University of Sheffield

UKRI Gateway to Research · FY 2026 · 2026-09

The enteric nervous system (ENS) is a complex network of neurons and supporting glial cells that regulates essential functions of the digestive tract. The ENS is produced during early embryonic development from specialised progenitors through a tightly controlled process. However, disruptions in this process can lead to serious gastrointestinal disorders that are difficult to manage and significantly impact patients’ quality of life. One of the most well-known of these conditions is Hirschsprung disease (HSCR), which results from the absence of enteric neurons in the lower part of the bowel. This loss of neural control prevents normal gut motility, leading to severe intestinal blockages that are life-threatening if left untreated. Currently, the only available treatment for HSCR is surgery. This involves removing the affected section of the bowel and connecting the remaining healthy, neuron-containing portion to the rectum. However, because part of the abnormal non-innervated (“aganglionic”) bowel must be retained, many patients continue to experience increased life-long, and sometimes lethal, digestive problems, including chronic constipation, incontinence, and infections. These complications not only reduce patients’ quality of life but also place a long-term burden on healthcare systems. A promising alternative to surgery is cell therapy, specifically transplanting ENS progenitor cells to restore the missing nerve supply in the gut. In theory, this approach could improve gut function after surgery and, in some cases, even eliminate the need for surgery altogether. However, a major obstacle to making this a reality, is the lack of a readily available source of ENS progenitor cells for transplantation. To address this issue, we have established a protocol for the unlimited production of ENS progenitors from human pluripotent stem cells (hPSCs). In a recent publication, we have demonstrated, for the first time, that these hPSC-derived progenitors can restore gut contractility in tissue samples from HSCR patients. This breakthrough suggests that stem cell therapy could provide a viable treatment for HSCR in the future. We now wish to translate this research into a clinically viable therapy. This project aims to: (i) Develop a regulatory-compliant differentiation protocol ensuring that the method for producing ENS progenitors meets clinical-grade standards and large-scale manufacturing with defined critical quality attributes. (ii) Carry out a preliminary assessment of safety, biodistribution and immunogenicity of our cell product following in vivo transplantation. (iii) Identify the pivotal safety testing requirements, which would need to be satisfied ahead of a first-in-human clinical trial application. If successful, this project will lay the foundation for a novel cell-based therapy for HSCR, offering new hope to affected individuals and their families. As an initial therapeutic strategy, we envisage that the ENS progenitor-mediated re-innervation of the short section of residual aganglionic gut following surgery would have a substantial impact on the success of the surgical approach and subsequent quality of life of patients. In the longer term, our cell transplantation approach could eliminate the need for surgery altogether in some patients, or offer an alternative to bowel transplantation in severe cases. Beyond HSCR, this technology could also pave the way for treating other enteric neuropathies such as achalasia and gastroparesis.  

UKRI Gateway to Research · FY 2026 · 2026-09

Double white dwarf binaries are an elusive population of our Galaxy and key to understanding a range of topics in binary evolution including the population of Type Ia supernova and R Corona Borealis stars. They also dominate the population of detectable gravitational-wave sources, with more than ten thousand potential sources in the Milky Way. This opens up the study of general relativity, tidal physics in degenerate matter and Galactic structure. They will also represent a challenge for the upcoming LISA mission, as a large background source of gravitational radiation. Eclipsing double white dwarf binaries are particularly important, as they allow detailed parameter studies of the components. Despite their importance, the faint optical emission and short timescale variability from eclipsing double white dwarfs makes them a challenge to find in significant numbers. The most promising method is to search for their periodic variability in all-sky synoptic surveys. Recent exploitation of light curves from ZTF has increased the number of known eclipsing double white dwarf binaries with short periods from two to nine, but larger samples require a deeper survey. LSST represents both an unprecedented opportunity and an enormous challenge for finding double white dwarf binaries. Simulations predict that LSST can detect of order one thousand double white dwarf binaries, but identifying them will require searching billions of objects for periodic variability. This is not computationally feasible using existing approaches to period search as tools such as the Lomb-Scargle periodogram are too slow, even when accelerated on GPUs. In this proposal we will develop a new, modern approach for period-searches by building a machine-learning powered emulator for existing period search algorithms. This emulator can be used by all astronomers looking for periodic variability to compute their periodicity statistic of choice in a computationally cheap way. We will make this tool publicly available, and deploy it to deliver a step-change in our understanding of the Milky Way's double white dwarf binary population.

UKRI Gateway to Research · FY 2026 · 2026-07

Biomolecular condensates made of RNA and protein – ribonucleoprotein (RNP) granules – are the fundamental “building blocks” of all cells. They serve as efficient bioreactors and signalling hubs, dynamically responding to the changes in the cell environment. Their normal function is critical for adequate cell response to external factors such as stress. These structures are connected into a “network” that enables their crosstalk and optimises their functions. Due to these important functionalities, RNP granules are frequently affected in human diseases, such as neurodegenerative diseases of aging. Therefore, RNP granule condensates offer an attractive point of therapeutic intervention. Better understanding of how these condensates form and function and how they are altered in disease states can inform targeted therapeutic solutions for incurable human diseases. During my fellowship project, I have obtained novel molecular insights into the crosstalk between nuclear stress-induced condensates rich in a protein called TDP-43. Using advanced imaging and novel biochemical assays, my team has uncovered how TDP-43 regulates a prototypical RNP granule the paraspeckle, and how stress-induced condensation controls TDP-43's availability and function during stress in neurons. Abnormal TDP-43 processing is a central event in amyotrophic lateral sclerosis (ALS). Our findings have led to a shift in the understanding of early pathological changes in these fatal, currently incurable neurodegenerative diseases. Our data suggest that TDP-43 serves as a critical regulatory hub for RNP condensates. However, how this multifaceted regulation is achieved by a single protein remains largely unknown. Establishing this can lead to a breakthrough in the treatment of diseases with TDP-43 pathology ("TDP-43 proteinopathies"). I hypothesise that the "hub" function of TDP-43 is regulated by its self-assembly states. Building on the above insights and research tools developed to date, my proposal aims to elucidate: 1) how the balance between single-molecule (monomer) and complexed (oligomer) TDP-43 states regulates RNP granules and RNA metabolism more broadly; 2) how this regulation is realised in neurodevelopment, via paraspeckles; 3) how the TDP-43 monomer/oligomer balance is affected in different ALS subtypes and the underlying molecular mechanisms; 4) whether this disease-causative imbalance can be modulated using small molecules. I will continue to lead a productive and innovative programme of translational RNP granule research established in the first phase of the fellowship - supported by the extensive laboratory toolkit and skill base of my team and those of collaborators. My proposal focuses on an RNA-binding protein with unique regulatory properties and the RNP granules it controls. This study will have broad implications for our understanding of the RNP condensate homeostasis in neuronal health, stress and disease and should inform novel therapeutic approaches.

UKRI Gateway to Research · FY 2026 · 2026-06

This project focuses on the border security economy. That is, the wide range of companies, contracted directly or indirectly by governments, to contribute to border control. This includes the provision of technologies such as IT platforms, scanners, watchtowers and drones; infrastructure such as detention and holding facilities; and services such as private security, escorting, and consultancy. We will focus this research on the border economy in two countries, while recognising that companies operate in many jurisdictions, and border security is shaped by global dynamics.   While international migration is generally understood by policymakers and publics to be a global challenge, there is little debate on borders and bordering. On the contrary, there is a general consensus that borders are good and necessary to control movement, and especially to stop irregular migration. Yet we know from research that highly policed and surveilled borders do not work to stop irregular migration. Instead, people on the move are funnelled towards the services of smugglers, and towards more dangerous routes. Highly controlled borders, then, actively produce irregularised migration and smuggling. But this does not mean that bordering does not serve other projects -the politics of nationalism and sovereignty, for example, and the business of border security.   Whilst NGOs and activists have exposed ‘scandalous’ contracts and the work of specific companies, there has been a lack of sustained academic engagement and a broader lack of interrogation of the political economy of borders from within migration and refugee studies. Much existing work in the UK has focused on the provision of immigration detention and privatised asylum housing. Through a comparative case design, this project focuses on the roles of the UK and Denmark in experimenting with, propagating and normalising border security business in their national contexts, in Europe and beyond. The project has three core objectives: To gather new data on the political economy of the Danish and British border security sectors, developing both a comparative and network analysis across the two case study countries; To use empirical findings to further the theorisation of the dynamics of marketisation, competition, militarization and racialization in the British and Danish border security markets; To disseminate the empirical and theoretical project findings to inform and impact various publics on the need for a political economic perspective on border control technologies, and their societal and humanitarian consequences.   Bringing together experts from the UK and Denmark, supported by an international advisory group from civil society and academia, the project will provide a timely intervention into academic debates and policy discussions on immigration and borders. The project will use rigorous academic research to inform public debate on the realities of this growing border security economy and what it means for domestic and international politics, human rights and democracy. With the aim of increasing accountability we will work with civil society stakeholders (Danwatch and CorporateWatch) to share findings with non-academic audiences via a variety of general and targeted knowledge exchange activities. These will include (inter alia) podcasting and writing for accessible publications, running workshops, and report launch events in both national parliaments.  

UKRI Gateway to Research · FY 2026 · 2026-06

Being able to forecast how wildlife populations change in the near future is becoming more urgent than ever. As climate change, habitat loss, and other pressures intensify, ecosystems are facing new and unexpected challenges. From setting sustainable harvest limits to protecting endangered species, conservation managers and policymakers rely on forecasts to make timely, effective decisions. Yet the reality is that reliable forecasts are often missing when they’re needed most. Traditionally, ecologists have made long-term predictions about how species will change over decades or even centuries. These long-term forecasts are crucial for understanding broader trends, but they are often too uncertain and too slow to be useful for real-time decision-making. One major problem is that many forecasting methods assume the relationships observed in historical data will remain unchanged into the future. In today’s world of rapid climate shifts and unpredictable environmental events, this is rarely true. Near-term iterative ecological forecasting (NTEF) offers a promising solution. Instead of projecting far into the future, NTEF focuses on making short-term predictions — days to a few years ahead — and then regularly updating those forecasts as new data come in. This “forecast-update-repeat” cycle makes NTEF uniquely suited for today’s changing world. It enables forecasts to remain current as conditions change, providing managers with up-to-date, decision-relevant information when they need it most. Despite its promise, NTEF is still in its early days. So far, ecologists have limited understanding of which modelling approaches work best, how to deal with uncertainty, or how to adapt forecasts when conditions change. Other fields, like weather forecasting and epidemiology, have overcome similar challenges by using ensemble forecasting—combining multiple different models into a single, more reliable prediction. But in ecology, ensemble forecasting for populations remains underdeveloped. This project will deliver a major leap forward by combining the strengths of NTEF and ensemble approaches. We will develop and rigorously test new methods that show us how to make short-term forecasts more accurate and useful in the face of uncertainty. By blending insights from different models, our ensemble forecasts will capture a wider range of possibilities and help managers act with greater confidence. To achieve this, we will connect three strands of work. First, we will conduct computer simulations to test how species' life cycles, environmental variability, and data quality affect the performance of near-term ensemble forecasts. Second, we will validate these ideas through laboratory experiments with live populations under controlled conditions, testing how well near-term, updated forecasts handle real-life unpredictability. Finally, we will apply what we learn to a unique long-term study of wild sheep, demonstrating how near-term ensemble forecasting can inform real conservation decisions in the wild. Beyond advancing science, this project will deliver real-world impact by co-developing open, user-friendly forecasting tools and training resources with leading conservation partners, ensuring they are practical and ready for adoption by researchers, conservation organisations, and policymakers. By pioneering near-term, iterative population forecasting, we will equip future decision-makers to stay ahead of change and take timely, effective action for nature in an unpredictable world.  

UKRI Gateway to Research · FY 2026 · 2026-05

The project’s overall aim is to lay the foundations for a new approach to understanding Cambodian experiences post-genocide, which integrates phenomenology and photography as a method of inquiry. 2025 marks 50 years since the fall of Phnom Penh to the Khmer Rouge and the start of the Cambodian genocide, in which a quarter of the population lost their lives. These events continue to structure experiences of the present in different ways for Cambodians, including in the country, the diaspora, survivors, and their descendants. Reckoning with the past involves understanding its multifaceted impact on present experiences, which is necessary for personal and cultural renewal. Phenomenology is centrally concerned with the ways that present experience is shaped by factors including: social practices, the past, and psychological phenomena. It seeks to understand experience from the subject’s perspective, articulating its more elusive aspects, and analysing how different phenomena show up in the structure of the experienced world. Photography grapples with the problem of visually representing complex features of our existence, and as such, can yield insight into the many ways experience is shaped by factors beyond the immediately visible. Phenomenology and photography thus offer a unique and complementary set of resources for understanding experience. We aim to develop an approach that integrates them through using both to investigate the complex ways that the genocide echoes through Cambodian experiences of the present. The project focuses on experiences of loss. It aims to provide an analysis of three experiential themes identified through our preliminary work as characterising different Cambodian experiences post-genocide: (i) experiences of absence, where a loss may have a peculiar quasi-presence; (ii) collective grief, which - rather than being a mere feeling - patterns the experienced world in different ways; (iii) experiences of being haunted by what is lost, including ghost experiences and the embedding of past traumas in the experienced landscape. The data for the project will be experiences of contemporary Cambodian artists based in Cambodia and the UK. This approach has been chosen because art is widely used by Cambodian individuals and communities to process traumatic events. Moreover, conversation about difficult and elusive experiences can be facilitated by using artworks as a starting-point for dialogue. Art’s roles in expressing experience can also afford the artist greater insight into it. By working with artists, two further aims of the project will also be realised. One is to develop a network of Cambodian artists in the country and diaspora, linking it to academic researchers. A second is to provide a new categorisation and understanding of some contemporary Cambodian artworks as expressive of experiential themes (i) - (iii), identified above. The project lays foundations for further research into Cambodian experiences post-genocide. Through contributing to a deeper grasp of such experiences, it will aid Cambodia’s task of reckoning with the genocide in service of cultural and personal renewal. The approach developed will also have application in other post-conflict situations. By fostering greater understanding of post-genocide experience, the research will benefit persons affected by conflict, and organisations working with them.  

UKRI Gateway to Research · FY 2026 · 2026-04

With increasing antimicrobial resistance and an ageing population, bone infection is a growing clinical challenge with major socio-economic and healthcare impacts. The detrimental effects on treatment complexity and patient prognosis may be further exacerbated following trauma, or in individuals already compromised by comorbidities such as diabetes and cardiovascular disease.. Bone infections have a devastating impact on quality of life and incur substantial healthcare system costs. There is a pressing unmet clinical need for innovative technologies that improve patient prognosis and cost-effectiveness of interventions to prevent bone infection. No injectable bone graft substitute materials are currently available that inhibit bacterial growth without addition of antibiotics. Injectability enables use in minimally invasive surgery, reducing time in theatre and improving patient recovery. Following extensive research, our group has patented1 an injectable dual action paste ‘DAP’ that stimulates bone healing and significantly inhibits bacterial growth (including biofilm initialisation by clinical isolates). However, our in vivo studies have shown that bone healing is enhanced and most consistent at sites where the DAP has partially fragmented to form a greater surface area. To induce fragmentation, we propose here a critical modification that will provide consistent and improved bone healing.  The aim of this project is specifically to combine granular calcium phosphates with DAP to develop and de-risk a new multiphasic medical device prototype (DAP putty), enabling consistent bone tissue regeneration, while preventing bone infection without the inclusion of antibiotics. The incorporation of granular calcium phosphate will promote disaggregation, impart a mouldable texture favoured by surgeons, and provide an improved resorption profile. Project aim/critical gap: Can we produce a clinically usable DAP putty with the required antibacterial and osteoconductive properties? Objectives: 1. Manufacture and characterise range of prototype DAP putty 2. Select composition with most promising characteristics to meet user and physiological requirements, including optimal: Injectability/ flow rate/ injection control - for ease of deployment and to fill contained defect site Handling consistency - providing additional mouldable characteristics to expand potential applications Fragmentation characteristics to promote bone ingrowth Ultimately, this will offer commercial advantages by enabling application in additional  clinical indications such as spinal, and thus an increased market share. DAP putty addresses these clinical and commercial opportunities, with no other competitor product combining these unique advantages in one injectable, ready-to-use device which can also be easily moulded by hand if required. This is highly desired by surgeons as no material preparation is required, and aids minimally invasive surgical procedures, saving surgical time and improving patient healing rates. The prevention of bone infections has a significant impact on the patient quality of life alongside a substantial reduction in healthcare costs. Crucially, we are developing a device with potent antibacterial activity in an era when antibiotics are becoming less effective, thereby presenting an alternative product to those reliant on antibiotic loaded bone graft substitutes. Our team is in a highly competitive clinical and market position, working closely with our longstanding industrial partner Ceramisys Ltd. who provide considerable industrial and regulatory insight and advice alongside access to their medical device manufacturing facilities. Advantageously, our patent protects both products as DAP is an integral part of DAP putty. If funded, this MRC Gap activity will be an essential de-risking step, leading to a full DPFS covering regulatory testing through to first in human clinical trials.

UKRI Gateway to Research · FY 2026 · 2026-03

Context: Xenon-129 (129Xe), a stable and non-radioactive noble gas isotope, can be highly magnetised using a process called spin-exchange optical pumping (SEOP), which aligns the nuclear spin of the xenon atoms to create what is known as ‘hyperpolarised’ 129Xe. When inhaled during magnetic resonance imaging (MRI), this hyperpolarised 129Xe enables detailed visualisation of lung airspaces and, due to its solubility in blood and tissues, provides valuable insights into lung gas exchange and blood flow/gas uptake into well-perfused organs such as the brain and kidneys. Challenge: A major challenge in SEOP is producing large volumes of 129Xe gas rapidly while simultaneously maintaining high levels of polarisation. Addressing this challenge is crucial for two primary reasons: (i) ensuring that 129Xe MRI can be routinely used in clinical settings, particularly in hospitals where rapid and reliable access to diagnostic tools is essential, and (ii) increasing the sensitivity of hyperpolarised 129Xe signals to enable new and advanced applications in MRI that can support both medical research and clinical needs. Purpose: This project has two main objectives: (i) to bridge the gap between current theoretical models and experimental observations in SEOP physics, thereby advancing our understanding of spin polarisation physics, and (ii) to enhance polariser technology by optimising its efficiency, accessibility and performance, while ensuring long-term operational sustainability. These advancements aim to improve the sensitivity and broaden the application of hyperpolarised 129Xe MRI in clinical and research settings, while deepening our understanding of the fundamental principles of spin polarisation physics Research environment: This work will be conducted within the POLARIS group at the University of Sheffield, a global leader in hyperpolarised gas physics and MRI technique development. The POLARIS group is an interdisciplinary team of physicists and clinicians, uniquely positioned to translate technological advancements into practical applications within research and clinical environments. Potential Applications & Benefits: This project combines foundational research in SEOP physics with innovations in polariser technology, promising significant improvements in the performance of xenon polarisers. Enhanced sensitivity in xenon MRI, supported by higher-throughput polariser designs is of interest to a range of MRI vendors (e.g., GE, Siemens, Philips, Canon) and pharmaceutical companies, which are increasingly using xenon MRI as an outcome measure in clinical trials for new respiratory therapies. Collaborations at Sheffield, including those with major companies such as AstraZeneca and GSK, demonstrate existing support for these applications. Furthermore, planned advancements will focus on reducing the size, carbon footprint, and operational costs of polariser systems, making them feasible for clinical sites requiring compact, cost-effective, 'turn-key' devices suited to daily use. The project aims to enhance interdisciplinary collaboration between physics and medicine and strengthen Sheffield’s role as a hub for pioneering research in hyperpolarised gas technology. By advancing polariser technology and deepening insights into spin polarisation physics, we aim to equip MRI with enhanced capabilities that address critical clinical and research needs. A deeper understanding of spin polarisation physics not only supports improved xenon MRI applications but also provides valuable knowledge to the wider research community, driving innovations in other imaging modalities and techniques reliant on spin polarisation physics. These advancements will transform the clinical use of xenon MRI, making it more accessible and impactful for patients and healthcare providers, while empowering clinicians with more effective diagnostic tools.

UKRI Gateway to Research · FY 2026 · 2026-03

Notch signaling is a fundamental biological pathway that regulates cell fate, tissue homeostasis, and regeneration across diverse tissues. In oral tissues, Notch3—a key receptor in this pathway—has been identified as a critical player in maintaining cellular equilibrium and responding to injury. However, its role appears dualistic, contributing to tissue regeneration under some conditions and exacerbating pathological changes under others, such as in periodontal disease and oral inflammation. Understanding this dual nature is essential for developing effective therapeutic strategies. This project seeks to explore the precise role of Notch3 populations in oral tissues, aiming to clarify whether they act as "friends" by promoting repair and homeostasis, or as "foes" by driving disease progression. To achieve this, we will use cutting-edge techniques to study how Notch3-expressing cells behave in both healthy and diseased conditions. This work will involve multiple computational analysis, including RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) of gingival Notch3+ cells, as well as metagenomic profiling of saliva, to uncover the genetic, epigenetic, and bacterial mechanisms underlying their function in health and disease. Furthermore, we will use cutting-edge lineage tracing techniques to study how Notch3-expressing cells behave, as well as genetic engineered mice to investigate the impact of functional modulation (activation/inhibition) of Notch3 in both healthy and diseased conditions. This comprehensive approach will uncover the mechanisms underlying the function of Notch3 in oral tissues biology. By addressing this challenge, the research aims to uncover actionable insights into the regulation of oral health and the progression of infectious-inflammatory diseases like periodontitis. These findings could pave the way for novel therapies that modulate Notch3 activity, improving outcomes for patients with chronic oral conditions. The project aligns with the Biotechnology and Biological Sciences Research Council's (BBSRC) long-term priorities by advancing understanding in tissue homeostasis and regeneration, a critical area for improving public health. It also holds potential applications in developing biomaterials and precision medicine approaches tailored to oral health care. Additionally, our work will enable the introduction of novel mouse models to the United Kingdom, that could be further used by collaborators interested in the Notch3 pathway. This research promises to contribute significantly to both fundamental biological knowledge and translational innovation in dentistry and regenerative medicine

UKRI Gateway to Research · FY 2026 · 2026-03

Lead Application - APP70417

UKRI Gateway to Research · FY 2026 · 2026-03

Control Shift Escape will provide new ways to understand, design for, and practice digital well-being today. Digital well-being is concerned with the complex and intersecting impacts of technology on the lived experience of human beings. Yet it is often reduced to controlling personal technological habits: resisting addictive designs, managing the psychological risks of social media, interpreting AI deep-fakes, and balancing the attentive drain of always-available work and social cultures. Relative experiences of digital well-being are thus frequently measured against, and correlated with, an individual’s ability to stay in technological control, or not. Cultural studies scholars have critiqued this focus on digital self-discipline as a new form of neoliberal responsibilization - making individuals responsible for managing the harms caused by deregulated and marketised social systems. Overall, the responsibilized view 1) unfairly blames individuals for decreased digital well-being, and 2) separates digital well-being from its situated socio-technical context - namely as it relates to the social determinants of health, issues of identity, material inequalities, or the capitalist platform environments it manifests within. Dominant accounts of digital well-being as self-control, then, are politically, epistemologically, and empirically limited. However, while its damaging effects have been made clear by humanities scholars, how and why such ideas persist, and even where they come from, remains little understood. Control Shift Escape seeks to address this gap and instead contribute a new way of understanding, designing for and practicing digital well-being through three key aims: Aim 1: To explore the current discursive shape, political limits and public spread of digital well-being as control. Aim 2: To construct original concepts, measurements, and designs for digital well-being. Aim 3: To provide new ways for public audiences to understand and practice digital well-being today. Control. Objective 1 is to better understand how and why digital well-being has come to be correlated with user-control. This will be achieved by examining the dominant psychological, computational and political literatures through which digital well-being is currently researched, discussed and designed, as well as how this spreads in public media domains. Shift. Objective 2 is to produce new concepts, measurements and designs that can study and approach digital well-being as a situated socio-technical phenomenon. First, the project will synthesise previously separate philosophies of technology and well-being to create original conceptualizations of digital well-being. Second, it will cultivate new networks of interdisciplinary scholars that can collectively develop new ways to measure and design for digital well-being in the future. Escape. Objective 3 is to create original ways for public audiences to understand and practice digital well-being through arts-based research. It will do this by working with Bloc Projects, a socially engaged arts charity in Sheffield, to commission an early career artist to create a free public exhibition and events programme in their gallery space and online, offering fresh ideas and practices of digital well-being for people to explore in an accessible way. Overall, this project will 1) provide a novel critical analysis of digital well-being as control, adding much needed theoretical depth and understanding to a pressing public issue, 2) generate new interdisciplinary scholarship by creating alternative concepts, measures, designs, and networks of digital well-being and 3) be publicly impactful by helping non-academic audiences reimagine what digital well-being means, and how it can be experienced and practiced, within our shared technological world.

UKRI Gateway to Research · FY 2026 · 2026-03

Sexual harassment and gender discrimination in the UK workplace contribute markedly towards a significant public health problem, serious women’s health issue and mental health crisis (TUC 2019; Adams et al 2020; Cox et al 2023). Over 1 in 2 women in the UK have experienced workplace sexual harassment and almost half gender discrimination (TUC 2016; 2019). The result is reduced health outcomes, job satisfaction and employee retention (Gale et al. 2019; McLaughlin et al. 2017; Acker 2006; 2011; McDonald 2012). This project goes beyond current research on sexual harassment and gender discrimination to develop an intersectional sociological approach geared towards change and transformation. Focusing on the NHS, this project combines interviews, vignette focus groups and social media story gathering to problematize existing assumptions about how sexual harassment and gender discrimination operate and identify solutions to this salient issue. The NHS is the biggest employer in the UK, with 77% of its workforce women and almost a quarter from minority ethnic backgrounds (Rolewicz and Palmer 2021; NHS Digital 2021; NHS Employers 2019). The scale and makeup of the NHS, as well as diversity of working environments within it, make it an ideal case study to investigate how sexual harassment and gender discrimination operate in the workplace and the consequences for women’s health. In addition, recent work has highlighted the prominence of sexual harassment and gender discrimination in the NHS (Adams et al 2020; Cox et al 2023; Begeny et al 2023). The British Medical Association’s recent workforce survey found that 91% of women doctors in the UK have experienced sexism at work and respondents of all genders reported an issue of sexism in the medical profession (BMA 2017; BMA 2021). Organisations focused on the working conditions of healthcare professionals in the UK have evidenced the significant prevalence of sexual harassment and gender discrimination in the sector and called for more action to be taken to tackle it (Unison 2021; MWF 2019; Cox et al 2023; Fessler 2018; Rimmer 2017). Whilst the NHS is the focus of this project, this work is applicable to many other sectors given the known prevalence of sexual harassment and gender discrimination in the workplace and their impact on health. Workplace sexual harassment is predominantly defined as ‘unwelcome and sexualised behaviour in the organisational context’ (Hennekam and Bennett 2017, 418), while gender discrimination includes all forms of discriminatory treatment based on gender. Systematic racism, sexism and classism produce unequal treatment in and experiences of work (Acker 2006; Minnotte and Legerski 2019; Healy et al. 2019; Tazzyman 2019). Intersectional research has illustrated that identity factors combine in complex ways to impact how people are treated and the discrimination they experience (Crenshaw 2013; McBride et al 2015). An intersectional approach to workforce is therefore vital, but is rarely applied in work on workplace sexual harassment and gender discrimination. Taking a multi-dimensional approach (contextual, experiential and institutional), this project will identify how sexual harassment and gender discrimination are conceptualised in the NHS, how they have been/are dealt with, and explore women’s experiences and the health consequences, through an intersectional lens. This will enable an assessment of how sexual harassment and gender discrimination could be better dealt with at an organisational and national level to enable a nuanced approach sensitive to combinations of race, gender, place, status and class.

UKRI Gateway to Research · FY 2026 · 2026-03

Advanced therapies based on human pluripotent stem cell (hPSC)-derived cellular products hold great promise for treatment of various currently incurable diseases. The capacity of hPSCs to generate large quantities of diverse, clinically relevant cell types is essential for the development of these advanced therapies. Clinical trials employing hPSC-derived differentiated cells are currently underway for a range of conditions, including macular degeneration, Parkinson’s disease and spinal cord injury, with many more on the horizon. However, a significant safety concern that stands to seriously jeopardise a successful translation of hPSC-based therapies is the takeover of cultures by genetically abnormal cells. It is now well documented that the scale-up of hPSCs for downstream applications inevitably causes genetic alterations, ranging from karyotypic abnormalities to single nucleotide variants, some of which have been associated with cancer. Such aberrations raise safety concerns, particularly regarding potential tumorigenicity of cell therapies upon transplantation into patients. Therefore, the primary concern in the context of regenerative medicine is ensuring that hPSCs or their differentiated derivatives do not harbour variant cells that would pose a risk of tumour formation upon transplantation. Nonetheless, it remains unknown which aberrations constitute a risk to patients and which are inconsequential for the safety of cell therapies. Moreover, current in vivo tumorigenicity assays have significant shortcomings as they are time-consuming, expensive and may not accurately predict human tumorigenicity due to species differences. The overarching goal of this collaborative program is to mitigate the risks associated with cellular therapies by establishing reliable pre-clinical models for evaluating the safety of these therapies and minimizing the occurrence of variant hPSCs during expansion. This will involve the development of standardized assays and tools for advanced therapies, to provide developers and regulators with the information they need to more swiftly move these potentially transformative medicines forward and to patients in need. Access to standardised safety testing methods will reduce risk of product development by establishing clear expectations of what is deemed acceptable by regulatory agencies for advanced therapy for early-stage clinical programs. Moreover, standardized methods will reduce the need for redundant investments in assay development and validation that are currently contributing to the high cost of advanced therapy development and manufacture. This Prosperity Partnership builds on the significant successes of the UK Regenerative Medicine Platform and provides a framework for new solutions to key safety challenges for advanced therapies. Recognising the importance of interdisciplinary collaboration in addressing these complex issues our Partnership brings together exceptional cross-disciplinary investigators alongside extensive industry participation. The substantial involvement of industry partners underscores the critical need for solutions to the challenges our Partnership addresses, demonstrating strong industry buy-in. Our partners are leading companies in cell therapy, already performing hPSC-based clinical trials, tool/media developers and Contract Development and Manufacturing Organizations (CDMOs) for cell therapy manufacturing. Together, our activities will directly contribute to solidifying the UK’s position as a global leader in advanced therapy, driving innovation, improving patient outcomes, and contributing to economic growth.

UKRI Gateway to Research · FY 2026 · 2026-03

How can we understand the geometry of a very complicated space? An efficient method is to probe it by counting how many subspaces of a certain type we can possibly fit inside it. For example, we can geometrically tell apart a rugby ball (an ellipsoid) from a miniature cooling tower (a one-sheeted hyperboloid) by asking “how many straight lines can they possibly contain?”: this number is zero for the oval ball, but infinite for the model tower. As with all things in Maths, when it comes to ramping up the level of difficulty of the question, sky’s the limit. We could for example ask, using the same logic, how to distinguish the quintic (2875 straight lines) and sextic (528 straight lines) Calabi-Yau manifolds, which appear in certain models of quantum gravity containing the minimal number of copies of the electromagnetic field. In general, the information amassed by counting curves of all possible shapes and forms gives a sort of “biometric passport” of a geometric space: on top of their intrinsic value, the curve-counts can be effectively employed to distinguish shapes for which the same enumerative problem gives different answers. The quest for an effective solution to enumerative questions received impressive momentum from a revolutionary discovery made in the early ‘90s by both physicists and geometers: solving the geometrical problem of counting curves in a given ambient space is tantamount to understanding a class of energy-minimising field configurations of an associated physical model defined on that same space. This surprising connection between Mathematics and Physics is important for theoretical physicists, as it puts on a rigorous footing the calculation of quantum mechanical observables for certain effective theories of matter, radiation, and gravity in four space-time dimensions. At the same time, it has been of invaluable importance for geometers: the intuition from quantum field theory has led to a series of remarkable (if conjectural) predictions about the original enumerative problem, often implying its complete solution. The most difficult setup in this subject is when the geometry of the space becomes singular by developing “spikes” somewhere, like the tip of a cone. On the physics side, this means that the interactions in the corresponding model become violently coupled, with light particles drastically affecting the long-distance behaviour of the system. Quantum field theory considerations here prescribe a mysterious universal law obeyed by curve-counting invariants near the “spikes” of the geometry (in jargon, its conifold singularities): this is a major conjectural statement where mathematicians have yet to rigorously make sense of the physics heuristics. This proposal delineates two pathways to the mathematical proof of this universal conjectural behaviour – known as the Conifold Gap Conjecture – for non-trivial families of Calabi-Yau manifolds. These methods sidestep the intricacies posed by the singular geometry by recasting the original algebro-geometric problem as a question in either i) the asymptotic analysis of a specific class of measures on flat space, describing the statistical mechanics of a certain gas of 2-dimensional particles, or ii) the combinatorics of certain sums over graphs, which appear in the study of Landau-Ginzburg models at higher genus. As an application, we will completely solve the all-genus Gromov-Witten theory of an important family of Calabi-Yau varieties.

UKRI Gateway to Research · FY 2026 · 2026-02

This project addresses a central challenge: how the labour interests of military personnel are communicated to, and negotiated with, the state. This is a recognised problem. Currently progressing through UK parliament, the government’s Armed Forces Comissioner Bill is an intended corrective to previous failings in this area. Across Europe, military personnel are advocating for inclusion in social dialogue, this being defined by the International Labour Organisation as "negotiation, consultation or simply exchange of information between, or among, representatives of governments, employers and workers, on issues of common interest relating to economic and social policy" (ILO, nd). Social dialogue is integral to the European social model, and is linked to social rights, equality, fairness, labour market competitiveness and adaptability (European Commisson, 2025). Social dialogue is bound to freedom of association (the right of workers to have their professional and social interests represented by a trade union or association) and right to collective bargaining (ILO, nd). The right to military labour association, recognising soldiers as workers able to form labour unions and associations, is contentious and unevenly accorded across Europe; it is well established in some countries but prohibited in others. In collaboration with EUROMIL (the European umbrella organisation for around 40 European military associations and trade unions) this project maps the political conditions (social and economic norms, understandings, and interests relating to military labour) that underpin uneveness in rights to military labour association and social dialogue. The projects aims to: Develop a novel conceptual framework. Current theorisations of military labour and its governance are sparse, fragmented, and do not satisfactorily conceptualise or analytically explain military institutions as formal domains of work and labour relations. The project will develop a new conceptualisation, 'military labour regimes', drawing on the notion of the labour regime as the social relations and institutions bringing together and stabilising arrangements of capital and labour in specific times and places to produce the conditions for certain forms of work (Baglioni 2022; Li 2017).  Deploy this framework to comparatively analyse the political conditions underpinning the uneven recognition of military labour association across three country case studies. EUROMIL describe how "a well-structured [military] social dialogue currently takes place in some European countries" whilst others "still significantly restrict the coalition and collective bargaining rights of their military personnel". Advocates for military labour association cite improved working conditions for military personnel in line with the European Union social and economic model, competitiveness with civilian labour markets, and improved organisational function, including interoperability. Such arguments are 'common sense' in some European countries, but nonsensical in others where the idea of soldiers as workers is paradoxical.  Deliver non-academic impacts with the collaborating partner whilst building out from this partnership to engage broader stakeholder communities. The project has been codesigned with EUROMIL to address a gap in their evidence base on European military labour governance and directly shape their approach. Understanding the political conditions enabling or restricting military labour association will enable EUROMIL and member organisations to design and justify meaningful models of social dialogue within diverse European political contexts. Beyond this partnership, understanding why social dialogue does and does not emerge in particular contexts will have applications for organisations such as the ILO (a United Nations agency aiming to improve working conditions and social rights globally) and the Ministry of Defence and British government.

UKRI Gateway to Research · FY 2026 · 2026-02

Background and Importance Growing cells must replicate and segregate metres of DNA. Failure to faithfully segregate DNA results in genome damage and instability, contributing to human diseases including cancer and rare genetic disorders, such as fragile-X syndrome. In extreme cases genome damage leads to cell death, and this is exploited by an increasing repertoire of drugs that target the enzymes involved, as cancer cells divide at an accelerated rate. Ultra-fine bridges (UFBs) are a type of DNA segregation defect, which involve minimal DNA entanglements of one or two strands. Depending on underlying DNA structure, they are resolved by different resolvases, namely TOP2A, MUS81/EME1 and GEN1, and additional resolution pathways are activated particularly if these resolvases fail. UFBs have largely been studied in a cellular context by examining the protein complexes that localise and act upon them, and which DNA processes, when targeted, promote their formation. However, in the complex environment of a cell, determining the underlying DNA structure and deconvoluting enzymatic contributions to the formation and resolution is challenging. Hence, reconstitution of UFB resolution pathways allows a clearer understanding of UFB resolution, ultimately enabling targeting. Our understanding of the DNA structure of UFBs stretched by cell division, is primarily derived from mechanical force response of naked DNA. However, we currently have a limited knowledge of the structural changes induced when DNA entanglements are subjected to force and how this affects enzymatic processing. My preliminary data suggest direct interactions are generated between the entangled DNAs in vitro, indicating significant structural changes. It is vital to understand the molecular basis of these structural changes and the consequence this has on resolvases and cell segregation. This will be achieved by three key work packages (WP): WP1. Determine the structural changes when entangled DNA experiences force. WP2. Determine how crucial resolvase activity and specificity is influenced by force. WP3. Generate systems to individually isolate effects of specific resolvases, cell-cycle stages and DNA sequences. Outcomes and benefits WP1 will use cutting-edge single-molecule and computational approaches, which I have unique expertise in, to establish the molecular detail of entangled DNA structure, allowing the development of hypotheses about how this affects resolvases and chromosome segregation in cells. DNA structural changes will be explored in the context of human disease sequences and the presence of clinical chemotherapy drugs, providing new knowledge of the molecular mechanism of disease and treatments. This work could provide insights into other DNA processes such as homology search, crucial for repairing DNA damage and maintaining genome integrity. WP2 will determine the impact of force-induced DNA structural changes on resolvases by developing single-molecule approaches. Given UFB resolvases are current or potential human drug targets, WP2 will result in system to test such drugs, as well as provide details of the molecular mechanism, helping to identify novel drug targets in the form of off pathway processes and new DNA structures. WP3 puts findings back into the complexity of the cell, to demonstrate effects observed in vitro hold in cells. This cellular system will enable further translational work. Collectively this work will yield new insights into the fundamentals of DNA mechanics and the mechanism of human disease, helping to aid design of future therapeutic approaches that could benefit cancer patients and the wider health care community.

UKRI Gateway to Research · FY 2026 · 2026-02

The built environment is the dominant user of highly carbon-intensive materials such as concrete and steel, leading to vast carbon emissions as well as global habitat loss and pollution. The Institution of Structural Engineers has neatly summarised the most effective strategy for combatting these harms – ‘Use less stuff’. Structural optimization is a powerful digital approach which finds out how much ‘less stuff’ it is physically possible to use whilst ensuring safety and functionality in a given scenario, along with the structural form which obtains this optimal material-efficiency. Applying such techniques at the early stages of the design process, before the initial structural concept has been fixed, provides the greatest possible material savings, with case studies suggesting reductions in material usage (and hence embodied carbon) of up to 50%. To achieve these levels of material savings requires the highest levels of design freedom to be permitted, i.e. requiring so-called topology or layout optimization. However, the current state-of-the-art methods available for this are not yet ready for widespread implementation within the built environment. Thus, the aim here is to develop a framework suitable for optimization-driven design at the concept stage, by addressing the key blockers below. Any real structure must resist a huge variation in loadings during its lifetime, yet current methods become impractical with more than a handful of loading cases. Furthermore, within an optimization-driven framework, it is typically unclear which cases may be critical for inclusion in a simplified initial phase. Incorrect decisions can lead to late changes at huge financial and environmental cost, or in the worst case even unsafe structures. The first objective of this project is therefore to develop effective techniques which will allow all loading cases to be considered from inception. A further limitation is that the structural forms which obtain the minimum material usage are complex and impractical to construct. However, previous studies have shown that significant rationalisation can be obtained with only a small increase in material usage – but suitable methods are needed to be able to identify these rationalised solutions in a timely manner. Developing such methods is the second goal of this project. The final objective is to facilitate the holistic design of structures, to permit these benefits to be realised for common scenarios which involve loads distributed over an area such as a floor or a façade. This will require combined optimization of span or panelling layouts and structural form. Sustainability of the methods themselves is also a key part of this project, attained by using rigorous and computationally efficient mathematical programming approaches. This avoids the need for power-hungry supercomputing time, or additional model training processes. Furthermore, these approaches provide exact, globally optimal benchmark values, which can be used to inform decision-making on more general questions, such as whether new construction is the right answer, or on the dichotomy between lean design vs design for future flexibility. The computational efficiency of these methods means they can be run interactively on standard laptop/desktops and provide solutions quickly to engage with fast-moving design workflows. To facilitate this in real-world settings, an open-source Python framework will be developed, accompanied by interfaces to industry-standard software and easy to use web-apps. Through this, it is envisioned that real-world adoption of these approaches will be accelerated, providing a crucial leap in the march towards net-zero.

UKRI Gateway to Research · FY 2026 · 2026-01

Streptococcus pyogenes, also called group A Streptococcus or StrepA, is a bacteria that can lead to simple issues like sore throats and skin infections, or serious conditions like scarlet fever and deadly diseases. In the UK, StrepA cases usually go up during winter and spring. In the year 2022-23, there was a dramatic and sudden rise in cases with over 50,000 people getting scarlet fever and nearly 500 dying. Even though these outbreaks have a big impact, we do not fully understand what causes them, making it hard to stop or lessen the effects of outbreaks. Several factors may cause these outbreaks, including changes in the bacteria's genes, bacteria spreading more easily between people because of new or different strains, and people being more prone to infections. My research aims to figure out what causes these outbreaks of StrepA infections. In my study, I will collect all StrepA bacteria samples from Sheffield's NHS labs over five years, along with important medical information about individuals that suffered these StrepA infections. First, I'll look at how the bacteria's genes change over time and see if these changes are linked to specific patient or disease patterns. Next, I'll examine certain StrepA strains in the lab using human tissue infection models to see if specific features in the bacterial genes affect how the bacteria act or their ability to cause disease. Then, I'll look at the genetic data and where the bacteria were found in the city, to understand how strains spread in communities and whether some strains are more successful at doing this. My study is novel and thorough because it looks in a detailed way at StrepA strains from all types of infections in a large UK city across a long period of time. Previous studies have focused on severe infections or scarlet fever cases, which is only part of the picture. The findings from my research will help us better understand why StrepA causes outbreaks and help us improve how we manage StrepA, predict outbreaks, and find ways to lower the spread of bacteria in communities. My study aims to greatly reduce the overall future impact of StrepA disease in the UK.

UKRI Gateway to Research · FY 2026 · 2026-01

Almost a quarter of a million orthopaedic joint replacements (e.g., hip and knee implants) were performed in the UK in 2019. With changing lifestyles and demographics, the burden of arthroplasty increases as more middle-aged patients with musculoskeletal conditions require joint replacements. About a third of these patients (e.g., 29-35% for age 50-54) require revision surgery to correct failed implants, with poorer clinical outcomes. Improving the long-term survivorship of primary implants can avoid revision surgery, save the NHS >£350 million each year, and significantly improve patients’ quality of life. Substantially porous implants fabricated using additive manufacturing technology (AMT) are increasingly used in joint replacement surgery, especially to fill in bone defects. These implants have the potential to enhance bone ingrowth and bone-implant fixation (osseointegration) for long-term stability. However, bone remodelling and the factors governing bone ingrowth into 3D porous structures are poorly understood and are different from those related to surface osseointegration. To achieve bone ingrowth, it is important to understand structural factors such as pore shape and size, local and overall stiffness, as well as the biological environment within the structure. This research will define these mechanisms by modelling the factors that drive bone ingrowth and osseointegration within the porous structures across time and length scales. The objectives of this study are: 1) Comprehensively understand the process for bone ingrowth and osseointegration within porous implants; 2) Derive the micro- and macro-environment required to optimise porous implant designs to achieve long-term survivorship; and 3) evaluate and predict the performance of multi-functional implants before validation from pre-clinical testing. An interdisciplinary experimental-computational and imaging-based approach will be used to characterise the mechanical and biological behaviour at various dimensions (organ, tissue, sub-micron level) and time scales to understand and predict pre-clinical outcomes. Computational tools and novel algorithms will be developed to model bone formation in implants at the cellular level and bone remodelling at the tissue scale. These tools will account for local stress/strain and create new algorithms to predict the effects of pore size and shape. Different coatings will be analysed, from osteoconductive to osteoinductive, using bone-like coating and growth factors. Results will improve understanding of how multiple (sometimes conflicting) mechanical and biological properties should be combined for long-term implant stability. This work will enable cost-effective and timely in silico assessment of multi-functional implants before physical and biological evaluation, handling numerous design parameters ranging from AMT to biological parameters. This methodology will be used to optimise an implant design to treat critical size bone defects, scalable to porous collars currently used in massive defect reconstruction, hip and knee implants to enhance fixation. In collaboration with industry and clinical partners, this approach will be applied to design full-sized prostheses such as spinal fusion and hip implants, upon successful validation of this feasibility study. Hence, this integrated mechanobiological modelling approach to design novel implants aims to expand UK orthopaedic implant manufacturers’ global position. It replaces part of the current pre-clinical testing for regulatory approval, aligning with the UK National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) guidelines. Additionally, this methodology enhances the selection of AMT process parameters, stimulating advanced material development and shorter time-to-market. Overall, this research contributes to EPSRC’s priorities in transforming early prediction and diagnosis, innovative technologies for physical intervention, and MRC’s focus on clinical and translational research.

UKRI Gateway to Research · FY 2026 · 2026-01

Context. Plants, algae and bacteria convert light into chemical energy to power the fixation of carbon dioxide into biomass, providing the oxygen and food that sustains the biosphere. However, natural photosynthesis operates with an efficiency of only ~2-3% in most species and even these modest figures are now threatened by the severe weather associated with climate change. Against this backdrop there is  increased demand for food and biofuel production to meet the needs of a growing population. Recent work has shown that genetic interventions aimed at improving photosynthetic photoprotection can increase tolerance to environmental stress and boost yield. However, the success of future interventions requires the fundamental underpinning science. A key area requiring improved understanding is the photoprotection of photosystem I, the most abundant solar-powered machine on Earth. The challenge. The chlorophyll-proteins photosystems I and II (PSI and PSII), within the chloroplast of plants and algae, convert light into chemical energy to power CO2 fixation into biomass. PSI and PSII are exceptional at harvesting solar energy, even when light is scarce. However, the flipside of this success is that on sunny days PSI and PSII are extremely susceptible to light-induced damage. PSII has evolved a complex, but very effective repair cycle to mitigate these sunburn symptoms. PSI on the other hand has no such repair cycle and therefore plants and algae go to great lengths to protect it from damage. Our recent work using gene editing in model green algae provided evidence that the location of a photosynthetic electron transfer protein, known as FNR, is critical to controlling photoprotection of PSI. This insight was obtained by artificially linking the FNR protein to either PSI or cytochrome b6f, the protein complex  that mediates electron transfer between PSII and PSI. The challenge now is to understand why and establish the mechanistic basis of PSI photoprotection. Aims and objectives. Compare the mutant and wild-type algae to determine how different locations of FNR on the membrane affect electron transfer and photoprotection functions. Elucidate the proteins FNR interacts with under conditions favouring photosynthesis or photoprotection. Understand how the structure and function of PSI and cytochrome b6f are affected through their interaction with FNR.  Potential applications and benefits. PSI photoprotection is crucial to the fitness and growth of plants and algae. If we can understand how this elusive process is regulated, we can make a significant contribution to improving their hardiness to climate change, which threatens to imperil our food supply. Furthermore, this work may provide a new platform for enhancing biofuel (e.g. hydrogen) production in algae to support our transition towards net zero CO2. Relevance to BBSRC strategy. It provides a further stride to understanding photosynthesis at the molecular level, revealing bottlenecks in the electron transfer systems. These findings may provide future genetic targets to improve productivity in food crops and light-powered cell factories, used for biofuel, pharmaceutical and high-value commodity chemical synthesis, thus addressing ‘sustainable agriculture and food’ and ‘renewable resources and clean growth’ priorities. The development of the TurboID and redox proteomic techniques to quantify protein-protein associations and downstream signalling will be applicable to a wide range of protein complexes involved in diverse cellular processes, thus addressing the ‘Transformative technologies’ priority. Finally, uncovering how structure and function are linked to power cellular bioenergetics, addresses the ‘Understanding the rules of life’ priority.

UKRI Gateway to Research · FY 2025 · 2025-12

Positional information is a fundamental principle in embryonic development. It describes how cells interpret the concentration of signalling molecules to acquire positional values, which are then interpreted into distinct morphological outcomes. In the classic model, a Sonic hedgehog (Shh) signalling gradient specifies the positional values of the three chick wing digits and four chick leg digits by acting as a morphogen. However, recent work on the mouse limb with five digits suggests that Shh does not act as a morphogen, but instead acts through undefined secondary signalling molecules. In this proposal, we will build upon two major recent advances from our lab: 1) The development of a mammalian-like pentadactyl chick leg model: The chick leg has a phalangeal count in its four digits that has remained stable for over 350 million years. We have developed a chick leg model with five digits that has a mammalian phalangeal count, which can give insights into the underlying mechanisms that caused evolutionary changes in amniote digit patterning. 2) The discovery of a Shh-Bmp2-p27Kip1 pathway in the chick wing: This pathway plays a key role in specifying the identity of digit 3 and inhibiting posterior digit formation, potentially explaining key differences between mammalian and avian digit patterning. We will characterise the digits of the pentadactyl chick leg model to understand how closely they resemble mammalian digit identities. To do this, we will compare the transcriptomic profiles of the digits in normal and mammalianised chick legs with those of mouse hindlimbs, focussing on transcription factors and signalling proteins potentially involved in determining digit identity. We will investigate the involvement of the Shh-Bmp2-p27kip1 pathway in determining digit number in the chick leg and explore whether different Bmp proteins specify its distinct digit identities. We will also determine if this pathway is expressed in the mouse limb to understand if its activity could be responsible for the evolutionary differences between avian and mammalian limbs. The implications of this research extend beyond basic developmental biology. They could offer new insights into limb malformations and birth defects, with potential applications in regenerative medicine and tissue engineering. By unifying different models of digit patterning, this project aims to bridge gaps in evolutionary biology and provide a comprehensive framework for understanding digit reduction and diversification among amniotes. This work aligns closely with the BBSRC Strategic Delivery Plan 2022-2025, particularly its aim of "Understanding the Rules of Life." By investigating how positional information influences digit patterning, we will contribute to a deeper understanding of the fundamental mechanisms that shape anatomy.

UKRI Gateway to Research · FY 2025 · 2025-12

Haemodialysis is an extracorporeal method to cleanse blood by removing metabolic waste. The patient’s blood is pumped through a dialysis module and returned back to the body, while a dialysate solution carries away the waste solutes extracted from the blood through semipermeable membranes. Haemodialysis typically involves 3 treatments a week lasting 3 to 4 hours, a long and costly process. Haemodialysis is critical because more than 850 million people are affected by kidney diseases worldwide, of which 2 million suffer from kidney failure. It costs the NHS 1.05 billion £ in 2023 (about 30,000 patients). There has been limited recent improvement in the science of haemodialysis as the design of haemodialysers has followed an established line of thinking. Our aim is to develop a radical new design that leads to a significantly improved efficiency of haemodialysis. The standard method of improving haemodialysis has been to increase the surface area of the membranes separating the two fluids. Thousands of blood-carrying hollow fibres with diameters as small as 200 microns are used in industrial dialysers. We wish to completely disrupt this traditional disciplinary thinking behind haemodialyser design.  Our radical idea is to introduce active mixing into the flows and not to increase the surface area. As established from the analogous theory of heat exchangers, mixing will enhance the solute removal by a hundredfold. The wall-shear stresses due to mixing will be kept significantly below the level causing haemolysis (destruction of blood cells) and will help remove the solute build-up on the membrane, a recognised issue with current methods that detrimentally impedes an efficient solute transfer. We will tackle this problem by utilising an interdisciplinary combined methodology involving numerical simulations, experiments and real haemodialysis tests. These tasks will be all coordinated and supervised by our highly specialised and complementary team, composed of experts in fluids engineering, renal medicine at the University of Sheffield and the Clinical Lead for haemodialysis at the Sheffield Teaching Hospitals. We will address three objectives: Quantify the role of active mixing in enhancing solute transfer and fluid dynamics through cross-validated simulations and experiments. Design, build and test our novel haemodialyser, using real blood and industrially available dialysate fluid. Verify that our dialyser leads to a more efficient dialysis and meets all safety requirements, i.e. avoiding blood haemolysis and clotting. Our project is of critical importance as it could lead to a transformative change in this area of medicine. The impact of our research will be immense because our radical design will lead to cheaper and faster haemodialysis, drastically improving the lives of millions of patients worldwide. Our impact will be beyond medicine, fluids engineering and physics because a significant enhancement of passive scalar transport will be relevant in other scientific areas, such as food processing, chemical engineering and biotechnology. Our more efficient dialysis system will help sustainability and a greener nephrology because it will lead to reduced carbon footprint and water usage. Part of our dialyser will be re-usable, leading to reduced material usage and related costs.  

UKRI Gateway to Research · FY 2025 · 2025-12

Context: Harms related to gambling behaviour have been found to affect all types of individuals. Gambling harm can negatively affect a persons’ finances, relationships, mental and physical health, employment and education, and risk of engaging in criminal activity. There is evidence that vulnerability to harm differs and that gambling harms are more likely to be experienced by some people, for example by economically and socially disadvantaged groups. Approaches to try to reduce gambling demand (people’s desire to gamble) and restrict supply (where and how often people can gamble), alongside therapeutic treatments (like Cognitive Behavioural Therapy), medicines, and self-help groups exist, but they are not always accessible to everyone. Health inequalities are unfair differences in health outcomes between different groups of people. Inequalities are linked to things like income, geographic location, ethnicity, and social exclusion. Intersectionality examines how these various factors like race, class, gender, and others, combine to create unique experiences of discrimination or privilege. Intersectionality in gambling research examines how multiple social identities and their associated inequalities intersect to shape gambling experiences and harms. The challenge the project addresses: Recent research on gambling harms has been limited to considering impact in specific populations (e.g. neurodiverse, LGBTQ+) rather than considering the differences between specific populations and the issues of intersectionality or relating this to the use of particular types of gambling products. There is a need to bring all of this research together to understand how and why gambling harm affects people differently and  how to best support people to manage their risk. Aims and objectives: We therefore aim to conduct a “rapid evidence review” to find and bring together all the research which can help to answer the following question: “What is the role of both specific individual factors, and the intersectionality of multiple risk factors, in driving inequalities in gambling related harm.” We will: search for academic studies as well as reports from important organisations such as the Gambling Commission, DCMS (Department for Digital, Culture, Media & Sport), OHID ( Office for Health Improvement and Disparities). We will ask experts and public advisors to help us to find evidence. Potential applications and benefits: The rationale for a review looking at intersectionality in gambling harm is the need to ensure that prevention approaches can be appropriately targeted, with tailored prevention and intervention programmes for specific populations, settings or individuals. A thorough understanding of how an individual experiences harm is key to understanding gambling overall, and to developing effective interventions to help people. We will produce a framework of gambling harm factors by gambling type, harm type, and sets of personal characteristics/inequalities, to support further research. We will produce a paper for an academic journal alongside research summaries for researchers and funders, policymakers and public audiences.

UKRI Gateway to Research · FY 2025 · 2025-12

Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions of people worldwide and presenting a critical challenge to healthcare systems, societies, and global economies. AD is typically categorised into two types: early-onset, which occurs before the age of 65, and late-onset, which develops after 65 and accounts for over 95% of cases. With an ageing global population, the prevalence of AD is expected to rise sharply, placing an increasing burden on healthcare infrastructure and creating significant financial strain. Although the clinical presentation and pathological processes in AD can vary widely in severity and affected brain regions, nearly all patients share two defining pathological hallmarks: deposition of amyloid-beta (Aß) plaques and neurofibrillary tangles of tau in the affected brain. Among these, the accumulation of tau correlates more closely with disease severity than Aß, highlighting tau dysfunction as a critical target for understanding and treating AD. The exact causes of late-onset AD remain unclear, but genetic factors play a significant role. The apolipoprotein E (APOE) gene is the strongest known genetic determinant of late-onset AD risk. APOE has three isoforms: APOE2, APOE3, and APOE4. APOE4 increases the risk of developing AD by up to 15-fold, whereas APOE2 provides a neuroprotective effect. Despite these well-established correlation, the molecular mechanisms through which APOE influences tau pathology and contributes to neurodegeneration remain poorly understood. This proposal aims to uncover how APOE influences tau dysfunction to better understand its role AD progression. Using advanced imaging techniques and human-derived models, we will investigate the isoform-specific effects of APOE on tau aggregation, propagation, and associated toxicity at the molecular level. Additionally, we will explore how APOE isoforms modulate tau uptake and inflammatory responses in astrocytes and microglia - glial cells that are crucial for maintaining brain homeostasis but also known to contribute to neurodegeneration in AD. By studying the interactions between glia and neurons, we aim to determine how these processes may exacerbate or mitigate tau pathology in an isoform-specific manner. Finally, we will examine the indirect effects of APOE isoforms on tau pathology mediated by Aß, focusing on how ApoE-Aß interactions influence tau dysfunction in both neurons and glial cells. This research will provide critical insights into the molecular and cellular mechanisms by which APOE isoforms drive tau-mediated neurotoxicity and inflammation. By clarifying how these processes differ across isoforms, the study aims to elucidate the pathways linking APOE to AD risk and progression. The findings have the potential to inform the development of isoform-specific therapeutic strategies, such as modulating ApoE lipidation or targeting specific signalling pathways involved in tau and Aß interactions. The outcomes of this research have far-reaching implications. For basic science researchers, this proposed study will address significant gaps in understanding ApoE-tau interactions in human models system and determine their contribution to AD. For translational science, the human cell models developed in this work, which focus on tau dysfunction, can serve as platforms for drug discovery and screening targeted at tau pathology. Ultimately, for patients and healthcare providers, the long-term goal is to enable more precise diagnostics and effective treatments, contributing to alleviating the global burden of AD.

UKRI Gateway to Research · FY 2025 · 2025-12

About 1.41% of adults worldwide struggle with problematic gambling. These individuals often experience relationship breakdowns, financial difficulties, and mental health problems. Several psychological therapies are used to address problem gambling. However, treatment outcomes can vary widely, including up to 40% of people dropping out of therapy. Therefore, it is important to understand why some people engage and respond better to therapy than others. As with other mental health problems, understanding treatment predictors and moderators can help us do this. Treatment predictors and moderators Most treatment predictors are characteristics that someone has before starting treatment, which influence how well they do, no matter what treatment they have. For example, being female and being of a younger age have been identified as predictors of poorer gambling treatment outcomes. Other predictors (process predictors) are factors occurring after the treatment starts. For example, client-rated therapeutic alliance develops after the therapy has started, and predicts gambling outcomes. In contrast, moderators tell us which treatments work best for which people. For example, gamblers with low and moderate-to-high readiness to change attended either cognitive motivational behaviour therapy (CMBT) or Gamblers Anonymous (GA) meetings. The CMBT group reduced their gambling spending and frequency regardless of motivation level, but only those with a moderate-to-high motivation reduced their gambling in the GA group. Gaps in the Literature There have been only two systematic reviews specifically examining predictors of gambling treatment response. They found that male gender and lower depression scores were the most consistent predictors of successful treatment outcome. However, evidence was generally limited or inconsistent. Neither review identified process predictors, and neither included moderators of outcomes. Therefore, there is limited evidence supporting consistent predictors and moderators of treatment outcome and drop out in gambling. Random-effects and quality-effects meta-analyses are also limited in this field. Quality-effects meta-analyses allow us to determine the differences in outcomes that are due to study quality, thus yielding more meaningful findings.  Variances in study quality are likely to introduce bias and therefore impact meta-analysis results. A comparison between the two types of meta-analyses will be beneficial when evaluating the effect of treatment predictors and moderators on gambling outcomes. Clinical implications Identifying who is more or less likely to do well and remain in treatment is important for improving patient outcomes and reducing rates of relapse. It has the potential to inform the development of new and existing interventions for problem gambling, and to personalise treatment to the individual (e.g., adding modules for people who have additional mental health problems, or matching patients to therapists whose style suits them best). This could make treatment more effective and efficient. Aims of this review The proposed rapid evidence review aims to: 1.      Update the two previous systematic reviews by including evidence relating to predictors and moderators of gambling outcomes and drop-out at different time points (including patient, therapy, and therapist effects, where available). 2.      Conduct a random-effects meta-analysis to estimate how strongly predictors and moderators influence treatment outcomes. 3.      Conduct a quality effects meta-analysis to see whether accounting for the quality of studies impacts the results of the meta-analysis. This will help to identify good practice in delivering high-quality, reliable, and valid research.