University of Glasgow

UKRI Gateway to Research · FY 2025 · 2025-08

Clinical trials are considered the best way of testing which treatments are made available in the National Health Service (NHS). Trials are run to benefit patients and so patients should be central to their design. Even though patient and public involvement (PPI) is considered important, patients and the public rarely have a say in key trial numerical aspects (for example, how big of a difference we look for when testing treatments). We aim to co-design new methods and tools to improve the involvement of patients and the public in a key numerical aspect in trial design and interpretation - the target difference. A "normal" (superiority) clinical trial tries to find out whether a new treatment is better than the current treatment. A non-inferiority trial tries to show the new treatment is not worse than the current treatment (but it may have other advantages, like lower cost or better safety). To make a treatment recommendation, new treatments need to be better or good enough by a certain margin. This is called the target difference. Most trials aim to detect a target difference that is important to relevant stakeholders, but they often exclude patients from decision making. For example, we may have a trial testing drug A against drug B to treat pain in patients. To decide if drug A is better than drug B, we will have to define a target difference in the patient reported outcome (pain). In this example pain is measured by asking patients "How much pain do you feel today?" in a scale of 1 (no pain at all) to 10 (a lot of pain). The trial may aim to detect a difference of 2 points in the pain scale after 10 days of being in the trial. This means that if participants in the drug A group had a score of 3 points in the pain scale and participants in the drug B group had a 5.5 score, we would decide that drug A is a better treatment. But is that a worthwhile difference to patients? Currently, target difference decision making is usually based on (informed) guesswork based on a small team's judgement which often excludes public partners (defined here as patients or members of the public part of the research team). Including patients and public partners would ensure trials consider patient important differences when they are designed. This would inform the target difference along with other considerations, like the trial's costs and clinician's views. It would also support the interpretation of trial results that help inform which treatments are available in the NHS. To achieve this, we propose to: - Work with patients and public partners to develop inclusive tools to (a) support a common understanding of target differences in the research team; (b) enable an efficient identification of patient important differences at the trial design stage; and (c) enable a meaningful discussion of existing target differences with public partners ahead of deciding the final target difference for the trial. We will identify and use current practice to support the design of these tools. - Pilot the full process - from identification of available target differences at the start of trial design, to a final meeting with all relevant stakeholders in the trial team including public partners, where consensus about the target difference is reached - Assess the feasibility, and impact of involving patients and public partners in deciding the target difference and draft guidance for trialists and public partners considering the findings Patients and public partners do not need to have a prior understanding of medical statistics to get involved. The tools will be developed to be understandable and accessible to people with different numeracy levels. Our project has been developed and will be informed by an advisory group including three experienced public partners. Ultimately, the tools developed in the project aim to improve the relevance of trials and reduce research waste by making patients the foundation of clinical research.

UKRI Gateway to Research · FY 2025 · 2025-08

The MRC - University of Glasgow Centre for Virus Research is the largest collective of researchers in the UK dedicated to the study of viruses that infect humans and at the human-animal interface. The centre has a substantial data science portfolio that ranges in scope from structural biology to molecular evolution, transmission and epidemiological studies. We are seeking funds to support the purchase of a high-performance graphics processing unit (GPU) based computer cluster for the development and implementation of artificial intelligence (AI) tools with a specific focus on virus structure and the application of structural biology tools to the study of virus diversity and evolution. Virus protein structures underlie fundamental interactions with their hosts in infection, replication, and immune evasion. Evolutionary change in these structures can therefore impact susceptibility of novel host species during spillover, virulence, and escape from drugs or vaccines. Examples include SARS-CoV-2 persistence in the human population due to ongoing antigenic change, and the risk of avian influenza adapting to humans. Machine learning and AI are transforming computational biology research. Notably, innovators in the field of protein structure prediction and design were awarded the 2024 Nobel prize in Chemistry for the impact they have had on life sciences through the development of AI approaches such as AlphaFold and RFDiffusion. Within the CVR, innovative applications of AI have recently included development of tools to identify the most likely natural host of viruses and whether they are likely to infect humans, as well as the most likely animal hosts of SARS-COV-2  based solely on viral sequence data, the use of protein language models to identify mutations that are likely to impact on viral phenotypes in human hosts and to predict virus-host protein interactions. We have also applied emerging AI protein structure prediction methods to investigate the deep evolutionary links between viruses. We have created a unique database of >85k viral protein structure predictions that spans >4.4k viruses of animals and humans (https://viro3d.cvr.gla.ac.uk/). This facilitates structure informed discovery of conserved functions across diverse virus species. In structural biology, and in particular cryogenic electron microscopy (cryo-EM) emerging AI tools for image denoising and structural motif detection are allowing researchers to begin to disentangle and interpret the information rich data produced by 3D imaging of the cell, enabling us to map the distribution of proteins, visualising biologically important processes in their native environment. AI automated model-building tools and enhanced refinement techniques are enabling faster and more robust structure determination of ever-smaller complexes. To support our work on the structural biology of viruses, and better integrate structure into computational models of virus evolution and host range, we aim to install a GPU cluster equipped with two types of GPU nodes, one optimised for training large machine learning models capable of representing viral genome sequences in new and richly-parameterised spaces, the other equipped for rapidly computing experimental and predicted protein structures based on established or newly developed models. Together this resource will ensure CVR researchers remain competitive in these fast-moving and exciting fields, supporting the development and implementation of new tools to underpin our pandemic preparedness mission.  

UKRI Gateway to Research · FY 2025 · 2025-08

Clinical imaging is undergoing a revolution with the advent of total-body PET (TBP), a transformative technology capable of imaging molecular processes throughout the entire body. TBP is a quantum leap forward in medical imaging offering 40-times greater sensitivity, with new capabilities such as whole-body-dynamic tracking, low-dose, multi-parametric and multiplex imaging. TBP has broad potential to improve early and accurate diagnosis in cancer, inflammation, infection, cardiovascular disease, stroke, and paediatrics, while also guiding therapeutic developments and precise deployment of new drugs and radiopharmaceuticals. However, fully realising the potential of TBP requires the development of new radiotracers, molecules that target specific disease mechanisms, and linkage with preclinical PET imaging systems to validate novel radiotracers in animal models of human pathologies.  These complete the translational pathway to drive forward the application of TBP providing critical insights for diagnosis, stratification, and treatment for patient benefit.  While Glasgow has a 20-year history in radiotracer development and preclinical MRI, its current preclinical PET imaging resources are at capacity and only available in the CRUK Scotland (formerly Beatson) Institute. This restricts access for University of Glasgow researchers in other disease areas such as inflammation, immunity, neuroscience and cardiovascular research and hinders translation of new molecular probes for new clinical applications. Introducing preclinical PET capability to our University-wide Whole Body Imaging Facility will meet a critical need for local research groups but also leverage Glasgow’s unique position to establish a preclinical molecular imaging platform accessible through two national MRC networks. The Total-Body PET Scotland Facility, jointly managed by the Universities of Glasgow and Edinburgh, is one of two national facilities funded by MRC in 2023 to deploy this game-changing technology through the National PET Imaging Platform (NPIP). Additionally, the MRC National Mouse Genetics Network (NMGN), directed from Glasgow incorporating the MRC Mary Lyons Centre, aims to develop new mouse models that closely mimic human diseases with a clear path to clinical translation.  Therefore, we propose an accessible, multimodal, multiscale imaging facility by integrating new preclinical PET/CT imaging equipment within a recently upgraded UoG preclinical MRI facility. This strategic investment will create a platform for developing novel PET radiotracers and enable interdisciplinary access to imaging technologies locally, whilst optimising NMGN and NPIP network productivity by allowing reciprocal access for preclinical disease modellers to PET technology, and PET developers to state-of-the-art disease models.  Our specific objectives are to establish a preclinical molecular imaging facility integrated with high-field MRI and spatial biology techniques for comprehensive, multiscale, dynamic disease phenotyping.  We will expand radiotracer development for new disease targets in immunity/inflammation, metabolism, and theranostics and advance imaging data analytics for whole-body studies, supporting precision medicine.  By enabling new tracers and technologies, UoG researchers can explore disease mechanisms beyond cancer for the first time, expanding applications across diverse fields of biomedical research. The integration of PET/CT and MRI will offer a unique preclinical imaging platform for broad biological understanding, while local expertise in spatial biology techniques will enhance the interpretation of PET/MR imaging, ensuring precise translation to clinical use.  This programme also builds collaborative networks across the UK (through NPIP and NMGN), giving researchers from over 20 institutions access to cutting-edge multimodal imaging. We aim that this will foster a new generation of scientists skilled in total-body PET, empowering research that leads to earlier diagnoses, improved patient outcomes, and more effective therapeutic interventions. 

UKRI Gateway to Research · FY 2025 · 2025-08

Neuropathic pain (NeuP) affects over 5 million people in the UK. Excessive electrical activity of damaged sensory neurons is key to NeuP, however, the cellular cues which drive hyperexcitability are not fully understood. Emerging evidence suggests that macrophages directly interacting with sensory neurons make an important contribution. Experimental animal models have greatly advanced our understanding of pain processing, however, most drug targets identified in these models have failed to translate. There is therefore a compelling argument to advance human tissue-based experimental models to study neuroimmune signalling in NeuP. In pilot work, we have established the first co-culture model of human iPSC-derived sensory neurons (iSNs) and macrophages (iMACs). Neuronal damage causes iMACs to undergo putatively proinflammatory morphological, secretory and gene expression changes, consistent with features seen in vivo. For example, we have observed marked increases in the secretion of known pro-algesic cytokines from iMACs when co-cultured with damaged iSNs. Moreover, iMACS induce an increased frequency of firing in normally quiescent iSNs, mirroring the spontaneous activity found in NeuP states in vivo Following on from this work, we now wish to identify which of our candidate pro-algesic mediators upregulated in iMACS are responsible for the hyperexcitability observed in damaged iSNs. In vitro models have a crucial role to play in drug discovery and we believe that our system has significant translational potential as a drug screening platform. Therefore, a secondary aim will be to optimise the model and make it an attractive analgesic testing platform, ready to be deployed widely.   NC3Rs training and legacy

UKRI Gateway to Research · FY 2025 · 2025-07

The proposed project aims to investigate patterns of participation in education and training among adults and their related potential benefits in the domains of (1) health, (2) work and careers, and (3) the social community. Structured according to three objectives, the project will utilize data from the UK’s Understanding Society Household Longitudinal Study (UKHLS). We will apply Propensity Score Matching techniques and multivariate longitudinal data analyses. The argument for this proposal is grounded in the findings of the first Work Package of our ongoing ESRC Standard Grant ‘A UK-Ireland investigation into the statistical evidence-base underpinning adult learning and education policy-making’ (ES/X000826/1), resulting in the need to supplement cross-sectional analyses on participation in adult education and training with longitudinal data. Engagement with learning opportunities beyond initial education is important to cope with fast changing economies and societies. This includes the rise of Artificial Intelligence and automation, an ageing population and the need to adapt to changing circumstances caused by critical junctures such as an economic crisis, Brexit, COVID-19 lockdowns and pressures to transform into green and digital economies. Supplementing more sophisticated analyses to the current knowledge base will increase the quality of evidence which we will share and discuss with policymakers and stakeholders across social policy fields such as education and training, the economy,  labour market and health. We will further nourish our existing partnership with the Learning & Work Institute and organise a one-day conference at the end of the project. Academic contributions will take the format of journal articles and conference presentations. The project will be carried out towards the fulfilment of three objectives. Objective 1: The first objective is to generate more sophisticated insights into the patterns and frequency of participation in adult education and training over time (12 years). Cross-sectional data do not give us insights in who the ‘frequent’ versus ‘occasional’ learners are, or who ‘never’ engages over an expanded period. Using data from Understanding Society, notable the ‘participation in any training’ variable, we will run descriptive statistics and longitudinal logistic regression models to test variations in participation at the individual level over time. Analyses will control for the core determinants of participation, which are age, gender, educational attainment and employment characteristics. Objective 2: The second objective is to zoom in on frequent and occasional learners and to investigate how their training characteristics vary over time. This is done through investigating their potential shifts in learning purposes, defined in Understanding Society through seven categories including ‘learning to increase skills at work’ and ‘for hobby or leisure’ reasons. Outputs of sequence analyses will visualise potential fluctuations in participation purposes and be supplemented by panel regressions, controlling for time variant variables such as job changes and age. Objective 3: The third objective is to reinvigorate the research agenda on the benefits of participation in adult education and training. In line with previous work, we will analyse potential benefits in three public policy domains: health, work and careers, and social community. Based on our cleaned dataset through Propensity Score Matching (PSM), making groups of learners versus non-learners more comparable, we will run panel regressions to investigate these potential benefits and their possible strength in relation to participation in training. As part of these analyses, we will simulate potential benefits in the short versus longer term.

UKRI Gateway to Research · FY 2025 · 2025-07

A significant neuroscientific challenge lies in uncovering the neurophysiological processes and circuitry of cognitive processing. This objective becomes increasingly pressing as we gain a deeper understanding of mental health symptoms and witness the advancement of artificial intelligence seeking to emulate brain functions. Recent breakthroughs are converging towards a framework that elucidates and reframes the neural substrates of cognition and cognitive dysfunctions, based on context-specific cellular mechanisms. Context sensitivity is vital for coherent mental experiences,  from accurately perceiving the sensory environment to adapting behaviour in social interactions. This framework describes how pyramidal neurons, the primary computational units of the cortex, have distinct basal and apical regions that process bottom-up (feedforward) and top-down (feedback) signals (different to the dominant integrate-and-fire concept). The integration of top-down inputs in the apical dendrites is pivotal for bestowing pyramidal neurons with context sensitivity, which forms the basis for fundamental cognitive processes and conscious awareness. We recently led a consortium across Europe consisting of neuroscientists, computational modellers, and theorists in the Human Brain Project to study context-sensitive feedback in the mammalian brain. We deepened our understanding of contextual mechanisms for perceptual inference across species, in human, monkey and mouse visual cortex. Furthermore, our brain imaging, electrophysiological and calcium imaging results recorded across different labs in Europe contributed to refining theories of predictive processing. Predictive processing is the most influential theory of brain function today, providing a framework for how the brain interprets and acts in the world by making predictions and updating its models when errors occur. The exchange of predictions and prediction errors is central to healthy brain function, and it is often assumed these processes occur in separate neuron types. However, theories of context-sensitive cellular mechanisms compel us to advance to a sub-neuronal level, suggesting that errors and predictions are exchanged within a single neuron.  Such mechanisms are challenging to study with non-invasive brain imaging, but understanding these mechanisms is essential for establishing baselines of healthy cognition. Utilising our cutting-edge 7T fMRI brain imaging platform at Glasgow, and paradigms disentangling sensory from top-down processing, we capture sub-neuronal mechanisms of prediction error detection at different layers of cortical microcircuits. Our approach is characterised by two key empirical strategies: (i) we design paradigms isolating internally generated contextual signals, by recording from retinotopic non-stimulated regions of primary visual cortex (ii) we measure laminar fMRI in these non-stimulated regions to localise functional signals to cortical layers housing the apical dendritic compartment of pyramidal neurons receiving top-down inputs. Specifically our objectives here are to reveal spatiotemporal interactions of predictive and sensory signals in visual microcircuits using state-of-the-art line scanning fMRI. We will also show how activity in laminar microcircuits relates to conscious experience. Lastly we will demonstrate how laminar microcircuit architectures are functionally modified by memory and learning. Our integrated approach pushes boundaries at intersections between psychological processes and animal neuroscience, converging towards a new field of cellular cognitive neuroscience. With deeper interdisciplinary exchange, laminar fMRI is an ideal mesoscale bridge towards closing explanatory gaps between neuronal mechanisms and system-level modulations. Our findings are relevant for biological and artificial neurons, with context-dependent motifs from biological vision being incorporated into formal specifications of artificial computation.  Investigating mesoscale circuit function will also be informative for computational psychiatry in cases where top-down contextual processing is dysfunctional, creating visual disturbances such as hallucinations.

UKRI Gateway to Research · FY 2025 · 2025-07

European Researchers' Night Scotland - an exciting pan Scotland showcase of research and researchers! This will be the tenth anniversary of EXPLORATHON in Scotland. Our new consortium features existing partners and new partners that reach Scotland's geographically remote highland island communities. Our project will inspire audience and communities with the latest, cutting edge research. We will demonstrate the relevance of research to everyday lives, bring researchers into schools, allow researchers to share their stories and promote research as an enviable career path. Our project follows the principles of Responsible Research and Innovation and will deliver inclusive events to a diverse set of audiences and reflecting the diversity of researchers working in Scotland today. We will work with partners across Scotland to reach communities previously not reached by EXPLORATHON.

UKRI Gateway to Research · FY 2025 · 2025-07

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

UKRI Gateway to Research · FY 2025 · 2025-06

At the level of individual cells, forces play a critical role in shaping and regulating tissue architecture and function throughout the lifetime of an organism, from early embryonic development to advanced age. Disruption to this force landscape in ageing, following a heart attack, and in other disease conditions is also recognised to be the root cause of many undesirable changes in tissue structure that ensue. However, these forces have never been measured at a cellular level inside a living animal, in fast-moving tissues such as the beating heart where forces are strong and rapidly fluctuating. A critical issue holding up biomedical research progress is the inability to measure these forces under real-world conditions. We will develop a new biophotonic approach that will for the first time permit direct imaging and measurement of cell tension forces with subcellular resolution, in rapidly-moving environments such as the cardiovascular system. FLIM-FRET (Fluorescence Lifetime Imaging Microscopy with Förster Resonant Energy Transfer) probes offer the exciting ability to make direct measurements of forces and other properties on nanoscopic scales - which is potentially game-changing for biological research. However, FLIM-FRET is a technically advanced technique to implement even under well-controlled conditions, and the complex tissue motions present within a living animal bring significant further challenges that have not yet been overcome. This is especially true in the dynamic environment of the cardiovascular system. We will therefore develop new computational microscopy techniques to tackle this challenge of measuring forces in moving tissue. The recent arrival to market of the first widefield time-correlated single-photon counting (TCSPC) array cameras has provided a means for massively parallel FLIM timing measurements of single photons. We will partner this capability with novel motion-correction strategies to develop a unique capability for fast, robust FLIM-FRET in highly dynamic tissues, and achieve world-first measurements of forces with subcellular resolution in the living, beating heart. Having developed our new approach, we will apply it to two ambitious biological challenge scenarios in heart tissue. First we will make direct measurements of cell-cell and cell-matrix tensions in 2D cultured human-derived cardiomyocytes. This is a model scenario widely used for evaluating new drugs, but clearly one that is hugely simplified compared to the human body. Our force-based investigation of the limitations of this model will ultimately lead to improved drug evaluation techniques, and thus faster and more reliable discovery of new medical treatments. Having refined our approaches on this scenario, we will then tackle our headline challenge goal of measuring cell-cell tension in the 3D beating zebrafish heart itself, providing a completely new method for biologists to understand the role of tension in driving the heart's normal development and its recovery following injury. Within the project timeline we are targeting forces in the heart, but we envision broad applications for our approach including: other types of FLIM-FRET probe; other motile environments such as the lungs and gut; measurements in behaving animals. We anticipate that, during and beyond the project lifetime, our approach will unlock biophysical insights into key questions about the role of cellular forces in shaping tissue architecture and function - ultimately impacting understanding and treatment of human heart diseases. Our work will accelerate discovery of new chemical pathways in cells that can be targeted by drugs for the next generation of treatments for human heart diseases.

UKRI Gateway to Research · FY 2025 · 2025-06

Mpox (MPX) is a zoonotic disease caused by infection with monkeypox virus (MPXV), an orthopoxvirus.  Two large outbreaks since 2022 have been declared by WHO to be public health emergencies of international concern (PHEICs) under the International Health Regulations (2005)[1-10]. The first global outbreak of clade IIb disease (2022 to present) resulted in infection of at least 15,000 people in multiple countries. UKHSA reported more than 4000 cases of clade IIb mpox in the UK with a peak during 2022.The emergence of a new clade I strain in DRC (clade Ib) resulting in spread to neighbouring countries, including Uganda during 2023 and 2024 has infected around 30,000 people and caused at least 800 deaths. Four cases of imported infection have occurred to date in the UK. This clade is associated with a higher case fatality rate than clade II mpox, although the mechanisms underlying this difference are not well understood, and presents a threat to UK public health

UKRI Gateway to Research · FY 2025 · 2025-06

Chronic pain is a major clinical problem that affects ~30% of the UK population and results in significant societal and economic impacts. Currently available treatments often provide inadequate pain relief, and a major reason for the limited success in design of new treatments is lack of knowledge about the neuronal circuits that underlie pain. Primary afferent neurons, many of which signal noxious stimuli, transmit sensory information to the dorsal horn of the spinal cord. The dorsal horn contains projection cells belonging to the anterolateral system (ALS) that convey this information to the brain, and these cells are required for the conscious perception of pain. However, the vast majority of dorsal horn neurons are interneurons, which are involved in local synaptic circuits that modify sensory signals before transmission to ALS cells. Most of the interneurons are excitatory, and these can be assigned to several distinct functional populations that can be distinguished based on morphological and transcriptomic criteria. One group of excitatory interneurons consists of vertical cells, which convey input from various types of primary afferent to ALS cells. Vertical cells are thought to be particularly important, as they contribute to hypersensitivity in pathological pain states. We have recently identified two different populations of vertical cell that are defined by expression of the gastrin releasing-peptide receptor (GRPR) or neuropeptide FF (NPFF), and have shown that these differ in anatomical, physiological and pharmacological properties. The GRPR cells are strongly implicated in the perception of itch, but little is known about the roles of the NPFF-expressing vertical cells in spinal processing of sensory information. This project will use a multidisciplinary approach to investigate the functions of NPFF-expressing vertical cells through five complementary workpackages (WPs). In WP1, we will use anatomical methods to define the excitatory synaptic input to these cells, allowing us compare this with the synaptic input to GRPR cells, which we have recently described. WP2 will involve recording of activity of the NPFF cells with electrophysiology and calcium-imaging, using an ex vivo “semi-intact preparation” in which a piece of skin remains connected to the spinal cord via intact peripheral nerves. This will allow us to determine the responses of the NPFF cells to natural cutaneous stimuli. In WP3 we will use chemogenetics to test the hypothesis that activating NPFF cells in vivo causes pain-like behaviours and is aversive. We will also use this approach to identify ALS neurons that are downstream of the NPFF cells, by revealing the activity marker Fos. WP4 will involve silencing the NPFF cells by means of optogenetics. We will test whether this suppresses responses to acute painful stimuli, and also whether it reduces the hypersensitivity and on-going pain seen in an inflammatory pain model. Finally, in WP5 we will use the semi-intact preparation to characterise a class of ALS projection neurons that receive numerous synapses from the NPFF cells. We will then optogenetically silence the NPFF cells to reveal their contribution to the sensory input to these ALS neurons. This work will provide important fundamental insights into pain neurobiology, by revealing neuronal circuits in the spinal cord that are involved in acute and inflammatory pain. It should also reveal potential targets for the development of new strategies for pain relief.  

UKRI Gateway to Research · FY 2025 · 2025-06

Meteorites and returned samples (e.g., from asteroids, the Moon, Mars and other differentiated bodies) have been extensively analysed to determine the source and abundance of water delivered to the early inner Solar System. These studies are largely based on hydrogen abundance and D/H ratio measurements of the mineral apatite [Ca5(PO4)3(F, Cl, OH)] and/or glass melt inclusions in these rocks. However, extraterrestrial samples have all experienced some degree of hypervelocity impact processing, potentially effecting change on their hydrogen inventory. It is therefore vital to understand how hydrogen is affected by impact processes in order to avoid misinterpretations of the origin and distribution of volatile elements in the Solar System. The aim of this research is to determine how impact processes affect hydrogen inventories (abundance and D/H ratios) within apatite and glass on airless planetary bodies and under martian atmospheric conditions. This aim will be achieved by: Objective 1: Simulating impact shock pressures on terrestrial apatite and basaltic glass standards with varying known water contents, using the University of Kent Light Gas Gun (LGG). One set of experiments will be performed under vacuum to simulate the environment on airless bodies, and one set will be performed under a simulated D-enriched martian atmosphere. Objective 2: Determining the precise shock stage (S1-6, and GPa equivalent) produced in the most shocked and less shocked parts of each experimental standard, via electron backscatter diffraction (EBSD) and transmission electron microscope (TEM) analyses. Objective 3: Identify how/if hydrogen abundance and D/H ratio has changed within the most shocked and less shocked parts of each experimental standard, using stepwise pyrolysis mass-spectrometry at the Scottish Universities Environmental Research Centre (SUERC). Objective 4: Collate the above results to determine the extent of potential change in hydrogen abundance and D/H ratio for a given shock stage in both apatite and glass on airless bodies and under martian atmospheric conditions. Knowing how, when and from where volatiles were delivered is fundamental to our understanding of rocky planet formation, evolution and habitability, both within and beyond our Solar System. This research will lead to a better understanding of hydrogen mobility during impact shock, and thus will provide a substantial advancement in our knowledge of water retention on rocky bodies throughout solar system(s) formation and evolution.

UKRI Gateway to Research · FY 2025 · 2025-06

Context and Challenge Radiotherapy is an effective and potentially curative treatment that is used for many solid cancers. However, a growing body of pre-clinical evidence indicates that radiotherapy may also induce a 'pro-metastatic' effect in any cancer cells that survive radiotherapy and thus promote increased spread of disease throughout the body. This fellowship aims to understand the complex biology that underpins this effect, and use this knowledge to identify novel treatments to use alongside radiotherapy to improve patient outcomes in the future. Objectives The initial phase of the fellowship gave important insight into the biology behind radiation driven invasion and from this identified potential chemotherapeutic inhibitors of radiation driven metastasis in two currently incurable cancers, glioblastoma and pancreatic cancer.  The renewal period will expand on these findings through the following aims: 1. Further investigate the underlying science of radiation driven metastasis to expose new therapeutic vulnerabilities 2. Investigate the clinical impact that radiation driven metastasis may have on pancreatic cancer outcomes by drawing on the clinical expertise of key collaborators. 3. Develop novel therapeutic targets identified in the initial funding period towards the clinic. Applications and Benefits The continuation of this fellowship into the renewal phase will have applications across academia, public health care and industry. The key beneficiaries will be: 1) Academic The data generated from both the initial screens and validation experiments will be shared with the wider scientific community to help advance the cancer biology field. In addition, the models that are used to assess invasion and metastasis will be made accessible to other groups through collaborations and the provision of expertise. 2) Public healthcare services By understanding the clinical impact of radiation driven metastasis and its underlying biology, this fellowship will facilitate a better understanding of the potential risk/benefit of radiotherapy in different patient populations. This fellowship also aims to identify novel anti-metastatic therapies that can be used to negate any increased risk during radiotherapy to improve its efficacy. These outputs have a strong potential to influence how patients are treated in the future. 3) Commercial private sector beneficiaries The engagement of industrial partnerships will allow the successful translation of new therapies that have already been identified in the initial funding phase of the fellowship. 4) Wider population The major aim of the proposed research is to uncover new treatments to improve outcomes for patients with cancers that currently have dismal prognoses. This will hopefully lead to crucial improvements both to symptom management and survival rates        

UKRI Gateway to Research · FY 2025 · 2025-05

This project emerges from newLEAF, part of The Future of UK Treescapes Programme. Working with partners and supporting organisations we will co-create inclusive, open access resources, significantly expanding upon the dissemination of the primary research output - a verbatim play - to reach new and diverse audiences. Our woodlands, forests and trees are critical for our environment, health, well-being and ability to move to a zero-carbon society. However, due to increasing risks from climate change, pests and diseases, and human behaviour, the future is uncertain for our treescapes and how we manage them. For newLEAF, Heddon (PI) and Clive (RA) produced a new play, Three Words for Forest, drawing on 30 interviews with a range of forestry specialists. Using interviewees' words, the play powerfully makes visible complex uncertainties, including climate change, geopolitical pressures, financial markets, government agendas, global mobilities, and human influence. It sensitively portrays the challenges faced by those working with forests, explores a range of practices and polarised positions across the forestry sector and identifies a general lack of public knowledge about forestry. The play was performed in Glasgow (UK Treescapes Conference 2024) and a filmed recording of it shared in two pilot workshops in England with stakeholders and their wider communities. Positive feedback from scientists, foresters, teachers and members of the public confirmed it as an innovative way to engage people in the complex issues attached to forestry, while also serving to remind wider publics that forests connect with and impact on all of us. Climate crisis and net-zero targets make future treescapes an urgent, collective issue. This project addresses three key challenges identified in the research which risk future forests' resilience: lack of public knowledge about forestry, inequitable access to information and action, and the impacts of polarisation across the forestry sector. Aims We will extend the impact of the research through three interconnected activities: i) collaborations with partners and community organisations to reach diverse publics through screenings of the film supported by workshops. ii) collaborations with disability and community specialists to create a suite of accessible versions of the recording and script of the play. iii) pilot workshops situating the play as a discussion tool for debates within the forestry sector. These activities will contribute to open-access, tailored resources for use in various contexts. Objectives and Benefits i) Engage meaningfully with diverse publics, including those currently marginalised from environmental debates, about different choices of forest management; increase understanding of risks facing trees and how to mitigate on a personal level. (Conceptual benefits: changes to knowledge, awareness, attitudes, emotions. Instrumental benefits: changes to behaviours, practices, actions.) ii) Inspire more people to visit, understand better, develop connections with and care for local forested environments. (Capacity-building benefits: changes to skills and expertise. Instrumental benefits: changes to behaviours and actions. Environmental impact: contribution to net-zero.) iii) Facilitate open dialogue in place of polarisation (Instrumental benefits: changes to practices, actions, policies.) iv) Evidence to partners the value of creative research methods. (Capacity-building benefits: changes to skills and expertise.)

UKRI Gateway to Research · FY 2025 · 2025-05

Elucidating how the brain makes, stores and updates "knowledge" is a key challenge in biology. A fundamental type of knowledge is spatial memory, formed by the hippocampus and its surrounding network and underpinning both spatial behaviours and memory for life events. Failure of the hippocampal system leads to profound disorientation and amnesia, as in Alzheimer's dementia. Spatial knowledge is supported in the hippocampus by place cells (PCs), each of which becomes active in certain places in the environment. PCs provide both a self-location signal and also an index of where, in the brain, associated information is stored as memories. Evidence suggests that some of the brain indexing function may take place during restfulness and non-dreaming (slow-wave) sleep. Waking movement, resting and sleep are distinguished by concurrent brain oscillatory patterns. The most prominent, theta, is found throughout the hippocampal network during active sensory processing. The PC signal in hippocampus is formed by combining complex multi-sensory signals with previously acquired memory. Given this complexity, we were recently surprised to discover place cells in a deeper and simpler brain structure, the AV nucleus of the anterior thalamus, which has completely different inputs. This is now the fourth thalamic region in which PCs have been reported and so we think these neurons are an important part of the spatial memory system. Relatedly, damage to anterior thalamus has long been associated with profound amnesia. Thalamus also has a critical role in organising brain activity patterns during sleep. Putting this information together, our guiding hypothesis is that the PCs in thalamus work together with those in hippocampus to help organise the memory indexing process. As a first step to addressing this hypothesis we plan to investigate how these neurons work together by combining the expertise of PI Jeffery in neuronal recording in awake animals, and Co-I Craig in cellular anatomy and manipulation. Both investigators have independently been researching thalamic interactions with hippocampus, and will join forces to answer the following questions: Where are thalamic place cells found and what are their characteristics? From where do they acquire their spatial and temporal signals? Might they have a role in spatial memory processing? Aim 1 will map the location of thalamic place cells and systematically document their properties to determine their similarities and differences, with respect to each other and to hippocampal place cells. It will characterise the spatial properties of their activity and also timing relative to the hippocampal theta rhythm. These investigations will show how the signal in thalamus is related to that in hippocampus and perhaps provide clues to the direction of flow of the place signals in the network. Aim 2 extends this by deploying a combination of anatomical tracing, activity suppression and neuronal recording in order to discover the source of the thalamic place and theta signals. Aim 3 investigates activity of thalamic PCs during rest and sleep, to determine whether thalamic PCs reactivate during rest/sleep as hippocampal place cells do, and if so, how this correlates with contemporaneous activity in both hippocampus and neocortex. These experiments will add greatly to our understanding of hippocampal-thalamic interactions, and potentially identify thalamus as a crucial player in the hippocampal-neocortical interaction that underlies memory storage. This would be important not just for basic science but also for medicine and industry.

UKRI Gateway to Research · FY 2025 · 2025-05

This project is highly multidisciplinary involving expertise in cancer biology, bone regeneration and bioengineering. This project will repurpose a fully developed and characterised in vitro humanised 3D self-structuring bone model ‘‘SSBM’’ as a relevant alternative to REPLACE and REDUCE the use of mouse models for studying myeloid leukaemia, leukaemic stem cell (LSC) persistence and breast cancer dormancy and bone metastasis. The SSBM form ‘’mini-bone’’ structures, which are created using fibrin hydrogels seeded with osteoblasts, casted between two calcium phosphate anchors points. Over time, the fibrin supports osteoblast maturation and differentiation to osteocytes, bone extracellular matrix (ECM) production and subsequent mineralisation forming a mineralising collagen-rich matrix that recapitulates in vivo native bone. The benefits of the SSBM include the ability to incorporate different cell types and to carry out prolonged cultures for >1 year. At present, no single model system exists, that accurately replicates human bone and its microenvironment. In the solid cancer field there is a real need to find an alternative to REPLACE and REDUCE reliance on mouse models to study cancer dormancy and bone metastasis. Currently no reliable models exist to investigate cancer dormancy in the bone. The current mouse models, used to study metastasis are limited, as most cancers preferentially metastasise to the lungs when transplanted. This often prevents a comprehensive or linear picture of bone metastasis, as visceral organ metastasis occurs quickly, usually within 3-4 weeks, and bone metastasis later, making these studies incomplete due to the necessity to cull animals early. These types of studies are often deemed ‘moderate to severe’, due to the pain associated with bone metastasis. In leukaemia, xenotransplantation of human leukaemic cells into highly immunocompromised mice are the gold standard in vivo models. However, these models are not ideal, with high variability observed between patient samples, low engraftment rates and often the leukaemia, which develops not accurately replicating the human disease. Even then, high numbers of LSCs are required resulting in low engraftment rates ~20% for chronic and 40-66% for acute myeloid leukaemia with <25% developing leukaemia. These assays also entail serial transplantation to assess the self-renewal of LSC, requiring multiple mice for prolonged periods of time. These models only provide a short window of 12-16 weeks to study the disease pathogenesis and carry out drug testing, they don’t facilitate the longer-term studies required to investigate LSC quiescence/dormancy. In breast cancer, bone mediated dormancy, can occur for several years, and is most prevalent in ER+ luminal tumours with approximately 20% of women undergoing late relapse. This inability to accurately recapitulate the cell-intrinsic and micro-environmental factors which maintain dormancy has prevented the development of therapeutic approaches to target the dormant cancer cells.  Even for metastatic bone disease which is more widely studied, therapies are deficient and once cancer invades bone tissue the cancer is widely untreatable. Research focusing on dormancy and bone metastasis has therefore been limited by the lack of clinically relevant models. Adoption of this SSBM by the cancer field would lead to widespread benefits: it would enhance our scientific knowledge of the endosteal niche, cancer dormancy and bone metastasis; provide a system to identify potential biomarkers to predict patients who are likely to develop bone metastasis and relapse; enable researchers to identify underlying mechanisms and therapeutic targets for better treatments to prevent relapse, ultimately improving longer-term outcomes for patients.

UKRI Gateway to Research · FY 2025 · 2025-05

The Space Nanomaterials Atom Probe (SNAP) represents the ideal solution for near-atomic characterisation of materials, with a specialist focus on space materials to support the booming UK space sector. In many cases, atom probe tomography (APT) is the only way to visualise the chemistry and isotopic composition of a material in three dimensions and with atomic resolution. The datasets reveal nanoscale structures that often define the overall material properties. Alongside our focus on space materials, the datasets produced by SNAP will be key to develop new quantum, semiconductor and energy-sector devices. Aim Our aim is to create SNAP: a user accessible next generation APT facility focussed on space materials research that will deliver first-of-their-kind characterisation of challenging materials vital to the space sector and energy transition (e.g., irradiated materials, semiconductor- thermoelectric-, functional-, and battery-related materials, and heterogeneous catalysts, etc). Objectives Our objectives are to: install the SNAP infrastructure; demonstrate the new capabilities of SNAP to characterise challenging materials (e.g., those that have been damaged by space weathering processes); provide a correlative materials characterisation and development service to the international community; grow a sustainable user base; and deliver impact including through collaboration with the commercial space sector. Context SNAP will be the first atom probe tomography (APT) facility in Scotland, the first UK-based LEAP-6000XR instrument, and the first APT facility worldwide to focus on space materials research, leveraging Glasgow as the heart of the UK space sector. SNAP is supported by APT expertise across the University of Glasgow (UofG), and the UK/international APT and space science communities. Co-locating SNAP with UofG’s complementary world-leading microscopy and materials engineering facilities will form an accessible one-stop-shop for correlative, multi-scale and multi-property materials characterisation. Applications and benefits The LEAP-6000XR is a significant advance on previous models and will enable first-of-their-kind measurements on new materials. SNAP’s deep-ultraviolet laser system improves sample success rates, data quality and dataset size on many materials. Automated operation enhances accessibility and ease of use. SNAP will analyse a range of previously challenging materials with low electrical/thermal conductivities and/or complex microstructures (e.g., semiconductor-, thermoelectric-, functional-, and battery-related materials, heterogeneous catalysts etc). This new functionality combined with a vacuum-cryo-transfer module (VCTM) permits measurements of volatile elements including hydrogen within materials, vital for evaluating hydrogen embrittlement, and will be particularly important for assessing space weathering damage and hydrogen implantation into spacecraft components. SNAP’s grand challenge Humanity aims to put people back on the Moon in permanent human settlements by the end of the decade. Such permanent infrastructure will be exposed to the harsh environment of space, which will induce nanoscale damage into these structures that is currently poorly understood and may result in catastrophic failure. SNAP, alongside UofG’s existing correlative analytical suite and James Watt Nanofabrication Centre’s materials fabrication labs, is the ideal tool to assess and mitigate against these processes that threaten our future in space. SNAP will form a collaborative consortium to address this challenge including academia (Universities of Oxford, Strathclyde and Heriot-Watt) and the local space sector (Inex, and Benchmark Space Systems). In addition to this key topic, with its advanced characterisation capabilities, SNAP will provide unique atomic-scale information on traditionally challenging materials across EPSRC’s remit and UKRI’s portfolio more broadly.

UKRI Gateway to Research · FY 2025 · 2025-05

As recent research points out, the language of sustainability is English (Delavan 2020). The UNESCO competencies framework on Education for Sustainability (EfS) makes no mention of multilingualism in shaping and supporting human-environment ecologies. Yet, learners have the right to their own languages as these resources help them understand their environments, sustain different knowledge systems, and provide creative solutions to current sustainability crises. Our project will embed multilingualism into Learning for Sustainability in Scotland (LfS), will develop new creative learning approaches, resources, and training to ensure that young learners can make meaningful contributions as active and responsible citizens. In line with EfS goals, Scotland has developed its own approach to Learning for Sustainability (LfS). The Scottish context is unique globally as it has shown an unwavering commitment to make LfS an entitlement for all school learners. Recent policies (Target 2030) provide support for implementing a whole-school LfS approach across Scotland. In a multilingual society where 154 languages are actively used by young learners, Scotland acknowledges the importance of multilingualism as an integral part of learners' education (Learning 2(+) Languages). However, the recent Measuring Quality in Initial Teacher Education report indicates that teaching in multicultural/multilingual settings is one of educators' highest professional development needs. This 3-year research project is designed as an interdisciplinary collaboration between researchers, local artists, teachers, LfS stakeholders and young learners within the context of Scottish primary schools. We draw on our research expertise in arts-based multilingual approaches and we implement and develop these within an original framework for sustainable living: permaculture design. Drawing on indigenous ways of living, permaculture is an integrated philosophy that aims to respond to current environmental and social crises by ensuring the ongoing cultivation of social, cultural, and natural resources to create self-sustaining systems (Holmgren 2002). Permaculture makes cultural rights an integral part of sustainable systems and enables us to bring language learning and multilingualism into the design of sustainable environments. We will follow permaculture principles to (1) develop an innovative interdisciplinary learning programme of shared expertise and collaborative learning on multilingual arts-based approaches and permaculture design, (2) conduct collaborative longitudinal research into the development of multilingual practices informed by arts-based methods and permaculture design in three primary schools, (3) implement and research the impact of such multilingual practices in at least ten other schools (4) co-create innovative resources and "multilingual living spaces" as the basis of a new LfS provision. The "living spaces" will be both sites of practice and research where participatory arts-based methods will be used to explore and transform learners' relationships with their environments. The project will offer new research insights into how multilingualism plays an integral part of LfS. The development of multilingual arts-based practices in the context of permaculture design will provide education stakeholders and policymakers with evidence and new capacity-strengthening models of LfS delivery, including resources for schools nationally and internationally. For the learners and their communities, the project will create an enriched inclusive environment where languages are woven into the design of sustainable human-nature ecosystems.

UKRI Gateway to Research · FY 2025 · 2025-04

The growth of plants is underpinned by fixing atmospheric carbon dioxide (CO2) and plays a crucial role as a carbon sink that helps mitigate global climate challenges. Stomata are the gates for gas exchange between the plant and the atmosphere and open to fulfil the demand of CO2 in photosynthesis. Photosynthesis sustains plant growth and powers all life on Earth. Stomatal control underpins the balance between carbon gain with water loss through the stomatal pore and is a focus for engineering of plant water use efficiency and carbon intake. Each stoma comprises two guard cells around a central pore in the epidermis. Changes in guard cell volume, associated with osmotic ion and water transport, regulate pore aperture. As in all eukaryotes, vesicle traffic in guard cells determines the populations of transporters, altering transport capacity and adjusting membrane surface area for dynamic changes in guard cell volume during stomatal movements. Plasma membrane H+-ATPases are primary transporters that energise membrane transport for stomatal movements. Studies from the past four decades suggest that H+-ATPase trafficking is an important factor in the regulation of their abundance and functions at the plasma membrane, but underlying mechanisms remained elusive. Our recent work suggests that Arabidopsis H+-ATPase AHA1 trafficking pathways affect stomatal responses to CO2 and that these pathways associate with at least one novel regulatory protein that binds the H+-ATPase. How does AHA1 trafficking sense CO2, and what is the impact on stomata? We propose here to resolve these challenges and to explore the novel components in the mechanics of membrane traffic control in eukaryotes. Addressing these questions will build fundamental knowledge and facilitate a paradigm shift in thinking about membrane traffic and environmental responses feeding new strategies to safeguard crops. The project therefore falls within the remit of BBSRC Committee B (Plants, microbes, food and sustainability) and is relevant to the BBSRC's strategic priorities to "explore novel concepts that have the potential to transform our understanding of life" to gain fundamental knowledge that will aid in "improving efficiency through better understanding of relevant biological processes" and its applications to tackle "environmental and plant productivity" by offering insights to produce more robust crops to fulfil the "global demand for food" in a "challenging climate". The developments will therefore "provision national capabilities" and enable "scientific discovery" in plant biology. Our cross-disciplinary approach is facilitated by a diverse and experienced team, and we aim to build upon these strengths, developing cutting-edge research tools, and by offering training to staff and students at the forefront of research in the field. Thus, the project will facilitate BBSRC objectives "in creating and sustaining the conditions for dynamic, diverse and inclusive research". We anticipate to "build excellence in science" through a programme that underpins research that supports "technology development", "training" and "education" that meets BBSRC focus on people and training. We have established links with industrial/technology transfer partners, and as relevant, we will seek in the future to transfer the new knowledge into crops, and thus our efforts are timely and they underpin stated goals of the BBSRC in knowledge transfer for "sustainable agricultural productivity" in the face of global environmental change.

UKRI Gateway to Research · FY 2025 · 2025-04

This knowledge synthesis project responds to the theme of Involvement and inclusion in governance structures with its focus on changing technological landscapes of participation by more diverse communities in Canada and the UK, and Systems of governance, with a particular view towards "the central role played by municipalities in recent crises" and the workings of "levels of governance and responsibilities between national, regional and local governments." The project's overall aim is to distil knowledge of how multi-level governance is constructed in Canada and the UK in an era of urban crises identifying clearly the knowledge gaps in the literature. Looking at how such crises are now conceptualized as poly- or permacrises, we will focus on how governance mechanisms and responsibilities have been changing. In doing so, and in slight digression from the conventional "methodological nationalism," we prioritize an urban view (looking at crisis urbanization as an ongoing process) and a city view (looking at specific crisis urbanisms as instances of crisis) in examining the emerging systems of governance across levels and scales of government. This changed epistemological stance does not see cities (their politics and governance) as primarily constituted "from above" but primarily "from below" (both contested concepts in a globalizing world). The governance of urban crises is not separate from, but interwoven with, urban ways of life and must reflect how urban residents and communities are experiencing, navigating and countering crises. We focus on contextualised accounts of the impacts, dilemmas and possibilities of living with and beyond crisis and on how the literature has reflected this interweaving of urban life and governance. This synthesis of knowledge will advance thinking on just and sustainable responses to crisis in cities in Canada and the UK resulting in an agenda for future research. In sum, this project will study the challenges facing, and agency shown by civil society, community activists, urbanists, focusing on diverse and often marginalised urban residents and communities living with crisis. From that perspective we will focus on how just and resilient structures can be built into urban life and how institutions and processes of governance can support them. We analyze contextualized and experiential accounts of crisis governance, as a contributing factor in the crisis of liberal democracy, taking seriously the capacity of people to develop skills to deal with crisis, and innovative ways of viewing crisis governance through dialogic comparison in a transatlantic perspective. Expected contributions and impacts: We will make an essential contribution to the scholarly and policy literature on multi-level governance from an urban perspective in Canada and the UK. It builds on past and ongoing joint work by the applicants on urban and regional governance and politics. The significance of this project lies in its direct response to the experience of urban communities over the past few years when, for example, the COVID-19 pandemic universally tested the resilience of municipal actors and as cities around the world have been threatened by wildfires and impacted by flooding, and other disasters. In Canada, this focus includes a look at the role of crisis in Indigenous communities (from boiled water advisories to racist violence) and the central role of Indigenous governance in that country's governance architecture. The project's "urban lens" promises empirical and conceptual insights on contemporary forms of crisis as they interweave with urban life and governance.

UKRI Gateway to Research · FY 2025 · 2025-04

Geothermal technology epitomises the challenges of effective interfacing between engineering, physical and natural sciences. A geothermal facility involves inducing heat flow through two thermal resistances in series. For shallow and deep closed-loop systems, one thermal resistance is represented by the geothermal borehole and its infrastructure (casing, grout/cement, heat exchangers and transfer fluid), which can be specified and engineered with high precision. The other thermal resistance is the ground itself, whose properties are variable and controlled by nature. Heat transfer fluid does not have direct hydraulic contact with the surrounding formation, only transferring heat through conduction, thus reducing geological and reservoir risk. In predicting the performance of a geothermal system, the variability of natural properties must be characterised empirically. Modelling techniques must be employed that propagate uncertainty to outcomes (i.e., available thermal power) in a transparent and statistically defensible manner. The important thermal properties in conduction-dominated settings for subsurface heat extraction and storage are thermal conductivity, volumetric heat capacity and internal heat production. However, databases of rock thermo-physical properties for geothermal engineers are limited and often do not specify measurement conditions. Furthermore, the various multi-scale datasets require mutual calibration against each other and empirical analysis of their relationships. Government funded studies have therefore recommended systematic data acquisition and compilation. All participating nations in this proposal have large ambitions for geothermal technology and share fundamental similarities: i) continuous shared geological "terrane" from Northern Ireland, through Scotland to Norway in the form of the Caledonian orogenic belt, ii) extensive areas of "hard rock" lithology: exposure is good and representative intact rock samples of uniform size can readily be retrieved and tested, and iii) generation of large quantities of renewable electricity that can be used in geothermal heat pumps (GHP). Caledonian rocks have high geothermal potential due to their high thermal conductivities and radiogenic heat production values. The THERMOCAL vision is to carry out a systematic measurement programme - with unified sampling and analytical methodologies - of lithologies in the Caledonian terrane and underlying Precambrian basement across northern UK and Norway. Bespoke modelling of closed-loop systems will allow Investigation on the impact of data on real-world geothermal engineering applications, such as GHPs - both shallow and deep. This will result in: i) a public, representative and quality-assured database of the thermal and radiogenic properties of lithologies of the Caledonian orogenic belt, ii) improved quality assurance for the determination of these properties via interlaboratory ring testing and method harmonisation, iii) the comparison between different types of data, and iv) calibrated modelling approaches to representatively incorporate uncertainty in rock properties into engineering heat transfer models of geothermal infrastructure, ultimately contributing to the de-risking of further geothermal developments. These outcomes will benefit geothermal engineers designing future sustainable geothermal systems, and households who require efficient and reliable clean heat. The outputs will also be of importance to fields including: underground energy storage, underground structures (e.g., tunnels) and storage of thermogenic wastes, while the gamma spectrometry data may provide background for evaluation of potential national uranium and thorium reserves.

UKRI Gateway to Research · FY 2025 · 2025-04

Stomata are pores that mediate gaseous exchange across the impermeable surface of plant leaves. They open in the light to allow CO2 entry for photosynthesis, and they close to reduce water loss and prevent leaf drying in the dark and when atmospheric humidity is low. Stomata are at the centre of a crisis in water availability and crop production that is unfolding and will escalate as global demand, especially in agriculture, outstrips fresh water supplies. Thus stomata are an important target in efforts to enhance crop performance and resilience while reducing water demands.   Stomatal movements are driven by solute and water transport across the membrane of the guard cells that surround the pore. Guard cells harbour ion channel proteins to facilitate solute transport, especially potassium ions (K+), for stomatal movements. One of these channels, GORK, is regulated by K+ outside to ensure outward K+ flux, regardless of the thermodynamic driving force on K+. Mike Blatt (MB) was first to identify this unique regulatory behaviour, now a widely-recognised as a feature of virtually all plant outward-rectifier K+ channels.   We do not yet know how K+ outside regulates channel activity, but experiments and structural analyses highlight two domains of the GORK protein that are important and are highly conserved among this group of channels across angiosperm plants. We know also that it is possible to enhance stomatal movements, with the promise of improved plant resilience and biomass gains, by engineering these domains in the channel to alter its regulation by K+ outside.   Establishing the mechanism of K+ regulation is clearly important to a fundamental understanding of these unique channels. It is set to establish a new model for channel gating that differs substantially from the canonical models; equally, it will inform future efforts to enhance stomatal function, crop yields and resilience.   We are confident that our findings will guide further efforts work with to crops. Alignments of GORK show a high sequence conservation across the angiosperms within the relevant domains. Furthermore, studies to date indicate a much greater scope for enhancing stomatal responsiveness by manipulating channel K+-dependencies.   Thus, we propose to resolve the underpinning molecular mechanism, both to expand our fundamental knowledge of the channels, providing training across a range of cutting-edge technologies, and to guide future work towards gains in crop efficiencies with benefits for producers, consumers, and the environment.   Two immediate challenges present themselves. The first challenge is to fully resolve the sites internal to GORK that are responsible and to test their contributions to the mechanics of K+-dependent regulation of GORK. The second challenge is to resolve the consequences and most effective strategies in manipulating GORK regulation that will maximise biomass gains and reduce water use by the whole plant.   We propose now to address these challenges. The research is for a greater understanding of a fundamental rule of life that will (1) resolve the internal mechanics of GORK channel K+ sensitivity, and (2) establish a strategic range of behaviours to inform bioengineering of the channel for enhanced biomass gains and water use efficiency.  

UKRI Gateway to Research · FY 2025 · 2025-04

Leishmaniasis, a neglected tropical disease caused by protozoan parasites of the genus Leishmania, presents a growing global health concern. In Thailand, the emergence of leishmaniasis, potentially transmitted by atypical vectors, poses a significant threat to immunocompromised individuals, particularly those co-infected with HIV. In addition, climate change is a potential increase in disease prevalence by altering insect vector distribution and population dynamics. Amphotericin B remains the primary treatment for leishmaniasis in Thailand, and Leishmania species of the subgenus Mundinia (L. orientalis and L. martiniquensis) exhibit relative insensitivity to this drug. Preliminary experiments displayed initial genomic and transcriptomic alteration after short-term treatments of L. orientalis with amphotericin B. This resistance is concerning as it may be associated with increased parasite fitness and potentially higher virulence. Addressing these critical issues necessitates a deep understanding of drug resistance and parasite adaptation mechanisms for the development of effective strategies for treatments. This research project leverages a pre-existing collaboration between researchers from the University of Glasgow (UK) and Kasetsart University (Thailand), which previously explored genomic structures of L. orientalis and L. martiniquensis strains in Thailand. The project aims to characterize molecular changes occurring during Amphotericin B selection in L. orientalis and L. martiniquensis using integrative omics technologies, parasite phenotyping and advanced computational analysis. We will investigate both innate and in vitro-acquired resistance using polyomic approaches, including bulk and single-cell sequencing and transcriptomics, proteomics, metabolomics and lipidomics, in parallel with assessing important phenotypes such as drug sensitivity and infectivity to macrophages. We will elucidate mechanisms of resistance and to identify markers that can predict Amphotericin-treatment failure. The collaborative research between the UK and Thailand teams will accelerate understanding these newly reported Leishmania parasites and benefit the control of leishmaniasis in Thailand and beyond. Bilateral knowledge exchange between Thailand and UK will be a key outcome of our project, leading to capacity building in Thailand and the establishment of critical collaboration between parasitologists working in the UK and scientists in Thailand, a country with an developing science base and an emerging problem with leishmaniasis.  

UKRI Gateway to Research · FY 2025 · 2025-04

There has been substantive growth among small-scale, online radio stations (SSORs) across the UK in recent years. The aim of this project is to investigate the impact and challenges faced by SSORs, to document and share best practices in support of capacity-building amongst these local creative institutions. In doing so, the project team will develop a framework for the study of SSORs as unique media actors. SSORs are a distinct, emerging type of cultural institution and represent a new form of radio broadcasting that appeared in the mid-2010s. These stations share four distinct characteristics: (1) They are local or ‘hyperlocal’: identified with a particular city, town, or region. (2) They broadcast exclusively online without licensing. (3) They operate on a voluntary basis and rely upon donations and fundraising to cover running costs. (4) Personnel tend to be drawn directly from local music and arts communities with stations serving as local hubs for creative industries. SSORs also tend to emphasise inclusion and accessibility. Stations can be entry points into creative industries for young people and their lower barriers to entry are especially significant for groups historically excluded or under-represented in music and related industries. As one SSOR partner explained, "Being a community radio station means representing our diverse community is imperative to our functioning as a community hub." Despite these important social and cultural functions, SSORs operate with little, if any, commercial or public investment. One SSOR put this candidly: "We are constantly under pressure to bring income in, which takes time and energy away from our goals to grow the station. There are also little to no resources on the ins-and-outs of running an internet radio station, so often we find ourselves taking shots in the dark at how we think processes should be done and hoping we're doing the right thing!" UK SSORs run primarily via voluntary support and depend on commercial platforms (e.g., SoundCloud, MixCloud) to archive content. Accordingly, they operate in extremely precarious and uncertain conditions with few successful business models. SSORs have been the subject of almost no existing research and have lacked resources to pursue funding. Over the course of the past two years these stations have begun to shutter at an alarming rate (Ross 2023; Limbu 2024). In response to these challenges, the project team will generate and make accessible new knowledge through a series of networking and capacity-building activities with SSORs and their key stakeholders, researchers, and library partners (National Library of Scotland and British Library). The questions we will examine are: What are the unique challenges faced in the day-to-day, medium and long-term operation of SSORs? How do SSORs connect to and support local creative industries ecosystems? Do SSORs represent a new model of online radio broadcasting? This project aligns with UK Innovation Strategy 2022-2025, as it seeks to directly support the growth of local enterprises by convening and creating a partner community to realise future potential and share best practice to enhance innovation and leadership in local music and related industries.

UKRI Gateway to Research · FY 2025 · 2025-04

On acceptance of his Nobel Prize for the discovery of Penicillin in 1945, Sir Alexander Fleming warned of the threat of antimicrobial resistance (AMR), stating ‘there is a danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug, make them resistant’. By 2019, Fleming’s fears were realised, with 1.27 million deaths directly attributed to AMR globally. Bacteria have the ability to rapidly evolve resistance and as a result, we have consistently observed resistance to antibiotics arising shortly after their introduction. Therefore, we must investigate therapies which are “evolution-proof” to improve the longevity of drugs and improve patient outcomes. In this proposal, I outline my plans to investigate antivirulence (AV) drugs as novel anti-infective agents. These differ from traditional antibiotics as their mechanism is not to kill or inhibit the growth of the infecting bacteria, but instead to prevent pathogens from causing disease within the host. One potential target for AV therapies is the Type III Secretion System (T3SS), a molecular syringe which delivers effector proteins to host cells and facilitates epithelial cell attachment in enteric pathogens. This is a shared virulence factor across pathogens such as Salmonella, Shigella,  Enteropathogenic and Enterohaemorrhagic Escherichia coli. Targeting of virulence factors such as the T3SS, which are not essential for survival, results in decreased selective pressure for the evolution of resistance. For enteric pathogens, the narrow spectrum of activity may reduce disruption to the native gut microbiome and reduce recurrent infections linked to antibiotics. I aim to apply the AV concept to a significant global pathogen; Shiga-toxin-producing E. coli (STEC). These are acute enteric pathogens which are responsible over one million cases of foodborne disease worldwide. These pathogens are completely reliant on the T3SS to colonise their host, highlighting them as prime candidates for targeting by AV drugs. In my previously published work, I investigated aurodox – a natural product of the soil bacterium Streptomyces goldiniensis – as a novel inhibitor of the T3SS. This work has demonstrated that aurodox transcriptionally downregulates the expression of the T3SS in EHEC, and the SPI-2 T3SS of Salmonella Typhimurium). I have worked alongside experts in infection biology to establish a bespoke murine model of EHEC disease pathology and have shown that aurodox prophylactically protects mice against the infection. In this fellowship, I will expand the testing of aurodox beyond the single serotype previously tested (E. coli O157:H7) to the ‘big six’ circulating STEC serotypes worldwide. I postulate that these experiments will demonstrate the robustness of aurodox, and demonstrate its translational potential for use as an AV therapy in the clinic. I will use synthetic biology to enhance the pharmacological properties of aurodox before testing the resulting compounds in vitro, an ultimately, I a murine model of STEC. Finally, I will expand my study of AV molecules beyond aurodox by identifying bioactive bacterial metabolites with therapeutic potential from unexplored environments. I will use a combination of deep metagenomic sequencing and traditional culture-based techniques to study the actinobacterial population of the bovine gut, which is the reservoir of STEC. These experiments will  form the foundations of my own unique research area as I transition to independence. These objectives contribute to the overarching goal of developing novel treatments for enteric pathogens with limited treatment options.