http://bura.brunel.ac.uk/handle/2438/32873 2026-06-29T18:49:36Z 2026-06-29T18:49:36Z Ramchunder, Z Kalef-Ezra, E Suleman, S Edzeamey, FJ Szunyogh, S Gittins, O Mena, NC Wade-Martins, R Valle, A Pourzand, C Anjomani Virmouni, S http://bura.brunel.ac.uk/handle/2438/33499 2026-06-25T06:10:18Z 2026-06-22T00:00:00Z

Title: Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting Authors: Ramchunder, Z; Kalef-Ezra, E; Suleman, S; Edzeamey, FJ; Szunyogh, S; Gittins, O; Mena, NC; Wade-Martins, R; Valle, A; Pourzand, C; Anjomani Virmouni, S Abstract: Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disorder caused by a GAA repeat expansion within the FXN gene, leading to reduced frataxin levels. This deficiency results in mitochondrial dysregulation, oxidative stress, and progressive cell death. Currently, only one approved treatment exists for FRDA in the United States, Canada, and the European Union, which improves neurological outcomes but has not been fully evaluated for broader disease symptoms. Therefore, identifying new therapeutic targets remains essential. Sphingolipids are increasingly recognized for their roles in neurodegeneration with emerging evidence indicating their dysregulation in FRDA. Here, we investigate whether sphingolipid-metabolizing enzymes are similarly affected and assess the therapeutic potential of targeting them. Our findings demonstrate that these enzymes are dysregulated across multiple FRDA models. Importantly, their modulation in vitro and in vivo significantly reduces mitochondrial dysfunction, enhances frataxin expression, and improves key pathological features of the disease, highlighting sphingolipid metabolism as a promising therapeutic target for FRDA. Description: Data and code availability: • All data reported in this paper will be shared by the lead contact upon request. • This paper does not report original code. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

2026-06-22T00:00:00Z Saula, AY Cevik, M Cliff, JM Ronacher, K Bowness, R http://bura.brunel.ac.uk/handle/2438/33249 2026-05-09T02:01:00Z 2026-04-23T00:00:00Z

Title: Immune dysregulation in tuberculosis-diabetes comorbidity: mechanistic and translational insights Authors: Saula, AY; Cevik, M; Cliff, JM; Ronacher, K; Bowness, R Abstract: Background: Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, and the rising prevalence of diabetes mellitus (DM) represents a major obstacle to TB control. DM increases susceptibility to TB, worsens disease severity, delays treatment response, and is associated with poorer outcomes, largely through disruption of host immunity. Methods: We conducted a systematic review of studies published between 1974 and May 31, 2023 that examined immunological mechanisms through which DM alters TB pathogenesis. In total, 81 eligible studies involving animal models, human participants, or combined approaches were identified and synthesised across different stages of TB. Results: Across studies, DM was associated with broad dysregulation of innate and adaptive immune responses, altered cytokine signalling, impaired granuloma structure and function, and reduced control of Mycobacterium tuberculosis (Mtb). Distinct immune profiles emerged between TB disease with DM and latent TB infection with DM, with heterogeneity partly explained by differences in study design, metabolic status, and disease stage. Importantly, emerging evidence indicates that pre-diabetes and intermediate hyperglycaemia may also compromise TB immunity and contribute to disease progression. Conclusion: Our findings highlight DM as a key immunometabolic modifier of TB pathogenesis. They also suggest that earlier metabolic optimisation and hostdirected therapeutic strategies could be explored as potential approaches to improve outcomes in this growing high-risk TB-DM population. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023431040. Description: Data availability statement: The data analyzed in this study is subject to the following licenses/restrictions: The datasets can be shared with researchers upon request. Requests to access these datasets should be directed to Aminat Y. Saula, ays27@bath.ac.uk.; Supplementary material: The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2026.1803046/full#supplementary-material .

2026-04-23T00:00:00Z Saleem, A Peng, Q Tang, Z Mohseni, YR Scottà, C Shangaris, P Smit, K Vermeij, WP Issa, F Lombardi, G Fruhwirth, GO http://bura.brunel.ac.uk/handle/2438/33179 2026-04-22T02:01:06Z 2026-02-06T00:00:00Z

Title: CAR-mediated release of IL-10 increases the function of regulatory T cells: relevance for future clinical application Authors: Saleem, A; Peng, Q; Tang, Z; Mohseni, YR; Scottà, C; Shangaris, P; Smit, K; Vermeij, WP; Issa, F; Lombardi, G; Fruhwirth, GO Abstract: Regulatory T cell (Treg) therapy emerges for various indications associated with a breakdown of immune tolerance. Antigen-specific chimeric antigen receptor (CAR) Tregs are frontrunners for transplantation and autoimmune diseases and are currently being clinically evaluated. We aimed to link CAR-antigen engagement with immunosuppressive cargo release into the local microenvironment to boost efficacy and reduce side effects. We used our HLA-A∗02 CAR and immunosuppressive interleukin-10 (IL-10) as model components to generate human CAR Tregs that release IL-10 upon CAR engagement. These were compared to CAR Tregs with constitutive or no IL-10 expression by evaluating phenotypes, antigen-specific IL-10 release, and suppression of effector cell proliferation in vitro and performance in vivo in a humanized xenogeneic graft-versus-host disease (xeno-GvHD) model. We demonstrated successful multi-construct engineering of CAR Tregs, which released upon CAR engagement 2.5-fold more IL-10 than CAR Tregs lacking the corresponding antigen-specific IL-10 secretion module. Neither phenotype nor function was affected by expressing this module. In the xeno-GvHD model, we showed the beneficial effect of IL-10 release, particularly evident when compared to constitutive IL-10 expression that impaired CAR-Treg efficacy. We provide first proof-of-principle for engineering human CAR Tregs to release an immunosuppressive cytokine upon CAR engagement. This approach will both enhance the potency of CAR Tregs at the intended target sites and limit their off-target effects. Description: Data and code availability: The data presented here are available on request from the corresponding authors.; Supplemental information is available online at: https://www.sciencedirect.com/science/article/pii/S1525001626000870#appsec2 .

2026-02-06T00:00:00Z Mann, R Tosi, S Tree, D http://bura.brunel.ac.uk/handle/2438/33171 2026-04-20T02:01:04Z 2026-03-24T00:00:00Z

Title: Clinical assessment meets laboratory science: adapting OSCE methodology for authentic biosciences evaluation in the age of generative AI Authors: Mann, R; Tosi, S; Tree, D Abstract: The proliferation of generative artificial intelligence (AI) tools has fundamentally challenged traditional written assessments across higher education, with particular implications for laboratory-based disciplines where written work may substitute for demonstration of practical competence, necessitating approaches that prioritise direct performance. This study presents the adaptation of objective structured clinical examination (OSCE) methodology from medical education to laboratory biosciences, demonstrating a practical framework for authentic assessment in the AI era. We describe and evaluate the transformation of a microscopy assessment in FHEQ Level 4 Biomedical Sciences from a traditional laboratory report to a 20-minute OSCE-style practical evaluation. The redesigned assessment maintained grade distributions while eliminating AI vulnerability through real-time performance demonstration and conversational examination. The implementation achieved close alignment between learning outcomes and assessment methods while providing inherent resistance to generative AI exploitation through direct performance requirements. Equity implications are complex and context-dependent, with potential barriers for students with communication differences alongside potential benefits for others, such as those with written communication difficulties, emphasising the importance of balanced assessment portfolios and appropriate reasonable adjustments. The cross-disciplinary adaptation demonstrates that OSCE methodology offers a scalable solution to AI-era assessment challenges, with performance-focused design maintaining academic integrity more effectively than restrictive policies while enhancing authenticity and equity outcomes. Description: Perspective.

2026-03-24T00:00:00Z