Biology subjects

Stone, J. M.

Publications and source records attributed to Stone, J. M..

6 recordsLinked to original sources

bioRxiv2026

Beyond Navigation - Tissue-contacting Fluorescent Lifetime Imaging reveals a pathology-linked lung cancer phenotype at the point of biopsy

Background: Accurate sampling of suspected peripheral lung cancers depends on access to the lesion and confirmation that the biopsy tool is in contact with target tissue. Current bronchoscopic navigation and imaging techniques can guide instruments to a target but do not provide real-time biological confirmation at the point of sampling. Fluorescence lifetime imaging microscopy (FLIM) provides molecular contrast by measuring fluorescence decay - how long photons continue to be emitted from fluorescent molecules. In the Precision Lung clinical study (ISRCTN15093468), the Prothea Imaging System (Generation 1) identified a candidate tumour-associated phenotype of spatially overlapped low fluorescence lifetime and low intensity (LLLI) from in-vivo imaging. We used this observation as the basis for a reverse-translational study to determine whether the LLLI phenotype is linked to cancer pathology; reproducible with the Imaging System (Generation 2); and distinguishable from normal lung tissue. Methods: Previously reported Precision Lung findings were used as the clinical starting observation and were not re-analysed. Validation was then performed using: (i) pathology linked benchtop FLIM of early-stage non-small-cell lung tissue microarrays encompassing malignant cell clusters of approximately 300 um2, matched to the EoT imaging scale; (ii) five sequential fresh lung-cancer resections imaged at tumour and comparator regions, including visibly blood-rich contact sites, using the (Generation 2) Imaging System; and (iii) systematic mapping of two ventilated non-cancer donor lungs, one from a smoker and one from a non-smoker, across all available lobes. The LLLI phenotype was defined as spatial co-localisation of low intensity and short lifetime. Results: Using a real time fibre based FLIM system, capable of deployment through a working channel of a bronchoscope, the LLLI tumour phenotype was optically identified in freshly resected tumour tissue. The same phenotype was identified in fixed tissue samples with known pathology, and with images taken in the Precision Lung clinical study. Whole human lung controls did not show evidence of the tumour phenotype. Conclusions: This evidence forms a reverse-translational chain that supports the concept of the Prothea Imaging System - as a platform that confirms that the tool is in contact with a region of cancer in the lesion, while preserving continuous access for biopsy or intervention.

cancer biology↗

bioRxiv2026

Endomicroscopic fluorescence lifetime imaging enables molecular detection and targeted sampling in the distal human lung

PurposeAccurate molecular characterisation of infection and inflammation within the distal human lung remains challenging, particularly in critically ill patients, due to limited access to the alveolar space and delayed diagnostic workflows. Molecular imaging approaches capable of real-time detection and targeted sampling could substantially improve diagnostic precision and the future translational development of molecular imaging probes and therapeutics. MethodsIn a preclinical setting, we evaluated a clinic-ready endomicroscopic fluorescence lifetime imaging microscopy (eFLIM) platform combined with molecularly targeted SmartProbes for in situ detection of bacteria and activated neutrophils in the distal human lung. A multifunctional 1.9-mm diameter imaging and sampling catheter (Eyes on Target; EoT) enabled real-time fluorescence intensity and lifetime imaging alongside directed alveolar microlavage via a 1.2-mm working channel. Fluorescence intensity and lifetime signatures of Gram-negative bacteria, Gram-positive bacteria, and activated neutrophils were characterised using three wash-free SmartProbes: NBD-PMX, Merocy-Van, and a neutrophil activation probe (NAP). Imaging and sampling performance were assessed in ventilated ex vivo human lungs. ResultsEoT reliably navigated to alveolar regions across all lung lobes in both phantom and ventilated human lung models. eFLIM distinguished alveolar microanatomy and enabled probe-specific molecular detection within the distal lung. Increased NBD-PMX signal was detected in Escherichia coli-instilled lobes, while Merocy-Van lifetime signatures selectively identified Staphylococcus aureus-instilled regions. Activated neutrophils were detected throughout lung tissue following NAP administration. Directed alveolar microlavage enabled recovery of cellular material and bacterial DNA from imaged regions for downstream analysis. ConclusioneFLIM using EoT combined with molecular SmartProbes enables real-time molecular imaging and targeted sampling within the distal human lung. This platform provides a translatable approach for evaluating infection and inflammation at the alveolar level and supports the clinical development of molecular imaging probes for pulmonary disease.

microbiology↗

bioRxiv2026

Fronto-Temporal Dysconnectivity and Cortical Excitability in High Schizotypy: Associations with Symptom Dimensions

BackgroundPsychosis has been conceptualised as a continuum extending from healthy individuals with psychotic-like experiences to clinical populations with schizophrenia. It is unclear which biological mechanisms found in chronic schizophrenia extend across the psychosis continuum to healthy individuals with high positive schizotypy (HS). In this study, we used computational modeling to test whether changes in effective connectivity and excitation/inhibition (E/I) balance reported in schizophrenia are also found in HS. MethodsA total of 2425 individuals from the general population were screened for HS. A subset (N=141) was invited for in-depth phenotyping. Resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) were recorded in n=69 HS individuals and n=72 group-matched controls with low schizotypy (LS). We used dynamic causal modeling to estimate effective connectivity between bilateral primary auditory cortex (A1), superior temporal gyrus (STG), and inferior frontal gyrus (IFG). ResultsBilateral backward connectivity from IFG to STG was significantly reduced in HS compared to LS. Widespread cortical disinhibition in the auditory cortex-IFG network correlated with more severe positive schizotypy scores and impulsive nonconformity. Reduced excitability in the same network was correlated with stronger cognitive disorganisation. ConclusionsOur results favour a psychosis-continuum hypothesis, suggesting that reduced top-down drive from frontal cortex and compensatory allostatic upregulation of cortical excitability, as observed in chronic schizophrenia, also extend to groups with sub-clinical psychotic symptoms. Frontal cortex dysfunction may serve as a biologically interpretable biomarker of psychosis risk and a target for preventative interventions.

neuroscience↗

bioRxiv2024

Coenzyme M: An Archaeal Antioxidant as an Agricultural Biostimulant

Rising global food demand necessitates improved crop yields. Biostimulants offer a potential solution to meet these demands. Among them, antioxidants have shown potential to improve yield, nutritional quality and resilience to climate change. However, large-scale production of many antioxidants is challenging. Here, we investigate Coenzyme M (CoM), a small, achiral antioxidant from archaea, as a potential biostimulant, investigating its effects on growth and physiology. CoM significantly increased biomass of the model plant Arabidopsis thaliana in a concentration-dependent manner consistent with it being metabolized. In tobacco, CoM increased photosynthetic light capture capacity, consistent with observed growth improvements. Interestingly, this effect was independent of carbon capture rates. Furthermore, CoM promoted early-stage shoot growth in various crops species, including tobacco, basil, cannabis, and soybean. Our results suggest CoM is a promising, scalable biostimulant with potential to modify photosynthesis and enhance crop productivity. Key PointsO_LIAntioxidant application improves plant growth but is typically too expensive to use widely. C_LIO_LICoenzyme M is a small, easily made antioxidant of Archaeal origin. C_LIO_LIApplied exogenously, Coenzyme M conditionally increases plant biomass. C_LIO_LICoenzyme M represents an antioxidant with potential to be a widely used biostimulant. C_LI

plant biology↗

bioRxiv2022

Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes

Converging lines of evidence suggest that dysfunction of cortical parvalbumin-expressing (PV+) GABAergic interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and levels of glutamatergic metabolites, and decreases in binding of GABAA 5 receptors and the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between PV+ interneuron dysfunction and these neuroimaging readouts have yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal PV+ interneurons leads to several synaptic, behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this PV+ interneuron disruption affects the hippocampal in vivo neuroimaging readouts in the Erbb4 model. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n=12) and their wild-type littermates (Erbb4F/F, n=12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated CBF and glutamine levels, as well as decreased SV2A density compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical PV+ interneurons in mice recapitulate some of the key neuroimaging findings in psychosis patients, and link PV+ interneuron deficits to non-invasive, translational measures of brain function and neurochemistry that can be used across species.

neuroscience↗

bioRxiv2021

Gestational methylazoxymethanol acetate administration alters α5GABAA and NMDA receptor density: An integrated neuroimaging, behavioral and pharmacological study

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in dorsal hippocampus CA1, ventral hippocampus CA1, and in ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of 5 GABAA receptors (5GABAAR), [3H]-flumazenil to quantify 1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. 5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-Flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of 5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

neuroscience↗