Biology subjects

Walters, E.

Publications and source records attributed to Walters, E..

3 recordsLinked to original sources

bioRxiv2026

Longitudinal magnetic resonance imaging and spectroscopy in a mouse model of cuprizone-induced demyelination

The cuprizone (CPZ) lesioned mouse is a widely used model of demyelination and remyelination, but most studies rely on histology at terminal timepoints, limiting understanding of disease dynamics. Here, we present a longitudinal multimodal magnetic resonance imaging and spectroscopy (MRI/MRS) study of CPZ-induced pathology, pooling control arms from three independent experiments (n = 40). Mice were imaged at baseline, then exposed to 0.2% cuprizone for 5 weeks and repeatedly imaged at days 24, 35, 49, 63 and 77 after the start of CPZ. Imaging included multiparametric mapping (MPM), diffusion tensor imaging (DTI), tensor-based morphometry (TBM), and single-voxel MRS in the corpus callosum. Histology (MBP, silver, GFAP, Iba1) was performed at selected timepoints for validation. An additional group of 18 CPZ-lesioned mice were imaged ex vivo using a different higher resolution MRI protocol and compared against 19 non-CPZ controls. MPM-derived MTsat{delta} and R1 reductions indicated robust demyelination in the corpus callosum and deep cerebellar nuclei by day 24, expanding to cortex and hippocampus by day 35. Partial recovery was observed by day 77 but changes persisted, consistent with histological evidence. TBM revealed dynamic volumetric alterations, including hippocampal and cerebellar expansion alongside cortical and subcortical shrinkage, persisting beyond CPZ cessation. DTI demonstrated early (days 24-35) decreases in FA and MD, followed by complex trajectories consistent with microstructural disruption and partial repair. MRS detected early increases in GABA, glutamine, taurine, and glutathione, with corresponding decreases in NAA, while inositol showed a biphasic decrease-increase profile, likely reflecting acute astrocytic dysfunction followed by gliosis - neuroinflammatory processes that were corroborated by immunohistochemistry. Together, these results demonstrate that multimodal MRI/MRS sensitively captures widespread, dynamic, and only partially reversible pathology in CPZ-treated mice. Longitudinal imaging provides a non-invasive, translational approach to characterising demyelination, gliosis, and remyelination, offering a powerful alternative to histology for preclinical studies and longitudinal therapeutic screening.

neuroscience↗

bioRxiv2025

DOMINO: diffusion-optimised graph learning identifies domain structures with enhanced accuracy and scalability

Spatial transcriptomics enables in situ molecular profiling, allowing to measure the cellular transcriptional output within the tissue. As the tissue architecture is conserved, spatial domains with specific transcriptional patterns can be identified, facilitating the discovery and understanding of functional tissue compartments. Thus, several methods to uncover and identify these spatial domains have been developed. However, most of these existing methods do not scale to rapidly increasing data sizes and focus only on local structure while missing the global view of the tissue. Here, we present DOMINO, a diffusion-optimised contrastive learning framework for spatial domain detection. DOMINO utilises graph diffusion convolution to propagate information beyond immediate neighbours and jointly optimises local and, importantly, global graph structure via contrastive learning. This novel framework yields biologically interpretable domains with clearer boundaries and scales to large datasets, outperforming state-of-the-art methods across healthy and malignant benchmark datasets. We apply DOMINO to a newly generated spatial transcriptomic dataset of endometriosis-associated ovarian cancers, which could not be processed by existing domain detection methods owing to its size. We uncovered conserved proliferative and non-proliferative tumour states that recurred across these tumours and were independently validated in an external clear cell ovarian cancer spatial transcriptomic dataset. Proliferative domains were characterised by elevated expression of EIF4A1 and HSPA8, increased cell cycle activity, reduced mast cell abundance, and coordinated stromal remodelling, including altered fibroblast states and spatial organisation. In parallel, integrative analysis across tumours revealed subtype-specific multicellular ecosystems associated with either endometrioid or clear cell ovarian carcinomas, together with a tumour-excluded stromal domain that could only be resolved through the integration of spatial and transcriptional information. These findings demonstrate how well DOMINO scales up and that it uncovers biologically meaningful spatial programs spanning tumour intrinsic states, tumour microenvironment interactions, and subtype-specific tissue architecture that are not recovered by conventional expression-based clustering approaches.

bioinformatics↗

bioRxiv2025

Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life development

Genetic deletion of the complement C3a anaphylatoxin chemotactic receptor (C3ar1), a key component of the innate immune response, is reported to induce behavioural phenotypes consistent with psychiatric symptomatology in mice, but when and where C3ar1 is needed in the brain is unresolved. These questions are significant because, as a G-protein-coupled receptor, human C3AR1 serves as a potential therapeutic target for disorders associated with complement dysregulation, such as schizophrenia. To provide a brain-wide (where) assessment of developmental C3ar1 activity, we used longitudinal (when) tensor-based morphometry, diffusion-weighted magnetic resonance imaging (MRI) and blood oxygen-level dependent functional MRI in male and female C3ar1-deficient mice and wild-type littermates, with behavioural assessment in adulthood. Unexpectedly, we did not find a robust C3ar1-dependent phenotype in any of these measures. Therefore, our study does not support neurodevelopmental hypotheses for C3ar1, which is encouraging for therapeutic strategies targeting this receptor since interventions are unlikely to disrupt brain development.

neuroscience↗