KING'S COLLEGE LONDON

UKRI Gateway to Research · FY 2025 · 2025-08

Background: Liver disease is the only common cause of death that is increasing in numbers in the UK, and is the biggest killer of people aged 35 - 49. Once individuals develop severe scarring of the liver, known as ‘cirrhosis’, there are no proven medications to reverse this. Depression is a worldwide problem and is more common in patients with cirrhosis (18-58%) compared to the general population (10%). Many different health conditions cause cirrhosis; increased rates of depression are seen in all causes. Depression in cirrhosis reduces quality of life and survival, and increases the likelihood of frequent admissions to hospital. The body creates inflammation to fight infection. However, there is too much inflammation in the bloodstream in cirrhosis, termed ‘systemic inflammation,’ which is harmful and can worsen liver disease and its complications. Systemic inflammation is also seen in individuals with depression, and may contribute towards the high rates of depression in patients with cirrhosis. However, this has not been investigated. Investigating the underlying driver(s) for the increased rates of depression in cirrhosis is an unmet need, as treating depression effectively in patients with cirrhosis will improve their quality of life and survival. Systemic inflammation can access the brain and detrimentally affect brain processes involved in mood. Specifically, this may reduce neurogenesis, the formation of new neurons (or nervous system cells), in the hippocampus, a small structure in the front of the brain that is responsible for memory, learning and emotion. However, we do not yet know how systemic inflammation reduces neurogenesis. I propose that the high rate of depression in patients with cirrhosis is due to increased systemic inflammation, and I hypothesise that this is due to a reduction in hippocampal neurogenesis. Objectives: To determine if there is greater inflammation in the blood of patients with cirrhosis and depression, than in those with cirrhosis without depression. To investigate if systemic inflammation in patients with cirrhosis and depression reduces hippocampal neurogenesis. To work out how systemic inflammation in patients with cirrhosis and depression reduces hippocampal neurogenesis. Methods: I will use stored blood samples from patients with cirrhosis with and without depression. I will perform laboratory work first to measure levels of inflammation in the blood of both patient groups, and compare them. I will then investigate how blood from these patients affects brain cells. These experiments will be performed in a laboratory dish, and not on living organisms. Potential applications and benefits: If I can discover how bloodstream inflammation contributes to depression in cirrhosis, this could identify new treatments. This would lead to further research studies to confirm if these treatments work. Ultimately, this could lead to improved quality of life and survival in this growing patient population and could influence clinical practice guidelines in the future. Effectively treating depression in cirrhosis would also reduce carer burden, alongside pressure on the NHS and economy. This work will also stress the importance of addressing mental health in cirrhosis, which will help to reduce stigma. Results will be circulated through journals, international conferences, patient networks and social media.

UKRI Gateway to Research · FY 2025 · 2025-08

Amyotrophic Laterals Sclerosis (ALS), characterised by destruction of upper/lower neurons and severe muscular wasting, is the most common motor neuron disease (prevalence ~ 6 cases/100,000 persons). Despite a surge in societal and Governmental interest, there remains no cure. ALS is thought to originate in upper centralised cells leading to skeletal muscle (SkM) denervation and muscle pathology. However, this belief has been questioned. Muscle of ALS animal models that preceded denervation and/or disease onset, show metabolic dysregulation, atypical muscle-specific transcriptional expression and reduced muscle volume, with further work showing denervation itself can be caused from intracellular defects within SkM. A growing body of evidence indicates SkM to be a key propagator in ALS aetiology. However, the tissue has received disproportionality low research attention, thus our understanding of SkM in ALS remains limited. This MRC NIRG project will tackle this shortfall. SkM is very complex, harbouring array of cell types including muscle specific cells (myofibers). Myofibers exist in a spectrum of sub-types, from type I (slow-type) to type IIB/X (fast-type), displaying divergent functional and molecular characteristics that further differ in disease states, with evidence suggesting that ALS myofibers are denervated in a subtype specific manner. The extent of myofiber subtype specific dysregulation across ALS disease-course remains unclear. Traditionally, SkM biopsies are examined in their entirety, capturing the molecular profiles of all the cell types and myofiber sub-types within the biopsy. This approach develops data that is non-specific to myofibers or sub-types and contains unnecessary noise when attempting to integrate multiple data types. While single cell approaches have been used in SkM, these methods are unable to capture full heterogeneity of myofiber populations and have been limited to a single data set per myofiber. New methodological approaches are required to provide deeper and more comprehensive understanding of ALS SkM. Building upon recent work, I developed a novel approach that enables the generation of four data sets from the exact same myofiber. Termed Single Myofiber Multi-Function Omics (SMyoMFO) analyses the biophysical properties of key sarcomeric protein, coupled with cell-wide proteomic and transcriptomic expression and epigenomic regulation of DNA. Crucially, all data originate from the exact same myofiber. We will use SMyoMFO to answer the hypothesis that a coordinated metabolic and molecular dysregulation occurs in a myofiber sub-type specific manner with these defects occurring early in disease-course. Aim 1. To examine the integrated dysregulation of specific myofiber subtypes in human ALS SkM. Aim 2. Analyse the myofiber subtype specific dysregulation in an animal model of ALS disease course. We will generate SMyoMFO data from control and symptomatic ALS human SkM samples (WP 1.1) ascertaining the heterogeneity in dysregulation across the myofiber subtype spectrum (WP 1.2). Due to ALS rarity, studying disease-course in human muscle is near impossible. We will therefore develop SMyoMFO data (WP 2.1) from a recently developed swine-model of ALS that best represents human pathology, analysing myofiber subtypes in pre-symptomatic and symptomatic muscle to understand disease course dynamics (WP 2.2). Combining human and swine-model data, we will determine the conserved dysregulation across species identifying translatable myofiber subtype markers in ALS (WP 2.3). This project will use bespoke methodology to provide unprecedented analyses of the extent of dysregulation in ALS SkM, promising to open up a vista of research and therapeutic opportunity in the disease field.

UKRI Gateway to Research · FY 2025 · 2025-08

A complex system consists of a large number of individual components that interact with one another and whose global behaviour emerging from these interactions is not apparent from the laws that govern the components in isolation. Climate change, spread of epidemics, criminal networks, neurological disorders and onset of diseases are all examples of complex systems with a potentially catastrophic impact on the livelihoods of human communities. Novel interdisciplinary approaches are on demand to understand how interactions lead to the observed global behaviour. Achieving this can help to prevent disasters, or inform strategies to minimise impact with limited resources. The potential for impact has recently put complexity science under the radar of governments and international organisations like the UN and UNICEF. Models of complex systems are often prescribed by a network where each node represents a component and the links prescribe the coupling structure of the interactions among the units. One of the main questions in the field is to find how the network structure and type of interactions shape the time evolution of a complex system. This is notoriously challenging to determine due to the large number of components and the intricacy of their interactions. This proposal addresses this question from the rigorous mathematical perspective and studies discrete time models of complex systems given by strongly coupled components. It considers systems presenting chaos — a staple of complexity — where, although deterministic, each component presents erratic behaviour due to the nonlinearity in its evolution laws. This proposal focuses on the challenges faced when dealing with large coupling strength between the components. The proposed investigation has two complementary aims: (1) to determine sufficient conditions for the emergence of equilibrium states in the thermodynamic limit where the number of units composing the system is infinite; (2) to quantify the rates of convergence to the thermodynamic limit and obtain control over the evolution of finite (but large) dimensional systems. This will allow us to answer questions like: What are the stable equilibrium states we expect to emerge in a complex system? How does their stability change changing the coupling strength? What are the correlations among coordinates in terms of the type and strength of the interactions?  The aims will be achieved by combining smooth ergodic theory (evolution of measure disintegrations on non-invariant foliations), probability (large deviations and concentration of measure), and analysis (study of the contraction properties of nonlinear operators).

UKRI Gateway to Research · FY 2025 · 2025-08

The nuclear envelope (NE) is a double membrane barrier which encloses the genome of eukaryotic cells, physically shielding the genetic material from the cytoplasmic environment. This creates a selective barrier that regulates the trafficking of proteins between the two compartments. During each mitosis, the NE is dismantled in prophase to allow the proper segregation of the duplicated chromosomes and then reassembled around the two nascent nuclei in late anaphase/telophase. Even though the circuitry of kinases/ phosphatase initiating and sustaining mitosis is well defined, how the latter mitotic events are fine-tuned to achieve a complete and timely NE sealing are still ill-understood. I will use a combination of genetic, proteomic, cellular biology and imaging approaches to shed light on how the ESCRT-III machinery is regulated by phosphorylation/dephosphorylation events and protein-protein interactions at sites of NE reformation during mitotic exit. Understanding the mechanistical aspects guiding nuclear reassembly will allow a better understanding of how mitotic exit events are coordinated in space and time to ensure a timely and functional nucleocytoplasmic compartmentalisation at every cell cycle. Moreover, NE defects are a known cause of disease, as chromatin exposure to the cytoplasmic milieu poses a threat to genome stability. Since ESCRT-III deregulation can lead to an impairment of NE integrity and eventually to a loss of nuclear compartmentalisation, a deeper understanding of how ESCRT-III proteins act in space and time could reveal not only new insights in the cellular mechanisms underlying pathology but also new therapeutical approaches.

UKRI Gateway to Research · FY 2025 · 2025-08

Assembling Certainty examines the ethical and epistemic implications of using Machine Learning (ML) in ‘open source investigations’ of civilian casualties in warzones. Combining backgrounds in software studies, digital sociology, and investigative practices, the project is led by Dr David Young (Project Lead, King’s College London) with Dr Josh Bowsher (Project Co-Lead, University of Sussex) and the casualty recording watchdog Airwars (Partner Organisation). Since 2014, Airwars has systematically documented civilian casualties arising from military airstrikes in conflicts, including Gaza, Syria and Ukraine, with the aim of holding responsible governments accountable. Over the past decade, open source intelligence (OSINT) has become an important framework for organisations like Airwars. To document civilian harm, Airwars pursues a necessarily deliberative process of assembling diverse (and sometimes contradictory) material posted on social media. However, the pace of commentary and challenges of verifying content means that using OSINT effectively is a growing challenge. Some organisations (New York Times, Forensic Architecture) have experimented with ML tools to analyse OSINT and verify civilian harm allegations, with some success. Such experiments also prompt us to re-examine how 'certainty' is assembled through novel human-machine knowledge practices, while critically exploring the consequent epistemic contingencies and gradations involved. Combining innovative practical and qualitative methods, this project will develop a ML toolkit with Airwars to explore its implications for their expert knowledges and specify guidance about its ethical use in future investigations. Working collaboratively, we ask: Q1. How does ML reconfigure the way investigators conceive of 'data' and 'sources'? Q2. How do established OSINT practices, expertise, and software interact during the process of designing/deploying an ML toolkit? Q3. Given ML inherently deals in probabilities, how might its use in investigations change our understanding of what constitutes ‘certainty’? The project will run for 20 months, organised around an autoethnographic approach to co-developing the ML toolkit. This will be scaffolded by qualitative interviews with the Airwars team: firstly, mapping their expertise, knowledge practices and ethical safeguards; and latterly, measuring the toolkit’s impact on their investigations process, noting possibilities, limits, and frictions. The project will produce: A ML toolkit (including, for instance, object recognition, image classification, semantic textual analysis) developed to support a specific investigation. PL-authored publication responding to Q2, documenting the development of the ML toolkit with Airwars. Two further publications co-authored by the PL and PCL responding to Q1 and Q3 above. A Guidance Document outlining considerations regarding when/how/why ML could be responsibly employed in casualty recording. A symposium consolidating a network of academics, journalists, and civilian-harm monitors involved with casualty reporting, acting as a launch event for the Guidance Document. The project has significant potential for social impact. The guidance document and symposium provide pathways to changing investigative practices regarding the use of ML and OSINT not only within Airwars, but also through their existing partnerships with humanitarian and news organisations. It also presents an important developmental opportunity for the PL to expand his research portfolio, develop skills through mentorship and training, grow a research community, and gain experience leading an expert multi-disciplinary team.

UKRI Gateway to Research · FY 2025 · 2025-08

It is essential to embed public involvement across all types of research, and to provide both learning opportunities and practical experience for researchers early in their careers (Vocal-MRC, 2022). This is particularly important in under-developed areas like lab-based biomedical research, which often happens in an isolated environment. The King’s/MRC Public Partnership Programme addresses this through two strands of work. The primary strand will foster a new generation of biomedical researchers who are confident and equipped to make public involvement a core element of their research. Targeting Early Career Researchers (ECRs) in the ‘Exploration’ (early post-doctoral) and ‘Transition to Independence’ career stages, we will support researchers at a pivotal moment—when they are preparing to lead impactful research but lack funding and connections to enable public involvement at proposal stage. Support will take the form of seed funding for pre-application public involvement along with lived experience-led training (funded separately), tailored one-to-one support, and mentorship from both public contributors and public involvement professionals. With King’s averaging 60 annual applications to MRC ECR schemes, we have a defined and manageable applicant pool from which we can support 30 projects with up to £400 each.   A secondary, invite-only strand will support up to three large-scale MRC infrastructure bids, such as the Centres of Research Excellence, with up to £1000. These strategic bids will benefit from our networks of national charities, community groups, and public contributors, ensuring public voices shape research priorities, approaches and investment decisions. Awardees will participate in mandatory structured training and be paired with a public involvement professional and public co-applicant as mentors. These mentors will provide awardees with individualised guidance in designing and delivering their involvement activities —an approach that addresses a common gap in existing programmes by pairing hands-on practice with expert guidance.  Programme Objectives: Equip 30 ECRs with the awareness, confidence, skills and networks to meaningfully involve publics in their research, increasing the quality, competitiveness, and relevance to healthcare of their research. Develop a cohort of 10 trained public contributors and community champions to help broaden community engagement in MRC research, leading to more positive involvement environments, reported against the Standards for Public Involvement, that allow diverse communities to directly shape MRC research, building trust between communities and researchers.   Capture 3-5 examples of best practice and innovation in public involvement in underdeveloped areas, such as biomedical discovery research and within large scale infrastructure bids.   Combine insights from this scheme with existing programmes to support a business case programme funding beyond 2027. Our team, including seven professional service staff, four researchers and eight public contributors, will co-deliver this scheme. We currently run three schemes supporting early-stage public involvement, including university-wide, mental health/neuroscience, and translational research focused initiatives. This new programme will expand our support into additional MRC areas, including Infections and Immunity, Molecular and Cellular Medicine, and Population and Systems Medicine. By strengthening ECR capabilities and embedding public voices in research from the outset, the programme will support a lasting culture change in how medical research, from discovery science to clinical application, is conducted, ensuring it is co-produced with communities and focused on real-world health impacts.

UKRI Gateway to Research · FY 2025 · 2025-08

Context: Each year, around a million 16 to 18 year olds sit high-stakes exams for university, apprenticeships, or employment. Ensuring swift, accurate, and reliable exam marking is crucial for these life-changing opportunities. Awarding bodies like AQA employ rigorous Quality Assurance (QA) mechanisms to ensure consistent marking and grading quality, yet tasks like standardising human examiners and marking open-ended responses are challenging. Current QA mechanisms cannot eliminate all risks associated with a highly manual and large-scale process. This triggers investigation into automated scoring systems. However, automating the scoring of high-stakes assessment is complex and requires emulation of human behaviour, involving assessing various factors such as content, scientific factuality, coherence, and logical reasoning, to name a few. Recent advancement of large language models (LLMs) has made it possible to explore innovative applications including student assessment. While LLMs offer numerous benefits, they also present new challenges. Challenges: To drive innovation in high-stakes exams, AI systems built on LLMs must address three challenges: Challenge 1 (C1): The AI system needs to be transparent and accountable, able to explain its suggested marks. However, training it to mimic expert human markers is challenging due to limited annotated data (human examiners are rarely required to explicitly explain a mark).  Challenge 2 (C2): LLMs ‘hallucinate’, that is, they may produce incorrect or illogical text. This poses a risk when analysing student responses. Tailored data and training of a neural modular framework are needed to address this.  Challenge 3 (C3): Human marking cannot be thoroughly objective, so the concept of marking ‘accuracy’ is subject to interpretation. Measuring explanation quality is even less defined. This presents a challenge when training and evaluating AI models.  Aims and Objectives: To address the aforementioned challenges we have defined the following objectives: Objective 1 (addressing C1): To develop a hybrid AI approach informed by the cognitive process of human scoring for explainable assessment of open-ended answers in high-stakes educational settings. Objective 2 (addressing C2): To develop a new generation of neural modular paradigm built on LLMs, leveraging a novel neural architecture to improve reasoning and decision-making. Objective 3 (addressing C3): To design a new performance evaluation framework for automated marking systems. Achieving the above objectives requires interdisciplinary research combining the assessment expertise of AQA and the AI expertise of King’s College London (KCL) to develop a new, modular AI system that will improve the quality of secondary school qualifications (e.g. GCSE and A-level), with benefits for students, schools, tertiary education institutions and employers. The system would assist AQA and similar companies with various quality assurance and quality control tasks for delivering exam results and certificates. Applications and Benefits: KCL would benefit from this project by acquiring data, insight and know-how around high-stakes exams. Collaborating with AQA would enable KCL to improve the theoretical foundations of AI (focusing on reasoning, decision making and explainability) and develop a real-world application that addresses practical challenges in education. First-hand involvement of KCL academics will increase the relevance and transformative impact of their work. For AQA, the adoption of an automated marking system will improve the efficiency and robustness of assessment processes, leading to financial, reputational and social benefits. While gaining a competitive advantage in the exams sector, AQA will be able to licence the technology and therefore improve the overall sector’s capabilities.

UKRI Gateway to Research · FY 2025 · 2025-08

Background and importance: Antibodies are essential for all long-term serum immunity against pathogens and vaccines. When challenged by infection or vaccination the immune system must produce highly specific and potent antibodies capable of neutralizing any foreign pathogen from a limited number of antibody-encoding genes. At the heart of antibody diversification lies the process of somatic hypermutation (SHM) whereby mutations are introduced into the antibody-encoding genes in B lymphocytes or B cells by the enzyme activation-induced deaminase (AID). Mutations create subtle changes in the "shape" of the antibody which alters its binding strength (also called affinity) for the target antigen on the pathogen or vaccine. However. this mutagenic process is not without risk. For instance, AID has undesirable "off-target" activity at cancer-causing oncogenes, which can lead to various B cell lymphomas. Moreover, SHM can generate self-reactive antibodies targeting healthy tissues that have severe pathological consequences in autoimmune diseases. Therefore, elucidating the mechanism of SHM is essential not only for our fundamental understanding of the immune response but also for our understanding of the origin of autoimmunity and major B cell malignancies. Aims and objectives: During SHM, AID preferentially mutates certain signature DNA sequences (also called sequence motifs). However, some motifs mutate much more frequently than others. Recent research has suggested that the DNA sequences surrounding the mutated motifs play a crucial role in determining mutability, hinting at the existence of a sequence grammar that dictates how efficiently AID acts at a given motif. However, the underlying molecular mechanism is unknown and constitutes a major gap in our knowledge of SHM. Understanding the sequence grammar regulating SHM and, therefore, how antibodies evolve during the immune response, is one of the core areas of research in the field of antibody diversification and the focus of this research proposal. We will approach this question by using the power of artificial intelligence to make predictions about genomic features linked with mutation followed by testing these predictions experimentally. Similarly, we will ask whether the rules governing SHM at antibody genes are the same or different at AID off-target sites in B cell lymphomas. Potential benefits and relevance: By gaining a deeper understanding of SHM biology, our research will paint a clearer picture of how our immune system achieves its impressive adaptability in combating pathogens. In doing so, this research will advance our basic knowledge of the "rules of life", a core priority of the BBSRC's long-term vision.

UKRI Gateway to Research · FY 2025 · 2025-07

An exciting innovation in the analysis of a biological system is sampling on a very small nanoscale using a specialised needle (nano capillary sampling). Cells are located under a specialised (confocal) microscope and cells or even small parts of cells can be sampled. This uniquely provides spatial information and can be performed on living cells which will allow scientists to understand important biological phenomenon such as how cells communicate with each other and how cells become cancerous. Our resource which we have called SEISMIC will provide an automated platform based on nano capillary sampling. We will work with users within the UK research community to extract single cells and their sub- cellular compartments under a microscope. The extracted cellular materials can be analysed using a variety of approaches such as mass spectrometry which separates molecules by mass and charge to profile for example drugs, metabolites and lipids or apply other techniques to profile nucleic acids. This will allow an unprecedented view of cells and can be applied to a plethora of biological questions which inform us on for example the rules of life or how pathogens cause disease or how cells age, information which can be harnessed to develop new therapeutic interventions which will ultimately benefit society. The SEISMIC resource will be available free of charge to BBSRC users for the first 36 months, either with or without downstream mass spectrometry analysis. Users will be able to perform their experiments using the facilities at Surrey, and hands on access to SEISMIC will be supported through travel grants. This facility will be the first of its kind in the UK and therefore will play a role in maintaining world leading science in the UK.

UKRI Gateway to Research · FY 2025 · 2025-07

Anorexia nervosa is a restrictive eating disorder that has a high rate of death. Approximately a third of people develop a persisting form of illness, which is often accompanied by depression, which is a barrier to recovery. Anti-depressant medications are not effective in treating depression in patients with chronic anorexia and new treatments are needed. Ketamine is currently used for the treatment of depression in the UK and may be effective in patients with AN and additional depression. The hope for this study is that people with both, anorexia, and depression, will experience relief from depression and thus get back their hope for improvement, motivation, and strength to fight their anorexia. The EDEN project aims to investigate the effect of ketamine in alleviating depression in 60 adults with a diagnosis of persisting anorexia and treatment-resistant depression. Participants in the study will randomly receive either ketamine, or a dummy pill, twice a week for a total of six months. To verify that the drug is tolerable, the first four doses will be given in the Clinical Research Facility at King's College London, where participants will be monitored by medical professionals. After this point, and if the drug is tolerated well, participants can take the drug home. All participants will also receive ten "psychoeducation and integration" sessions which are designed to increase the beneficial effects of ketamine. The main outcome will be looking at whether a sufficient number of people were recruited into the study and did not drop out over the duration of the study period, and whether people found the drug, as well as taking part in the study itself, acceptable. Measurements of depression, anorexia symptoms, suicidality, and quality of life will be taken after 28 days, and 3-, 6- and 7 months. Blood samples will also be taken in order to look at levels of ketamine.

UKRI Gateway to Research · FY 2025 · 2025-07

Recent research has reported a startling five-fold difference in maternal mortality rates among women from Black African/Caribbean ethnic backgrounds and almost two-fold difference among women from South Asian (particularly Pakistanis and Bangladeshis) ethnic backgrounds compared to White women. The COVID-19 pandemic has exacerbated these pre-existing inequalities with studies finding that over half of pregnant women with COVID-19 were hospitalised and seven of the eight pregnant women who died were from ethnic minority groups. These figures demonstrate that the current levels of reproductive and maternal health care inequalities constitute a serious public health crisis which requires a radical rethink of research and policy. Structural frameworks around migration status further impact the accessibility and eligibility of free NHS care, intensifying the barriers to equitable healthcare for ethnic minority women. Those with ambiguous, uncertain, or insecure legal status are subject to immigration controls and are only able to access NHS services through health charging arrangements; accessing care with precarious status can even lead to detention and/or deportation. Not only does uncertainty about legal status deter migrant women from accessing care to which they are entitled, but ambiguous legal migration is often racialised, such that those from an ethnic minority background may be presumed to be ineligible for care without verification. Evidence of these serious inequalities has already spurred on controversial policy initiatives pre-dating COVID-19, and issues related to such health disparities are increasingly at the forefront in policy agendas (e.g. the Royal College of Obstetricians and Gynaecologists - who is a key collaborator of this research proposal). Whilst policy attention is welcome, there has been an absence of sufficiently rich approaches that centralise women's experiences whilst contextualising these within the barriers associated with migration status. There is also lack of evidence on the role of health care professionals in engaging with legal and ethical implications of migration status dependent care. The project will help fill in these notable gaps, with an overarching aim of utilising research into the reproductive, antenatal, and postnatal care provided to ethnic minority and migrant women to help overcome barriers to equitable reproductive and maternal healthcare. Our research will interrogate the complex intersections between legal and racial prejudice, which are documented to produce barriers to healthcare across the whole of a reproductive life course. Drawing on the expertise of an interdisciplinary team of philosophy, bioethics, law, and sociology scholars and practitioners, with international and comparative experience, we will interrogate the theoretical and legal frameworks that contextualise women's experiences, by bringing them into dialogue with ethnographic case studies that will be produced with the active participation of women. This multifaceted approach will give insights and understanding of different reproductive stages, sites of lived experience and action. We will advance a methodologically innovative framework, developing the 'Call and Response' method, co-producing a sensory archive, engaging in arts-based participatory workshops, to encourage dialogue across different actors (minority and migrant women, NHS professionals, policy and advocacy stakeholders, interested publics), to heighten awareness, deepen understanding, and ground future policy strategies. The project will also provide methodological training to early career and postgraduate researchers working on interdisciplinary, qualitative projects, thereby furthering both AHRC research and research training objectives.

UKRI Gateway to Research · FY 2025 · 2025-06

Low socioeconomic status (SES) is associated with lower cognitive performance, academic achievement, and long-term success during childhood. These disparities have significant costs to individuals, families, and society as a whole. However, the underlying mechanisms that explain the association between SES and these outcomes are still not well understood. This is a critical gap in our knowledge, as it hinders our ability to develop effective interventions to promote equitable outcomes. To address this, the proposed project aims to shed light on the underlying neural and environmental mechanisms of the association between low-SES and lower cognitive performance and achievement. By understanding these mechanisms, we can develop targeted interventions to improve the lives of children from low-SES backgrounds. Our ability to identify the neural and environmental factors that contribute to socioeconomic disparities in cognitive function and academic achievement has been impeded by several critical challenges. These challenges include a reliance on studies with small cross-sectional samples, insufficient consideration of the critical period of infancy characterised by dynamic neurodevelopment and heightened plasticity, a focus on household SES thereby overlooking the importance of the neighbourhood context, and a lack of emphasis on identifying modifiable environmental factors for intervention. Additionally, prevailing theoretical models on links between SES and brain development are inconsistent with empirical studies, hindering the advancement of knowledge in this domain. To address these critical gaps, this study will test a novel conceptual model and elucidate the underlying neural and environmental mechanisms that explain the association of SES with children's cognitive function and academic achievement. Specifically, the objectives of the project are to: Characterise the relationships between SES and brain development during infancy and adolescence; Identify environmental factors that mediate the association between low SES and brain development; Characterise the role of brain development in the association of low SES with cognitive and academic outcomes. This proposal will leverage existing large, population-based datasets to ensure the reproducibility and generalisability of the results. Further, the proposed research will examine various environmental factors both within the home and in the neighbourhood, allowing for a nuanced understanding of their relative contributions to SES-related differences in brain and cognitive development. This project is a critical step towards understanding the underlying mechanisms that contribute to socioeconomic disparities in youth achievement. By addressing this gap in our knowledge, we can develop effective interventions to improve the lives of children from low-SES backgrounds. In light of the recent availability of high-quality longitudinal neuroimaging data, the high prevalence of childhood poverty in the UK (29%) and worldwide, as well as the increasing inequality witnessed in recent decades, this study is timely and addresses current contextual needs. The discoveries stemming from this research have substantial potential to contribute novel insights into the roots of achievement disparities and identify targets for intervention. Ultimately, the insights gained from this project will pave the way for more informed decision-making in research, education, and policy to promote equitable outcomes.

UKRI Gateway to Research · FY 2025 · 2025-06

Each major progression in biological understanding is driven by advances in technology to enable novel and disruptive discovery. Super-resolution techniques such as single-molecule localisation microscopy (SMLM) have revolutionised spatial biology by enabling nanoscale imaging of biomolecules. The latest challenge for super-resolved imaging optical modalities is to achieve functional read-outs of biological activity: A new paradigm beyond the observation of spatial and temporal patterning. MINFLUX (MINimum Fluorescence photon fLUXes) microscopy has achieved near-angstrom resolution, however, significant challenges remain in making it broadly impactful for research. Limitations include access to instrumentation, low throughput, restricted fields of view, and the lack of integrated multiplexing or functional capabilities. Fluorescence lifetime imaging microscopy (FLIM), when used for measuring Förster Resonance Energy Transfer (FRET), is a powerful technique for studying protein interaction and states of activity, offering critical insights into molecular pathways that govern cellular behaviour. Acting on comparable lengthscales to MINFLUX, FRET is a multiplier in experimental precision and sophistication, potentially adding significantly to the super-resolution toolbox. No such implementation has so far been reported indicating a clear route to development for this team. This project aims to address this technology gap, increasing the speed and throughput of MINFLUX super-resolution microscopy by developing a simpler, more affordable, and user-friendly paradigm, with integrated single-photon counting FLIM capabilities. Our innovative approach replaces the single laser beam in MINFLUX imaging with an optical lattice, enabling simultaneous monitoring of a multiplicity of molecules simultaneously. This expands the field-of-view and enhances throughput, addressing two key limitations of the state-of-the-art. Leveraging our expertise in microscope design for massively-parallelised FLIM (Ameer-Beg) and super-resolution techniques (Jose), we will design an optical system reducing complexity and cost. We will employ state-of-the-art single photon avalanche diode (SPAD) arrays for detection, with embedded-FLIM imaging and on-chip processing to enable real-time analysis. Our primary biological exemplar, will be demonstration of the nanoscale integration of biochemical and mechanical signalling between the cell and the extracellular matrix within focal adhesions on the cell surface. We will focus on elucidating the dynamic architecture and functional significance of clustering of key proteins (FAK, Vinculin, and Paxillin) which are essential for cell migration. The impact of our research will resonate across multiple sectors. With only one MINFLUX system operational in the UK, to date, we believe that the developed technology will provide a valuable resource for researchers in diverse fields, helping to address complex biological questions with greater precision and speed. The addition of fluorescence lifetime contrast is unique in the world, and will provide a platform for spatio-temporal exploration of cell signalling at the nanoscale. We will make this microscope widely accessible to our collaborators within the Comprehensive Cancer Centre and, through our long term initiative, the Microscope Innovation Center (BioimagingUK node). This project has the potential to be transformative for research at the single- and few-molecule level. Our project aligns perfectly with the contemporary trend of precision medicine and targeted therapies - in particular those aimed at receptor trafficking and inhibition (EGFR: Cancer), at dysregulation of metabolism (In mitochondria: Neurodegeneration) or in cell migration (ARP2/3, Vinculin force transduction: Focal adhesions): Areas in which this research group has active collaborations and research projects. Our project will develop the tools to enable us to directly investigate the roles of focal adhesion proteins in cellular processes, such as cell migration, invasion, and signalling.

UKRI Gateway to Research · FY 2025 · 2025-06

Context and Challenge: Cultural pessimism about ageing endangers all facets of intergenerational solidarity; it shapes perceptions of the worth and value of human beings and directs decisions about care, research and funding priorities. The Sciences of Ageing and the Culture of Youth (SAACY) offers a conceptual framework with which to overcome such cultural pessimisms and influence policy change. It pursues two questions: how does culture frame the questions and paradigms of leading researchers in ageing and diseases of old age? And how do scientific research developments act as cultural force; how do they influence societal approaches to dementia? Driven by the PI’s dual career path between the life/medical sciences and the health humanities, SAACY has striven to answer these questions by reaching across disciplines and sectors. Her literary scholarship has explored the dynamic conversation between scientific, medical and wider cultural discourses about ageing across the 20th century; qualitative work investigates older people’s experiences; and in partnering with national/local charities, SAACY involves older people in transforming wider societal attitudes to ageing. An engagement programme has already attracted attention from the third sector and other representatives of the policy world to SAACY’s first policy report, and a second policy lab will formulate a manifesto to build a coalition across the private, public and third sectors. Aims and Objectives: SAACY+3 expands on the research, impact and training enabled by SAACY, seeking to consolidate the PI’s position as a leading researcher in the health humanities with specialism in dementia and ageing, while focusing resources on maximizing SAACY’s potential to achieve attitudinal changes to ageing. It has three objectives: O+31. to pioneer a model for how humanities-led research (archival and co-produced) can inform policy and practice, especially attitudinal change to ageing at midlife, through working with creative industries. SAACY+3 seeks to maximize SAACY’s impact to achieve attitudinal changes to ageing by targeting people aged 40 to 65. The main conduit for this will be the production, distribution and impact campaign of a not-for-profit feature film based on SAACY research. O+32. to explore non-mainstream narratives about ageing in ways that challenge decline and successful ageing narratives alike. This new research will lead to a generally accessible short book, ‘Fixing How We View Ageing’, targeted at general readers and health and social care policy makers, as its messages chime with major national and international agendas on healthy ageing. O+33. to investigate the divides between approaches to ageing and dementia of the life/medical sciences as compared to the social sciences and humanities; to formulate a funding bid for a project on the myths and realities of the two-culture split that harnesses the PI’s expertise of working across disciplines and leads by developing science literacy in the academy and beyond. Potential applications and benefits: Resonating with the World Health Organisation Decade of Healthy Ageing baseline report, that healthy ageing will only be achieved if we ‘change how we think, feel and act towards age and ageing’, SAACY has already taken significant steps towards informing practices and policy development. A shift in attitudinal change to ageing especially at midlife would have far-reaching implications for how we retire, treat and care for older people, fund research and care, and understand intergenerational relations. SAACY+3 will contribute to the conversation about how we can live healthier and happier lives even as we age.

UKRI Gateway to Research · FY 2025 · 2025-05

Fungal pathogens kill ~2.5 million people every year, six times more than malaria or influenza, and are deadlier than most bacterial infections.  In direct response to these alarming figures, the World Health Organisation recently commissioned the first ‘fungal priority pathogens’ list, and cited Candida albicans in the ‘critical’ group (of highest concern).  This response highlights the need to better understand the biological processes that drive and influence C. albicans pathogenesis. During infection, C. albicans can alter its morphology from yeast cells to invasive ‘pathogenic’ hyphae.  However, the transition from yeast to hyphae is a tightly regulated process, and subject to environmental and genetic influences. Critically, clinical isolates of C. albicans often display a “spectrum of pathogenicity”, ranging from overtly pathogenic (producing invasive hyphae, invading tissues, and causing damage), to overtly commensal (producing no invasive hyphae and causing no tissue damage).  These observations suggest that an additional level of regulation influences C. albicans pathogenicity. C. albicans hyphae are ‘pathogenic’ at mucosal surfaces because they secrete candidalysin; a pore-forming peptide toxin that causes tissue damage, inflammation, and symptomology. To produce candidalysin, C. albicans must express a gene called ECE1. Once expressed, the Ece1 protein is processed into eight small peptides, the third of which is candidalysin. Importantly, efficient processing of Ece1 is context-dependent, and essential for candidalysin production, while the amino acid sequence of candidalysin is also critical for toxicity and potency.  However, while candidalysin secretion is critical for pathogenicity, it is only the final step in a carefully regulated cascade of events that are required for full C. albicans virulence, including adhesion; invasion; hyphal maintenance; ECE1 expression, and candidalysin processing and secretion. Numerous studies have catalogued the fungal and host phenotypes associated with C. albicans clinical isolates, both in vitro and in vivo.  However, no studies have controlled for all these critical variables when comparing C. albicans clinical isolates in pathogenicity and commensalism research.  Consequently, this has led to confusing, inconclusive, and often contradictory data regarding the importance of hypha formation and candidalysin in pathogenicity and commensalism. In preliminary studies, we have identified a set of ‘pathogenic’ (damaging) and ‘commensal’ (non-damaging) C. albicans isolates where all these criteria are controlled for, and in which the Ece1 processing context and candidalysin amino acid sequence are identical.  These isolates will allow the first accurate analysis of the underlying mechanisms that control C. albicans commensalism and pathogenicity.  Using these strains, we will (i) delineate the regulatory network that controls the yeast-hypha transition and ECE1 gene regulation, which determines candidalysin production; (ii)  identify genetic polymorphisms and epigenetic modifications associated with C. albicans pathogenic and commensal phenotypes; and (iii)  determine the host immune responses associated with C. albicans pathogenicity (infection/inflammation) and commensalism (colonisation/health) in vivo.  These data will provide the first comprehensive understanding of how and why C. albicans acts as a pathogen or commensal in vivo.  

UKRI Gateway to Research · FY 2025 · 2025-05

Congenital heart disease (CHD) affects approximately 1% of live births. Detection of CHD through routine fetal ultrasound screening continues to rise, however accurate identification of babies who require life-saving surgical intervention immediately after birth remains challenging for many complex cardiac anomalies. Prenatal diagnosis, reliant predominantly on 2D ultrasound, is often incomplete, even in expert hands, due to difficulties in visualising the 3D structure of the heart and vessels. Additionally, 2D Doppler ultrasound provides only a limited understanding of blood flow in fetal heart and vessels. In the postnatal life ultrasound limitations have been addressed by cardiac MRI, which provides 3D visualisation, volumetric and vascular flow measurements. Fetal MRI has seen a growing role in diagnosis of fetal anomalies, but it is susceptible to corruption by fetal motion and maternal breathing. To address this, we have developed motion corrected 3D MRI, by composing multiple fast 2D acquisitions into a consistent 3D volume for static structures. Imaging the beating fetal heart, however, presents additional challenges: not only does it beats three times faster than in adults, but until recently there was no practical method that could measure fetal heart rate during acquisition in real time. In our previous work we proposed motion-corrected 3D+time fetal cardiac MRI with the fetal heart rate estimated after acquisition directly from the imaging data, but this did not accurately capture beat-to-beat heart rate variation, resulting in errors which have so far prevented clinical adoption of these techniques. Recently, a CE-marked, MRI-compatible Doppler ultrasound gating device has become available. This device can accurately measure the fetal heart rate and provide an external gating signal directly to MRI scanner in real time. This recent technology provides new exciting opportunities for development of high temporal resolution imaging of the fetal heart. To date, due to lack of motion compensation, the Doppler gating has been limited mainly to 2D anatomy and flow imaging, which is still highly susceptible to fetal motion. In this project we propose to develop Doppler-gated motion-compensated 3D+time MRI of moving fetal cardiac anatomy and flow. This new technology will unlock opportunities for large clinical studies to enable accurate diagnosis, discovery of novel biomarkers and understanding of pathological in-utero development in different forms of CHD. We will close the current technological gap by combining new Doppler ultrasound gating device with our motion corrected fetal 3D MRI technique. Our preliminary results show that Doppler-gated 3D+time imaging of moving fetal cardiac anatomy is not only feasible and efficient, but also provides accurate measurements of fetal cardiac function superior to image-gated 3D+time MRI. We now intend to further develop this technique to generate motion corrected Doppler-gated 3D+time flow and evaluate 3D+time anatomical and flow imaging on a large dataset of 300 fetal subjects. We aim to develop a practical vendor independent acquisition and software tools for accurate volumetric measurements of fetal heart function, based on Doppler-gated “off-the-shelf” MRI sequences that can be easily deployed in any centre with an existing fetal MRI programme. The proposed technology has potential to improve clinical management of fetuses with suspicion of severe forms of CHD, by ensuring that babies who require urgent postnatal surgery are more accurately diagnosed before birth. Additionally, confident exclusion of severe lesions will reduce pressure on NHS resources and the emotional burden on affected families.

UKRI Gateway to Research · FY 2025 · 2025-05

Context: Funders, researchers and governments want the R&D system to deliver maximum value for decision-makers, and ultimately the UK population. To support this goal, metascientists often compare research outputs with funding allocation patterns, or support funders by studying internal review and allocation processes. The Areas of Research Interest (ARIs) offer scope for additional metascience enquiries. Published by government departments, ARIs are regularly-updated statements of research need. The team (including Government Office for Science, Overton) have worked with ARIs since 2019, supporting optimisation of their production and use. We have studied how academics engage with the ARIs (refs), and produced a searchable, indexed database of all ARIs, and linked this with UKRI grant award datasets. Preliminary work shows ARIs can inform strategic priority-setting by funders. Funders already draw on stakeholder priorities and landscape analyses to identify gaps, but often in an ad hoc or informal way. ARIs offer a mechanism for more rigorous, granular analysis identifying gaps, trends, and cross-cutting themes. This requires careful facilitation to ensure independence and rigour. Our pilot process to support strategic priority-setting working involved triaging ARIs by comparing ARIs with funding allocations to identify evidence gaps; searching for relevant research outputs to further refine these gaps, and co-creating strategic priorities with funders, experts and officials in facilitated workshops. Aims and objectives: This project will generate robust evidence about this transparent, rigorous mechanism for funders to take engage with national research priorities articulated by government departments by: Creating and sharing a dataset which brings together the ARIs, funding awards and research outputs: the ARI Research Dataset. To optimise the identification of evidence gaps, a research dataset drawing on the ARI database will be created for sharing with metascience researchers. It will include ARI equivalents from other governments at multiple levels, and awards and outputs from other funders. Large language models used to automate matching will be refined. Analysing patterns, overlaps, and gaps between ARIs, research profiles and outputs, and funding allocation patterns. Our previous work shows than 87% of ARIs can be matched with a relevant UKRI grant. This analysis allows us to accurately and transparently identify evidence gaps, and overlaps where clusters of awards address topics of importance to government. Identification of relevant research profiles and outputs allows us to refine these gaps and measure research impact on policy, by identifying cases where ARIs have been cited in outputs. Scaling up collaborative co-creation workshops with funders to explore how ARIs can be most usefully incorporated into priority-setting. Independence of funding and policy is crucial. We will test and refine our triaging process with national (UKRI, NIHR) and international (Horizon, MHFS) funders. Developing and testing our pilot process to support strategic priority-setting will help funders respond to government priorities and guide useful research activity. Universities and researchers will be able to identify areas for policy-relevant research, synthesis and knowledge exchange. Identification of cross-cutting themes and existing evidence will allow government to support internal learning, improve efficiency of internal research and analysis, guide engagement and commissioning more strategically. We will improve connectivity within the metascience research community and demonstrate the ARIs utility for improved scrutiny and analysis of funding and policy priorities.  Ultimately, this project will maximise the value of existing investments in research and provide a rigorous and transparent approach to identifying research gaps.

UKRI Gateway to Research · FY 2025 · 2025-05

The UK does not eat enough plant foods despite significant strides in understanding their impact on health. Barriers to increasing plant food consumption are complex and interventions to increase consumption have shown limited long-term change. Diversifying plant food intake may be a more achievable option, but the health effects of such an approach are unknown, a challenge our research aims to address. Evidence for the benefits of plant foods, in particular the quantity of fruits and vegetables is convincing. In contrast, there is a lack of evidence investigating the impact of plant food diversity on health and disease. Despite this, the World Health Organisation (WHO) recommends increasing "the variety of fruits and vegetables consumed" to "ensure a better general dietary pattern" , which although theoretically increases odds of achieving nutrient requirements, has not been extensively tested. Recommendations focus on fruits and vegetables, excluding other nutrient-dense plant foods with proven health benefits (e.g. grains, legumes, nuts, seeds). Observational data shows associations between plant food diversity and gut microbiota diversity, a common marker of gastrointestinal health and researchers have begun elucidating mechanisms by which diet-related changes in the gut microbiome benefit cardiometabolic health. Still, there is lack of intervention studies and high-quality evidence for the role of plant food diversity on gastrointestinal and cardiometabolic health. Despite two decades of public health campaigns, the WHO recommendations for quantity of fruits and vegetables (at least 400g/d = 5 portions/d) remain unmet. Failure to meet this recommendation contributes to health inequalities. Unfortunately, interventions to increase the quantity of fruit and vegetable consumption have variable success. The most effective method to change behaviour is to limit the need to change behaviour. Focussing on diversity of plant food intake is a strategy potentially requiring less behaviour change than increasing quantity. Research into the health effects of plant food diversity stands to inform future public health strategy and food industry focus. For example, focussing on diversity via reformulation of food products or multi-buy food offers. Our research will address a crucial gap in scientific evidence by establishing whether increasing plant food diversity in a population that a) consumes below UK average quantity and diversity of plant foods and b) does not achieve recommended fibre intakes, will improve dietary intake, and confer gastrointestinal and cardiometabolic health benefits. The project will address the following objectives: first, we will design two test diets, both providing the same quantity of plant foods (UK average), and either a) high diversity of plant foods (intervention) or b) UK average diversity of plant foods (control); next, we will conduct a randomised controlled parallel-design feeding study comparing the intervention and control test diets on health outcomes in healthy adults; we will then assess the impact of test diets on dietary intake; and finally we will measure the impact of plant food diversity on the gut microbiome, physiology and symptoms, and cardiometabolic outcomes. This will be the first RCT to assess the impact of plant food diversity on human health, paving the way towards enhancing the efficacy of current public health messages. Low intakes of fruits and vegetables are associated with poor health outcomes, thus by conducting the trial in this population, we aim to determine the potential health gains that can result from focussing on diversity, rather than quantity, in a cohort that stands to benefit most. The results will provide direction for future research into the benefit of plant food diversity for the maintenance of health, informing public health messaging, food industry guidance and educational strategies to improve dietary intake and limit the burden of disease.

UKRI Gateway to Research · FY 2025 · 2025-05

This project aims to develop a set of digital twins of people with motor neuron disease. We will then carry out a clinical trial using computer simulations to replicate what would happen in real life. We can use that knowledge to improve the design of a real trial, making it shorter and more efficient. The digital twins will also mean that in the real trial, fewer people will need to take a blank version of the treatment (placebo) and more people will be able to take the real treatment, which is very important in a terminal condition like motor neuron disease. Aim of the project The aim of this project is to make a computer-generated population of people with MND. These virtual people, or "digital twins" can then be used to greatly improve clinical trials, reducing the number of people who need to take placebo in the real world, improving the design of studies, improving the rules for inclusion and exclusion, and ensuring that trial timelines are more likely to be met. Why is this project needed? Our understanding of what causes MND is rapidly improving, and as a result there are many new potential treatments that need to be tested in clinical trials. To be accepted as valid evidence for licensing a new therapy, a clinical trial needs to give some people a placebo, rather than the active drug. In a disease that is inevitably fatal, like MND, the use of placebo leads to ethical concerns, and the field has responded by shortening trials and randomizing more people to treatment arms than placebo arms. These changes make it more difficult to detect a treatment effect, and other approaches are needed. One option is to model MND to generate virtual populations that have the same characteristics as real trial participants. What difference will this research make? This modelling would allow more accurate prediction of the effects of different clinical trial designs, might be used to predict the potential results of a trial even if everyone were on active therapy (no placebo), and could be used to supplement real trial populations to reduce the need for large numbers of people on placebo. What this project involves This project will use various methods to generate virtual populations of people with motor neuron disease, comparing the performance of each one with real MND populations. The methods will include simulation, database manipulation, artificial intelligence and machine learning. Real clinical trial data will be used to test the behaviour of the virtual populations, assessing the strengths and drawbacks of each approach. The final method will use a combination of all successful techniques to produce a robust, high performing virtual MND population, suitable for trial design and analysis. Sharing of results and how the work relates to other research The project is complementary to other research in the UK and internationally. There are other groups working on virtual trial populations using alternative approaches, and we will share our methods and results to inform each other. The project will directly impact clinical trials research. All our results will be shared with the general public through social media (primarily X and LinkedIn) using language understandable by the general public, as well as through more traditional channels such as open access scientific publications.

UKRI Gateway to Research · FY 2025 · 2025-04

We established the ESRC Centre for Society and Mental Health (CSMH) in 2020. Our aim is to generate transformative research evidence to inform strategies to reduce mental distress and ill-health, minimise inequalities, and improve outcomes. The imperative for this has grown since 2020. Multiple co-occurring crises (e.g., Covid-19, cost-of-living, climate extremes) are transforming the UK’s social, economic, and political landscape. There have been sharp increases in insecurity, disadvantage, and threat in many aspects of life and rates of mental distress and ill-health have risen, with far-reaching and unequally distributed socio-economic consequences. The focus of CSMH-2 (2025-2028) is on: extending our research to deepen understandings of social change, inequalities, and mental health; working with partners to translate the evidence into actionable policies and scalable practices; and building capacity. Our objectives are to: 1. Synthesise and extend our research to address knowledge gaps, supported by CSMH resources and by leveraged funding. 2. Expand our partnerships, establishing national and international collaborative networks and opening new pathways to impact. 3. Engage with policy- and decision-makers, via our partners and multiple pathways, to translate our outputs into policy and practice solutions to reduce mental distress and ill-health, minimise inequalities, and improve outcomes. 4. Further embed and develop inclusive partnership working that centres equality, diversity, and inclusion, continuing our transformation of how mental health research is done. 5. Continue to build capacity among a new generation of researchers, equipped with the knowledge and skills to advance understandings of society and mental health and impact policy and practice. We bring together multiple disciplines (e.g., sociology, anthropology, epidemiology, psychology) and stakeholders (e.g., policymakers, community groups, schools). We will expand our three programmes focusing on Younger Generations, Marginalised Communities, and Work and Welfare. In each, we will generate in-depth, place-based  knowledge of: (1) why, in the context of recent crises, rates of mental distress and ill-health have increased, inequalities widened, and outcomes worsened in some places and social groups; (2) what processes and mechanisms mediate and modify experiences of mental distress and ill health, connecting, and thriving; and (3) what works, i.e., what policies, community initiatives, and interventions reduce mental distress and ill-health, minimise inequalities, and improve outcomes. Four new hubs will support this work by ensuring our research impacts policies and practices (Communications, Policy, and Impact Hub), is conducted in partnership with people with lived experience (Lived Experience Hub), and capitalises on and contributes to innovations in theory and methods (Theory and Methods Hub) and data infrastructure (Cohorts, Linkages, and Interdisciplinary Data Resources Hub). In our new CSMH Capacity Building and Learning Forum, we will continue to build capacity and provide career progression for Early Career Researchers, community partners, and people with lived experience. By the end of three years, we will have transitioned CSMH to a world-leading research centre, with independent funding streams that support innovative and impactful interdisciplinary research well-beyond the lifetime of this award, and contribute, in the long-term, to demonstrable reductions in mental distress and ill health and inequalities and improved socio-economic outcomes.

UKRI Gateway to Research · FY 2025 · 2025-04

Interactions between waves and vortices play a crucial role in a vast range of physical scenarios, ranging from atmospheric fluid flows to superconductors. In superfluids, vortices can arise as discrete, indivisible units with quantised circulation, giving rise to many celebrated quantum fluid phenomena e.g. topological phase transitions and quantum turbulence. However, the detailed dynamics of vortices is less well understood in quantum fluids with a free surface - i.e. a liquid interface like the one commonly seen between air and water - which is a prominent feature of strongly interacting quantum systems like liquid helium. This project will develop a microscopic theory of quantum vortices in the presence of a free surface, focussing in particular on their interaction with surface waves. Our theory will elucidate the fascinating stability properties of these systems observed in recent UK experiments, and find ways of using the free surface to control vortex dynamics. Advancements in understanding these strongly interacting quantum systems could have applications in emerging technologies, which can drive innovation and economic impact. Alongside the scientific objectives, the project will leverage its ties to the UK quantum community to produce a series of short films about the National Quantum Technologies Programme (NQTP) - increasing public awareness of this important investment. These films will be displayed as part of an Art-Science exhibition (2025) in collaboration with researchers at the University of Nottingham, culminating in a mini-documentary sharing some of the most important success stories of NQTP. The filming process will be further used as an opportunity to engage with junior researchers in the UK community, providing them with an online platform to share their research with a broader audience. In doing so, the ambition of the project is to identify the next generation of outreach talents, with the long-term goal of making cutting-edge research more accessible and raising science literacy in the general population.

UKRI Gateway to Research · FY 2025 · 2025-04

Deep brain stimulation (DBS) is now a standard of care therapeutic intervention in which electrodes are implanted deep into a patient’s brain so that an electrical stimulus can be applied to precisely targeted nuclei for neurological conditions and movement disorders including Parkinson disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder;  DBS treatment of numerous other neurological and neuropsychiatric illnesses are under active investigation. More than 160,000 DBS implants had been performed worldwide, as of 2019, and this patient population, which includes people at all stages of life, including children, is rapidly growing. Although the mechanisms underlying DBS are not yet fully understood, it is becoming increasingly apparent that DBS results in widespread changes in structure and function of the brain. Magnetic Resonance Imaging (MRI) is the standard of care modality for anatomical brain imaging, can provide radiation free functional brain imaging, and is regarded as a primary modality for clinical assessments as well being a powerful neuroscience research tool. During imaging, MRI scanners generate (transmit) radiofrequency (RF) magnetic fields to excite signals and then detect very weak RF echoes. Optimal imaging requires both intense excitation fields and deployment of sophisticated array receivers for signal detection– 32-channel receiver arrays are the gold standard. Unfortunately, RF excitation fields can cause currents to flow in DBS devices creating risk of focal heating, potentially damaging tissue. For this reason, DBS devices (as well as many other common devices, such a cardiac pacemakers) are classified as MR conditional, with specified constraints that must be applied to the MRI RF transmit system during imaging to ensure safety. Parallel Transmit (pTx) is a platform technology that enables much greater control of generated RF excitation fields during MRI. pTx systems with 8 or 16 channels are common in ultra-high field (7T) MRI scanners, but for mainstream clinical neuroimaging with MRI at 3T, systems with only 1 or 2 channels are used. We have shown in simulations, in test objects and in animal studies that 8- or 16-channel pTx can fully control risk from implanted electrodes in clinical scanners, while equalling and even surpassing the performance of conventional RF systems operating without constraints. This has potential to provide significant gains in clinical care for patients with DBS electrodes and we wish to initiate clinical studies to test this. However, to prove genuine clinical utility and demonstrate imaging performance superior to current systems in conditional mode, requires a level playing field for signal reception. Although 32-channel receivers are common in clinical practice, no commercially available devices are compatible with high channel count pTx transmit systems at 3T. Thus, clinical studies of DBS patients can have optimal receive and constrained transmit, or optimal transmit but inferior receive. It is perfectly feasible to achieve optimal transit and optimal receive for prospective clinical trials, but the cost of putting in place a receiver array unbalances grant proposals, and the delay and project risk in building or procuring one as a lead-in item creates a failure point in any rational project plan. This proposal seeks to fill this “gap” by building a 32-channel receiver array to be used in prospective clinical trials of pTx for safe implant imaging. Our primary target is to enhance MRI for DBS patients, but the resulting device would allow testing of pTx methods for other kinds of electrodes too.

UKRI Gateway to Research · FY 2025 · 2025-03

Microbial non-ribosomal cyclic peptides (NRcPs) such as colistin, vancomycin and daptomycin represent a major class of clinically vital antibiotics that underpin our healthcare. However, antimicrobial resistance against these critical drugs could soon render them useless, creating a devastating global health crisis. ESKAPE pathogens in particular, already pose a serious health threat worldwide as they exhibit multiple antimicrobial resistance (AMR) mechanisms. Thus, we urgently need new classes of antibiotics with novel mechanisms of action to combat AMR. Our approach to tackle AMR is to develop a new class of dual warhead metallo-peptide antibiotics by linking NRcP antibiotics to metal complexes. Conjugation of the two entities will expand the chemical space to be explored in NRcP derivatives and result in one or more gains of function of the metallo-peptides over their constituent parts e.g. novel mechanisms of action, improved selectivity. While, metal complexes are successfully used in cancer treatment and imaging diagnostics they are largely absent from antimicrobial therapy. Thus, a potentially powerful weapon against AMR has been neglected. This proposal is made possible by the previous work of the multidisciplinary team from King's College London and the Francis Crick Institute in the investigation and development of novel synthetic methods towards NRcPs and new to nature antibiotic metal complexes. We will use our extensive preliminary work to enable the development of a "mix and match" platform to create and test metallo-peptide libraries. This proposal thus represents a genuinely innovative direction in antimicrobial therapy to tackle the AMR crisis.

UKRI Gateway to Research · FY 2025 · 2025-03

We know that early modern London was a multilingual city: in the law courts, in foreign-language churches, in markets and shops, at the Royal Exchange, in coffeeshops and clubs, workplaces, printers' shops, booksellers, and on the stage, Londoners would encounter a multitude of different languages. But what did that everyday encounter with multilingualism feel like for early modern Londoners? This project investigates the emotions of early modern multilingualism, reading a wide range of resources (journals, court records, church records, letters, plays, masques, linguistic handbooks, satire, diaries) for what they can tell us about the encounter with different languages. It aims to produce 1) new avenues of research for early modernists, historians of emotions, and modern linguists; 2) a research method that involves thinking creatively with our material; and 3) an understanding of early modern London that restores a forgotten history of multilingualism. The project's approach is collaborative. A multidisciplinary network of academics, an audio producer, and a software developer are working together using workshops, conferences, and archival work to produce three linked outputs: a collection of essays exploring the locations of multilingualism and the emotional responses of early modern Londoners; three immersive audio pieces that make these encounters audible for modern audiences; and an interactive online map plotting multilingual sites with embedded sound, visual, and text files. We aim to produce a collection of essays that expands the boundaries of our knowledge of multilingual interactions in the early modern city by focusing on the emotional responses of Londoners to everyday experiences of multilingualism, and thus provide an impetus for future work in this area. This work is breaking new ground in early modern studies as it combines for the first time the history of multilingualism with the history of emotions. We hope that a wider audience beyond the academy will also benefit from the project's explorations and public engagement outputs. By demonstrating the multilingual nature of very ordinary interactions in the early modern city, we aim to change attitudes about modern multilingualism. Historically, multilingualism has been the necessary condition of travelling and trading cultures, but this story has fallen out of the historical narrative. A 2021 survey found that 25% of English-speakers in the UK felt uncomfortable hearing foreign languages spoken around them, a discomfort that reflects the ubiquity of English in the modern world and the lost opportunities to hear other languages. But historically, monolingualism is the anomaly, and people in the early modern city would have been used to negotiating multilingual spaces as part of their everyday lives. This project seeks to restore a lost history of multilingualism to mono- and multi-linguists alike.

UKRI Gateway to Research · FY 2025 · 2025-03

Neurocognitive conditions such as epilepsy, learning impairments, autistic spectrum conditions (ASC) and ADHD impact 3-4% of all children in the UK.  However, often these conditions are not diagnosed until symptoms first present during mid-childhood, at which point the window for most effective intervention may have closed. This has both societal and personal consequences, since considering ASC alone, less than 22% of affected individuals currently find full time employment, with costs of care and lost earnings exceeding £32bn pa. The first objective of this proposal is to develop a suite of tools that support precise, early phenotyping of these conditions from fetal magnetic resonance imaging (MRI), with view to improving clinical understanding of how (and when) the brains of these individuals deviate from expected patterns of development, in order to inform diagnosis and improve targeting of early infant support. This is motivated by a growing body of evidence that suggests that atypical neurodevelopment starts in the womb[1][2][3]. It also follows a trend towards increased clinical use of MRI, in cases of suspected genetic/clinical risk, or from concerns raised during routine ultrasound. This is because MRI generates clear and detailed images that improve detection and characterisation of alterations, making it vital when guiding parents  towards the need for postnatal support/monitoring. Despite these benefits, early imaging-biomarkers of neurodivergent development remain elusive. One key reason for this is that these conditions impact the cortex, or layers of tissue at the surface of the brain, which fold during neurodevelopment in order to fit within the skull. This biomechanical process is sensitive to any small changes in initial conditions and/or the rate of cell growth. As a result every human’s brain folds differently, and this makes it very challenging for clinicians to determine whether any unusual pattern of folding falls within the range of normal variation, or reflects early signs of cortical malformation. Our team brings together world-leading expertise in fetal MRI reconstruction and cortical modelling, with clinicians who have pioneered the use of fetal MRI for clinical reporting, and longitudinal research studies. Collectively we have accumulated >3000 scans, representing a range of clinical/reference populations and acquired across a range of acquisition protocols. This puts us in a unique position to be able to build models which disentangle natural cortical shape variability and the effect of scanning protocols, from neurobiological phenotypes of interest. Moreover, our methods will be informed by current understanding of the cellular biology underpinning cortical development, to annotate the sites of major cortical folds as they emerge, while sampling corresponding locations in the transient regions of the subplate and ventricular zones, from which cortical neurons emerge and migrate. From this we can then extract metrics of tissue maturation from these locations, harmonised across clinical and reference populations, to build normative reference charts from which early markers of atypical cortical development may be detected as outliers. Our vision is that these tools be failure-proof and simple-to-use - enabling users to reconstruct anatomically-precise surface-models of the fetal cortex and transient layers, with all emerging folds automatically labelled. As a  result, our secondary objective is to trial use of these visualisation tools as supplements to clinical reporting - reducing the time needed for neurologists to read images, while making it easier to appraise the entire shape of the fetal cortex from a single holistic view.