elevating pgACC serotonin altered local neural activity and weakened the influence of reward environment on motivational state while leaving sensitivity to immediate reward opportunities intact. This was accompanied by reduced functional coupling, decreased local glutamatergic metabolite signal and increased serotonergic signal at the target, with repeated delivery well tolerated. Together, these findings establish a translatable platform for focal neuropharmacology and identify pgACC serotonin as a regulator of context-dependent motivation.

neuroscience↗

bioRxiv2026

The material properties of the cell determine microbubble-induced cell deformation and permeabilisation

Mechanical properties influence how cells withstand and transmit force, but their role in clinically relevant, high-frequency therapeutic perturbations remains poorly understood. Ultrasound-stimulated microbubbles can locally deform cells and tissues to enhance drug delivery, yet therapeutic responses vary markedly across mechanical microenvironments. How cellular material properties govern microbubble-cell interactions at megahertz loading rates - well beyond the range accessible to conventional mechanobiology - remains unresolved. Here we combine ultra-high-speed imaging with digital image correlation to map microbubble-induced deformation in living cells at ultrasound frequencies. We show that oscillating microbubbles generate harmonic deformation waves whose spatial decay defines a micrometre-scale attenuation length governed by cytoskeletal organisation and intracellular viscoelastic dissipation. Pharmacological softening or stiffening alters both deformation propagation and wave speed, and these mechanical changes predict permeabilisation efficiency in tumour-derived and primary human bone-marrow stromal cells. These findings establish cellular viscoelasticity as a determinant of microbubble bioeffects and suggest that tissue mechanical state can be used as a design parameter for ultrasound-mediated therapeutic delivery.

bioengineering↗

bioRxiv2025

Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli

Urinary tract infections (UTI) remain a major global health burden, with high recurrence despite antibiotic treatment. The escalating prevalence of antimicrobial resistance further compromises therapeutic efficacy, contributing to an estimated 260,000 deaths annually. Conventional in vitro susceptibility assays often fail to predict clinical outcomes, underscoring the urgent need for physiologically relevant infection models. Here, we examined how microenvironmental complexity shapes uropathogenic Escherichia coli (UPEC) responses to antibiotics and bacteriophages using: human urine, a three-dimensional urothelial microtissue model (3D-UHU), and a novel mesofluidic system (P-FLO) that introduces physiologically relevant flow dynamics to the 3D-UHU. P-FLO was engineered from cost-effective 3D-printed components compatible with standard Transwell systems. Among the antibiotics tested, nitrofurantoin exhibited the greatest potency in minimum inhibitory concentration assays, but it failed to fully eradicate infection within the more physiological 3D-UHU model. A bacteriophage cocktail (LCPR1) showed markedly reduced activity in urine compared with nutrient-rich media, highlighting the influence of infection-site conditions. In contrast, in 3D-UHU, LCRP1 modulated host responses without reducing bacterial burden. Combination therapy (nitrofurantoin + LCPR1) eliminated planktonic bacteria under static conditions but offered no added benefit against adherent or intracellular populations relative to antibiotic monotherapy. Incorporating flow revealed additional layers of complexity, where shear stress induced bacterial elongation and attachment and altered drug performance, diminishing the efficacy of nitrofurantoin and combination therapy against planktonic populations despite increased drug exposure. Together, these findings demonstrate that the bladder microenvironment and its mechanical forces modulate host-pathogen interactions and profoundly influence UPEC infection dynamics and therapeutic outcomes, emphasizing the need for advanced, physiologically informed models to guide treatment strategies in the post-antibiotic era.

microbiology↗

bioRxiv2025

Bidirectional Crosstalk Between Bladder Cancer Cells and Normal Fibroblasts Drives Phenotypic Reprogramming and Modulates Chemosensitivity

During early bladder cancer progression, invading tumour cells first encounter normal fibroblasts (NFs) residing in the lamina propria. Whether and how this interaction shapes tumour behaviour and treatment response, however, has not been systematically examined. While cancer-associated fibroblasts (CAFs) are established drivers of tumour progression and therapy resistance, the role of their precursor NFs in shaping bladder cancer behaviour has been largely overlooked. Here we dissect bidirectional interactions between bladder cancer cells and NFs using indirect (conditioned media) and direct co-culture systems. Fibroblast-conditioned media (FCM) significantly reduced proliferation while accelerating migration in both RT112 and T24 bladder cancer cells, consistent with a pro-migratory "go-or-grow" phenotypic shift. Immunofluorescence revealed FCM-induced cadherin switching reduced E-cadherin and elevated N-cadherin, indicative of an epithelial-to-mesenchymal transition (EMT)-like state. Reciprocally, NFs acquired CAF-like features within 48 hours of tumour cell exposure, with significant upregulation of SMA and FAP confirmed by both immunofluorescence and flow cytometry. Functionally, increasing fibroblast-to-cancer cell ratio progressively attenuated mitomycin C (MMC)-induced cytotoxicity, demonstrating a stromal-mediated, ratio-dependent protective effect against intravesical chemotherapy. Data from the Cancer Genome Atlas (TCGA) for Urothelial Bladder Carcinoma provided corroboratory evidence that fibroblast-enriched tumours exhibited a strong transcriptional correlation with EMT, elevated resistance-associated transcriptional signatures, and significantly poorer overall survival. Collectively, these findings establish tumour-NF crosstalk as a critical and bidirectional regulator of bladder cancer phenotypic plasticity and chemoresistance, and suggest that fibroblast-targeting strategies combined with intravesical chemotherapy may offer a rational approach to overcoming stromal-mediated treatment failure.

cancer biology↗

bioRxiv2024

Characterisation of Gas Vesicles as Cavitation Nuclei for Ultrasound Therapy using Passive Acoustic Mapping

Genetically encodable gas filled particles known as gas vesicles (GVs) have shown promise as a biomolecular contrast agent for ultrasound imaging and have the potential to be used as cavitation nuclei for ultrasound therapy. In this study, we used passive acoustic mapping techniques to characterize GV-seeded cavitation, utilizing 0.5 and 1.6 MHz ultrasound over peak rarefactional pressures ranging from 100 to 2200 kPa. We found that GVs produce cavitation for the duration of the first applied pulse, up to at least 5000 cycles, but that bubble activity diminishes rapidly over subsequent pulses. At 0.5 MHz the frequency content of cavitation emissions was predominantly broadband in nature, whilst at 1.6 MHz narrowband content at harmonics of the main excitation frequency dominated. Simulations and high-speed camera imaging suggest that the received cavitation emissions come not from individual GVs but instead from the coalescence of GV-released gas into larger bubbles during the applied ultrasound pulse. These results will aid the future development of GVs as cavitation nuclei in ultrasound therapy.

bioengineering↗

bioRxiv2020

Creating supported plasma membrane bilayers using acoustic pressure

Model membrane systems are essential tools for biology, enabling study of biological processes in a simplified setting to reveal the underlying physicochemical principles. As cell-derived membrane systems, giant plasma membrane vesicles (GPMVs) constitute an intermediate model between native cellular plasma and artificial membranes. Certain applications, however, require planar membrane surfaces. Here, we report a novel approach for creating supported plasma membrane bilayers (SPMBs) by bursting cell-derived GPMVs using an ultrasonic pressure field generated within an acoustofluidic device. We show that the mobility of outer leaflet molecules is preserved in SPMBs, suggesting that they are accessible on the surface of the bilayers. Such model membrane systems will be useful for many applications requiring detailed characterization of plasma membrane dynamics.

biophysics↗