University of Bath

UKRI Gateway to Research · FY 2026 · 2026-09

The growth of galaxies in our Universe is regulated by their ability to accrete gas, convert this gas into stars, and expel it back to cosmological scales in large-scale galactic outflows. But how do galaxies launch these outflows? How do they propagate and break out of the galaxy? And what damage, if any, do they inflict on the gas surrounding galaxies? The fact that these questions remain unanswered highlights limitations in galaxy formation theories, posing a pressing concern for our ability to answer the key question: “How do stars and galaxies evolve?” (STFC Science Challenge A5). This project addresses gaps in our understanding of galactic outflows by leveraging cutting-edge numerical models to guide the interpretation of new galactic outflow surveys at cosmic noon (z~2), the all-time peak of star formation in the Universe. Recent advances in spectroscopic instrumentation (e.g. Keck/KCWI, VLT/KMOS) now enable the routine detection of galactic outflows at cosmic noon and the quantification of their energetics across large samples. However, uncertainties remain in inferring how much mass, energy, velocity, and chemical elements are flowing out of a galaxy from emission and absorption lines. Due to the multi-phase nature of outflows, different emission or absorption tracers track different spatial extents, geometries, and energetics, making it challenging to obtain a complete observational picture of outflow energetics and complicating comparisons with theoretical models. This proposal addresses these observational challenges head-on. We will quantify potential biases and known unknowns in galactic outflow observations by leveraging a new suite of cosmological simulations from the Megatron project, in which the PL plays a leading role. These simulations are specifically designed to robustly predict the ionic structure of cosmological, stellar-driven outflows at cosmic noon. Megatron makes two critical theoretical advances: (i) solving for non-equilibrium ionic chemistry and radiative transfer together in a cosmological context to accurately predict ion densities, and (ii) using an outflow-targeted resolution strategy to accurately capture mixing between gas phases. These steps enable direct predictions of the intrinsic emission and absorption properties of galactic outflows for optically thin transitions (e.g. Ha, OIII 5007Å, SiII 1207Å, CIV 1548Å). This project will complement this setup with Monte-Carlo radiative transfer post-processing, incorporating the spectral shapes and shifts of resonant lines (e.g. Ly-a; MgII 2803Å) and accounting for dust re-processing. This will build a complete picture of outflow tracers from the ultraviolet to the optical. Analysing these spectral diagnostics exactly as an observer would, we will quantify how outflow geometry, multi-phase structure, and kinematics bias inferences of outflow energetics at cosmic noon. Our findings will directly inform observations from new surveys on the Very Large Telescope (KMOS, MOONS, ERIS), in which this team is involved. Our findings will also be of interest to other astronomers involved in surveys with similar science cases but covering different redshift ranges, samples, and spatial resolutions (e.g. on MUSE). To maximise impact, all synthetic emission and absorption lines will be made publicly available as part of the Megatron data release, enabling the community to test other spectral inferences unrelated to outflows (e.g. metallicity from emission lines). With project leaders combining world-leading expertise in both numerical and observational galaxy formation, all simulated data in hand by the start of the project, and a skilled RIA to deliver timely scientific analysis, this team is well poised to undertake this high-impact project.

UKRI Gateway to Research · FY 2026 · 2026-03

The space environment has a critical influence on satellite operations, navigation and communication. In Sub-Saharan Africa (SubSA), the space environment poses unique challenges due to the location beneath the region of the ionosphere called the equatorial anomaly. This region of complex physics is prone to disturbances that disrupt satellite signals and adversely impact navigation and communication signals.  These disruptions are called space-weather events.    This collaboration between the University of Bath, the Technical University of Kenya and the Kenya Space Agency addresses the need for building capacity in the space sector in SubSA. The project will deliver research and education that underpins multiple United Nations Sustainable Development Goals.     The value of the space industry to Africa is predicted to be over £18 billion by next year (2026). The Kenya Space Agency has recognised that educational partnerships are essential in creating a highly-skilled workforce equipped to meet the growing demands of the space sector. This project will address their identified priority areas of satellite technology in agriculture, disaster management and environmental monitoring.   Each of these application areas rely on the continuous operation of satellite navigation signals, but there is a problem because these signals are disrupted by space weather.        This project aims to conduct research to support a real-time monitoring system for space-weather across SubSA that will warn about space-weather events that impact the reliable operation of satellite-based services. This will enable the creation of new technologies and systems that can accurately account for threats and improve the reliability and resilience of infrastructure in SubSA. Understanding the physics of the ionospheric region, real-time monitoring, and translation to a user-friendly interface reporting on system impacts are all essential elements. This planned research and development is crucial for unlocking the full potential of space technology and driving economic growth in the region.     This project will have significant benefits for SubSA, including: * Building expertise in space-environment physics and space-environment engineering  * Improving reliability and resilience of critical communications, navigation and timing systems * Increasing safety and efficiency in future transportation and commerce * Transforming awareness and management of space-environmental threats     The project will develop key capabilities that will transform SubSA capacity in space weather:     1. A new generation of trained scientists with expertise in the physics and ability to apply their knowledge about the space environment to satellite-based services. This will be achieved through collaborative research and dedicated workshop events.   2. Enhanced research capability in instrument operation and data analysis to correctly interpret and understand the behaviour of the SubSA ionosphere.  This will be achieved through research underpinning the development of a real-time assimilation system.   3. Translation from physics computer modelling into real world applications, through enhanced expertise and wide user engagement.   Key Personnel include:    Project Lead (UK)– Professor Cathryn Mitchell, University of Bath, UK Project Co-Lead (UK) – Dr Biagio Forte, University of Bath, UK Project Co-Lead (International) - Dr Daniel Okoh, Technical University of Kenya Project Co-Lead (International) - Prof Paul Baki, Technical University of Kenya Project Researcher (International) - Dr. Awuor Ochieng Aderoi, Technical University of Kenya Project Researcher (International)- Mr. George Ochieng, Technical University of Kenya   Project Co-Lead (International) - Mr Joseph Muriithi, Kenya Space agency Project Co-Lead (International) - Mr Harold Safary, Kenya Space agency Project Specialist (International) -  Ms Mary Dusabe, Kenya Space Agency

UKRI Gateway to Research · FY 2026 · 2026-01

Most of us will have to deal with persistent severe pain in our lifetime. When we do, pain can redefine how we see ourselves, our world and our future. Pain can throw us back on our history and affect how we see things going forward. “Can I cope with this?”, “What are my limits?” and “Will it always be like this?” are common questions at the centre of how people grapple with a life in pain. The answers to these questions can provide a sense of control and bring predictability to a future that might otherwise feel limited and chaotic. Our personal history – or autobiographical memory – can shape how we answer these questions, but autobiographical memory is rarely researched in chronic pain. To better understand and help people with pain, we can draw on research in common mental health problems such as Depression where advances have helped us understand how our autobiographical memories can influence our wellbeing: personal memories contribute to our sense of who we are and they offer solutions to adversity; they can remind us of better times and of occasions when we have overcome challenges; they shape how we imagine and anticipate possible future events and the optimism we get from such imaginings; and, they can be shared, creating bonds with others and telling them about our need for help. Difficulties recalling autobiographical memories are common across mental health problems and are associated with a worsening of these problems. Improving autobiographical memory improves mental health. Building on our work in mental health, we propose that how one remembers one’s past and uses it to understand and manage pain is likely to be a core mechanism in the emergence, maintenance and resolution of chronic pain. Through investigations – with particular attention given to recruiting people who are underrepresented in research but overrepresented in pain clinics (e.g., very elderly, obese, those living in rural communities and the poor) – we will answer several important questions Q1: How does pain impact our autobiographical memory? Q2: How does autobiographical memory influence the severity and impact of pain? Q3: How do other psychological (e.g., attention) and social (e.g., support from others) variables influence the association between autobiographical memory and pain? Q4: Can enhancing autobiographical memory be used to manage pain? As so little is known about the role of autobiographical memory within pain, we need to conduct investigations across the entire ‘bench-to-bedside’ spectrum. Accordingly, we will answer these questions in controlled laboratory settings where pain is induced among healthy people (WP1) and out in the world among sufferers of chronic pain by surveying people using their mobile devices throughout their day (WP2). We will then apply and further test this new knowledge by deploying a mobile tool for improving autobiographical memory which has yet to be tested within a pain context (WP3). The validity, feasibility and acceptability of these WPs will be established through concurrent engagement with lived experience experts throughout the lifespan of the project (WP4). This project will provide the most thorough characterisation of autobiographical memory in pain to-date, filling in a significant missing piece in the psychological puzzle of pain. In doing so, it will contribute to the development of an effective, accessible and low-cost tool for resolving the pain that may affect us all.

UKRI Gateway to Research · FY 2026 · 2026-01

The aerospace sector is on the cusp of great change. Aviation accounts for over 2% of global energy-related carbon emissions and with global demand for passenger aviation predicted to grow by more than threefold by 2050, revolutionary designs are needed to tackle the climate crisis and meet Net Zero targets. The UK government has placed liquid hydrogen (LH2) fuel at the core of its long-haul Net Zero aviation strategy. LH2 delivers approximately three times the energy per unit mass of kerosene and 100 times that of lithium-ion batteries, and most significant of all, emits no carbon dioxide when burned. However, LH2 fuel requires larger storage volume compared with kerosene and tanks must withstand extremely low temperatures of -253?, the boiling point of hydrogen. This represents a number of new research challenges. While cryogenic storage tanks for non-aerospace applications are typically metallic, the cost, weight, performance and safety considerations differ greatly compared to a commercial aircraft. Carbon fibre reinforced polymer (CFRP) composites are already used widely in commercial aerospace structures for their high strength-to-weight properties. The potential weight reduction and performance benefit offered by a composite LH2 fuel tank makes it a priority area for development. However, there is limited understanding of composite behaviour at -253?, and in particular, the response to safety-critical extreme dynamic loading events such as impact, hard landing and crash remains unknown at these temperatures. DYNAH2 will deliver the first data on modern composite materials under dynamic loading at LH2 temperatures. Material characterisation experiments will be performed using the unique cryo-cooled split-Hopkinson pressure bar apparatus at the University of Bath. This new data will be used to inform numerical models, capable of capturing the measured temperature and rate dependence of CFRP. In collaboration with Project Partners, GKN Aerospace and the National Composites Centre, DYNAH2 will deliver new understanding of tank design for this safety-critical application. The future of sustainable aviation relies on the safe storage of LH2. Certification of composite LH2 storage tanks cannot occur until the low temperature, dynamic properties are fully understood.  These insights represent strategic importance to the UK economy whose aerospace industry aims to maintain its prominent position during the sustainable aviation revolution. DYNAH2 will contribute to the strive towards safe, clean, affordable and secure energy and transport which will directly benefit the wider public and the environment.

UKRI Gateway to Research · FY 2026 · 2026-01

Characterising cell cycle dynamics is fundamental to our understanding of biology including in cancer, immunology, developmental biology, toxicology, within-host infectious disease dynamics, ageing science and tissue engineering. In the past decade, genetically encoded cell cycle probes have revolutionised proliferation assays in cells and model organisms - allowing live imaging of cell cycle dynamics. RLM’s group previously developed two widely adopted biosensor systems based around Fucci (Fluorescent Ubiquitination-based Cell Cycle Indicator). We have now developed the most sophisticated probeset to date (Quiescence ubiquitination based cell cycle indicator - Qucci) allowing the discrimination of G0, G1, S and G2/M cell cycle phases in cells and mice. However, the impact of these models is hindered because no unbiased mathematically sound methodology exists to extract cell cycle phase lengths, cell cycle times or their distributions from a population of cells using any existing assay. Existing methods of cell cycle analysis rely on either: 1) live imaging of complete cell cycles or the transitions between cell cycle phases; 2) quantification of cell numbers over time to calculate a doubling time or; 3) derivation of the cell cycle time by pulse labelling of S-phase to calculate its length followed by upscaling to the entire cell cycle (classical Thymidine analogue studies). We have implemented method 1 and 2 and extended method 3 to Fucci/Qucci based live imaging data and performed extensive mathematical modelling. Our modelling reveals that; method (1) suffers from both spatial and temporal censoring (unintentional exclusion of some cell subpopulations with particular characteristics). For example, in populations of moving cells, subpopulations with longer cycle times are less likely to remain in the field of view and divide during the imaging period; method (2) suffers from incorrect assumptions on the distribution of cell cycle lengths. Our modelling has shown that populations of cells simulated with the correct distribution will grow more slowly than those with an assumed underlying exponentially distributed cell cycle time but with the same mean. Consequently, this will lead to mischaracterisations when cell cycle parameters are inferred from growth curves; method (3) is flawed because it employs the assumption that the number of cells in each cell cycle phase should be proportional to the length of that phase, which our modelling and experiments have revealed to be incorrect. We now understand the functional form of the underlying distribution of cell cycle times, which will allow us to correct both for spatial and temporal censoring bias and to account for the non-uniformity in the distribution of cells throughout the cell cycle. In this project we will develop the mathematical framework required to correctly calculate both inter-division times and the times of different phases of the cell cycle using any one of these methods. With a focus on live imaging methods, including Fucci/Qucci, we will deliver an open source software package for Imagej/Fiji designed for non-specialist end users. Our software will incorporate  pre-trained neural networks able to classify the cell cycle phases and to automatically extract cell inter-division/cell phase times from time-lapse data generated from legacy Fucci models and Qucci. Using our mathematical framework, the tools we develop will be able to characterise cell cycle times and distributions for a given dataset. Delivering these analysis tools with the ‘gold standard’ Qucci models will have a transformative impact on the biosciences.

UKRI Gateway to Research · FY 2025 · 2025-12

Context Controlling blood sugar levels after meals is an important component of health. Excessive rises in blood sugar levels form the basis for diagnosing diabetes but are also relevant to the general population. Even modestly increased blood sugar levels for a period of time can increase fasting glucose and impair insulin sensitivity and secretion. Understanding postprandial blood sugar regulation is therefore important for the maintenance of health across the lifespan. Controlling postprandial glycaemia even within the generally healthy population, can benefit health and longevity.   Challenge and Opportunity Current nutritional approaches for blood sugar control normally rely on changing foods that are eaten or result in undesirable effects such as increased insulin levels. Our pilot data suggest that adding a small amount (equivalent to just over one teaspoon) of the milk sugar, galactose, can prevent excessive rises in blood sugar levels without compromising on insulin levels. If this is confirmed, and underlying mechanisms understood, this provides a new approach to control blood sugar levels without needing to avoid/substitute preferred foods. People could eat their preferred foods with added low-dose galactose (imperceptible in a meal) for better blood sugar control.   Aims and Objectives This project will establish the degree to which adding low-dose galactose to a meal can control blood sugar levels. People will consume standardised glucose drinks (75g glucose, as an oral glucose tolerance test). People will consume these with and without the addition of galactose, and with the addition of another sugar (fructose) for an extra comparison. We will use state-of-the-art labelling methods (dual stable isotope technology) to follow what happens to the glucose that is ingested and understand what happens to sugar being released by the liver and sugar being taken up by other tissues like the muscles. These methods can tell us how the addition of galactose can control blood sugar levels. For example, the galactose could slow down the appearance of glucose from the gut and/or liver released into the blood, or it could increase the disappearance of glucose from the blood into muscles. We will measure the appearance of our label on exhaled breath, which will establish whether ingested sugar is stored, or burned as fuel. We will also explore other potential ways in which galactose might control blood sugar levels by measuring key hormones and metabolites that contribute to blood sugar control (for example, insulin, fatty acids, and incretin hormones which potentiate insulin secretion). This additional evidence of how galactose can control blood sugar levels will provide the understanding required to best make use of this approach across a variety of settings.   Applications and Benefits The findings from this project will several applications and benefits, including a better basic understanding of the nutritional regulation of blood sugar control. The evidence can be incorporated into public health guidelines and improve population health, and in healthcare settings for targeted nutritional strategies for blood sugar control. The food industry can benefit from this evidence to provide a rationale to produce new food products and novel application of galactose as a functional food ingredient. Furthermore, this novel application can repurpose a by-product of the dairy industry (lactose) into a value-added product, thereby having economic and environmental benefits. This will also train early-career scientists in important scientific methods of nutrition research and product development.

UKRI Gateway to Research · FY 2025 · 2025-11

Our proposed Policing Academic Centre of Excellence (P-ACE) brings together multi-disciplinary expertise from across the University to provide a fast-track, two-way knowledge mobilisation platform between police and academia. Specifically, with P-ACE funding, we will bring together University of Bath's leading scientists across psychology, management, digital security and behaviour, health, criminology, mechanical engineering, and computer science to collaborate with a diversity of policing partners, both existing and new, in an innovative way to address policing challenges. We have substantial expertise across the selected ARI, with particular strengths in responding to the climate crisis, public perceptions and trust, crime prevention and safety in both online and offline spaces, workforce wellbeing, vulnerable interviewing, surveillance, data and analytics. We plan to unite, formalise, and build upon this expertise so we can provide an excellent and agile response to identified policing needs, via the dissemination of existing or creation of new collaborative research and knowledge exchange projects. Our aims are: To develop our existing expertise into operationally useful tools and training while also cultivating a dynamic network of our academic and policing partners to develop a shared vision between academia and policing. To identify and facilitate placement opportunities between police and academia to support professional development and an embedded culture of two-way KE between our academic and policing communities. With careful deployment of the flexible fund, we will ensure the co-creation of new research that responds to the needs of modern policing. Ultimately, our goal is to establish ourselves as a world-leading centre of academic excellence for policing, working alongside the other P-ACEs to unite our diverse research expertise, whilst also collaborating with both existing and new policing networks to ultimately develop, deliver and translate a robust evidence base across the ARI. With specialised KE support from our appointed KE facilitator and oversight from our advisory group, we will ensure that our objectives are realised and that our world-leading research at Bath is synthesised and shared with relevant policing partners. We will employ a KE facilitator who has prior expertise in presenting research to practitioners and policy makers, ensuring that the initial months of the P-ACE have parallel processes of a) translating our existing knowledge and expertise into practice while b) beginning the conversations about the longer-term research programme. We have an expanse of existing resources at Bath, in the form of institutes and centres, KE and policy specialists, and dedicated Knowledge Transfer Partnership (KTP), consultancy and research support teams, which we will leverage to ensure our objectives are met. The vision and values of our proposed P-ACE align with those of the University of Bath more broadly, notably in delivering excellence and working in partnership, supporting a sustainable community, and fostering inclusion, equality and diversity. Indeed, a core aim of the University is to develop centres of expertise in collaboration with partners to address national needs. Thus, given our expertise, networks, vision and values, the University of Bath is ideally placed to host a Policing Academic Centre of Excellence.    

UKRI Gateway to Research · FY 2025 · 2025-11

Heat stress occurs when the body absorbs more heat than it can release, leading to serious health issues such as dehydration, heat exhaustion, and potentially life-threatening heat stroke. It is an increasingly pressing concern in workplaces, as it impairs workers' physical and mental abilities, resulting in fatigue, slower reaction times, and reduced productivity. In 1995, global productivity losses due to heat stress were equivalent to 35 million full-time jobs. By 2030, this figure is projected to rise to 80 million, driven by increasing temperatures and climate change. A such, the risks associated with heat stress not only affect the health and well-being of workers but also have a global impact on businesses, creating significant barriers to economic growth. Workers in sourcing destinations for UK companies, particularly in heat-prone regions such as South Asia, Western and Central Africa, and Southeast Asia, are especially vulnerable. Existing labour rights and occupational safety guidelines often provide general advice but fail to address the specific needs of workers dealing with heat stress in supply chains. Consequently, access to Heat Stress Protection (HSP)—which requires both preventive measures (e.g., hydration, rest, shade, nutrition, ventilation) and effective remediation (e.g., treatment, social security, scheduling)—remains severely limited for many workers in these environments. Additionally, there is limited knowledge about how access to HSP affects productivity, broader labour rights, and workers' overall lives. The project, developed in consultation with policymakers, businesses, civil societies and workers, will develop a practical, worker-focused holistic framework to improve access to HSP in supply chains. It will focus on the unique challenges workers face and provide actionable solutions in four key areas: How workers manage heat stress in their daily lives. The workplace, supply chain, and institutional factors that affect access to HSP. Links between access to HSP, labour rights, and dignity at work. The relationship between access to HSP and worker productivity. Using an ambitious research design, qualitative fieldwork will be conducted in the UK’s rice supply chain in India, with research conducted in two types of workplaces in the same supply chain: a) outdoor sites: rice farms and b) indoor sites: processing mills. The framework for HSP in supply chains, developed through rigorous research with input from various relevant stakeholders will: Improve workers’ health, safety, and dignity and overall quality of life. Provide groundbreaking research and actionable insights for academics across disciplines interested in labour rights, inequalities, climate change and sustainable supply chains. Help businesses cut health-related costs, boost productivity, and build sustainable supply chains, positioning UK companies as global leaders in managing heat stress. Offer policymakers evidence-based recommendations to support sustainable growth and improve safety standards of UK companies and their supply chains. Support civil society and multilateral institutions in advancing labour rights, climate resilience, and economic development, aligning with global initiatives focused on achieving a Just Transition. By improving access to HSP in supply chains and developing on-the-ground solutions tailored to workers' real experiences, this project aims to safeguard workers, strengthen businesses, and contribute to a fairer and more sustainable global economy.

UKRI Gateway to Research · FY 2025 · 2025-10

During this Fellowship, I will develop a research proposal for a future large-scale project exploring the societal impact of new weight-loss medications and the transformation of human conditions into targets for pharmaceutical intervention (known as ‘pharmaceuticalisation’). Obesity is one of the UK’s most pressing public health issues – in 2022, 64% of adults in England were overweight or obese. Now, a new generation of weight-loss drugs is reshaping the treatment landscape. These medications have been hailed as breakthroughs, helping patients lose up to 20% of their body weight. But behind the hype lies a bigger question: who really benefits from this transformation – patients, the NHS, or drug companies? These drugs are entering a highly commercialised healthcare environment, raising serious concerns about how public health priorities may be shaped by corporate profit motives. Companies are increasingly using sophisticated marketing strategies to increase prescriptions, from digital pharmacies, influencer advertising, and may even directly market drugs to patients, which is illegal in the UK. These activities are outpacing regulatory systems designed to safeguard patients. While most research has focused on how these drugs work, much less attention has been paid to their wider social and political consequences. My doctoral research uncovered evidence of unethical pharmaceutical practices, resulting in a formal complaint upheld by the industry watchdog, highlighting the urgent need for greater scrutiny. Building on this, I will consider methods to explore how weight-loss drugs are promoted to patients, doctors, and policymakers, and what this means for public trust, narrative shaping, and the commercialisation of healthcare. These questions are tied to broader debates about the Americanisation of UK healthcare, including the rise of direct-to-consumer style advertising; how patients’ bodies are presented and financialised through emerging and traditional forms of marketing; and whether individualised medical solutions can meaningfully address a systemic public health issue – or risk deepening weight stigma and widening inequalities. This Fellowship will also focus on the role of patient advocacy. Using a globally unique dataset developed during my doctoral studies, I will analyse over a decade of pharmaceutical industry payments to UK patient organisations. This will explore how financial relationships may shape patient organisations’ advocacy, discourse, and activities – particularly in the lead-up to major obesity drug launches. I will track the evolution of funding patterns over time, uncovering how advocacy can be both empowered and constrained by industry ties, and what this means for public trust, organisational independence, and health policy agendas. To support this work, I will undertake advanced analytical training, publish an influential research article, and translate my findings into accessible formats. To ensure my work informs wider conversations around transparency and accountability in healthcare, I will also lead a programme of public and policy engagement. This will include targeted collaboration with media, policymakers, patient organisations, and healthcare providers to ensure my research findings inform public debate and policy development. I will offer expert commentary to ongoing government and parliamentary consultations on transparency in pharmaceutical funding and ethical marketing practices. By the end of this Fellowship, I will have submitted a compelling and innovative future research proposal, published a high-impact research article, and helped shape conversations around pharmaceutical transparency, patient advocacy, and the ethics of industry-driven health solutions. At its heart, my work is about protecting public health from undue corporate influence.

UKRI Gateway to Research · FY 2025 · 2025-09

Diophantine equations are polynomial equations where one seeks solutions in the whole numbers or rational numbers. These are an important area of research, with Andrew Wiles’ 1995 solution of Fermat’s Last Theorem one of the crowning achievements of 20th Century Mathematics. Originally viewed as a curiosity from antiquity, they have found spectacular applications to modern society through cryptography. Trying to solve an individual Diophantine equation can be very challenging. Things get even more interesting when one has a family of Diophantine equations, given by varying coefficients. Here is the challenge to study the distribution of equations with a solution. My research project will focus on problems of this type. In the first part of the fellowship I introduced a new conjectural framework for problems of this type. The renewal will focus on expanding upon this framework and proving new cases of it. This will involve combining tools from algebraic geometry and analytic number theory, which lie in very different parts of the mathematical landscape.

UKRI Gateway to Research · FY 2025 · 2025-09

By 2040 home is expected to overtake hospitals to become the second most common setting for death in England and Wales (Bone et al, 2018). As the preferred place of death for most people and often used by service providers as a proxy for a ‘good death’, evidence on the impact of housing on dying at home and the provision of domiciliary end of life care services is limited. This is particularly the case for those living in urban poverty (Rowley et al, 2021) who are more likely to experience smaller homes, overcrowding, poor living conditions, and precarious rental tenancies. Despite this ‘home’ as a conceptual good at the end of life is rarely interrogated. It is critical to understand the significance of home and the impact of housing in order to arrive at meaningful, efficient and cost-effective delivery of end of life services, and it is ever more pressing for patients and their families given the relationship between housing conditions, health, and illness trajectories (Institute of Health Equity, 2020). There have been calls for more attention to be paid to the impact of housing on dying (for example Local Government Information Unit, 2012) including from a recent ESRC-funded study of social deprivation at the end of life in Scotland (see Quinn et al, 2023). In addressing this knowledge gap, this study will make distinctive interdisciplinary contributions to theory, policy, and practice from historical, social, clinical, and policy perspectives. Split across four internationally leading research centres, its objectives are to: Provide a detailed analysis of the history and evolution of policy on dying at home since the 1970s, to understand how the concept of ‘home’ is deployed in this policy narrative and why this outcome has come to dominate the end-of-life policy and practice landscape; Identify the meaning of ‘home’ and the role and impact of housing type and tenure on dying at home, from the perspective of patients and family members living in urban poverty and service providers; and Establish thorough stakeholder engagement throughout the conceptual, empirical and analytical phases, and make recommendations that recognise the distinct values attached to the concept of home and the impact of housing type and tenure on decisions made with regard to location of end-of-life care for people in urban poverty. We have four work packages to meet these objectives. Work package (WP) 1 is an archival analysis of policy on dying at home, exploring the values assigned to ‘home’ as a desired location at the end-of-life. Commencing six months later and taking place concurrently, WP2 and WP3 will examine dying and the provision of end-of-life services across housing types and tenure in two areas of urban poverty in England. Bringing together the policy analysis and empirical components of the project, the final work package will synthesise and analyse data thematically to make recommendations for policy and practice, identifying potential for improvements in home-based end of life care services, health and social care commissioning and the management of housing in areas of urban poverty. The study will thus present the opportunity to address critically the prevailing narrative that dying at home is a proxy for a ‘good death’ and the extent to which housing in areas of urban deprivation delivers a home in which people can die comfortably and with dignity.

UKRI Gateway to Research · FY 2025 · 2025-09

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

UKRI Gateway to Research · FY 2025 · 2025-09

Each cancer patient has a unique combination of proteins that promotes the growth of their tumour. In personalised medicine, these proteins are identified, and a drug that inhibits their function is administered to the patient. Though this approach is often highly effective, and results in less side effects compared to standard chemotherapy, it only works for 10% of patients because drugs for most cancer proteins are lacking. Many of these proteins are deemed ‘undruggable’ as they function through protein-protein interactions (PPIs), which are difficult to disrupt with small molecules as interfaces are typically void of binding pockets. Undruggable proteins possess reactive hotspots that can be targeted with covalent inhibitors. Covalent inhibitors permanently inhibit the function of an undruggable protein by forming an irreversible bond at a hotspot. Identifying a covalent inhibitor that selectively targets an undruggable cancer protein while leaving proteins present in our healthy tissues unmodified is a difficult process. If a drug lacks selectivity it can cause severe side effects for patients. In this fellowship, I will develop a technology platform to enable millions of targeted covalent macrocycles (TCMs) to be rapidly generated and screened against undruggable protein targets. TCMs are particularly suited to inhibiting undruggable proteins as they have the combined properties of a peptide macrocycle and a covalent inhibitor. They bind to shallow PPI interfaces with high affinity and selectivity by forming interactions over a large surface area and achieve irreversible target engagement by modification of a proximate hotspot. Crucially, I will incorporate molecules into my library that selectively target tyrosine hotspots as these are highly enriched at PPI interfaces. To prototype my platform, I will identify a TCM that modifies tyrosine 82 on Ras-like protein (RAL) and blocks interaction with guanine exchange factors (GEFs). RAL-GEF PPIs promote pancreatic cancer progression through multiple mechanisms but are considered undruggable as they lack binding pockets for small molecule engagement. There is an urgent unmet need for new treatment options for pancreatic cancer patients as they have only a 1% chance of surviving for more than 10 years after diagnosis – a statistic that has remained unchanged for four decades. Consequently, a RAL-selective drug could be highly beneficial to this patient population. Ultimately, this work will enable selective inhibitors to be rapidly identified for a variety of undruggable proteins, which in the long term will allow more cancer patients to benefit from personalised treatments.

UKRI Gateway to Research · FY 2025 · 2025-09

Today’s power networks are largely preconfigured and rigid, limiting their ability to adapt to a large influx of renewables, low carbon technologies, and emerging threats.  Recent events, from price hikes to supply outages in Spain and Heathrow show such rigid systems carry high costs and risks.  What is required are efficient and agile networks that allow millions of intelligent devices and subsystems to work together to deliver energy affordability, resilience and net zero. However, the existing analytical approach to network operations and investment  seeks optimal solutions and assumes datasets are both perfect and widely available. This approach is not scalable to  millions of new devices with incomplete data, nor the growing complexity and uncertainty. The aim of this research is to introduce artificial intelligence technologies (AITs) at scale to support network operators to develop two crucial capabilities, enhancing network agility and flexibility to achieve high speed and accuracy in their decision making to:  cope with a vast combinations of possible network links, mass flexible devices and their dynamic interactions; allow energy network operators to make intelligent decisions, both for short-term operations and long-term development, with agility and confidence.   Whilst AITs offer promising potential for energy system challenges, much machine learning technology is predicated on the future looking like the past.  For the rapid decarbonising energy system, the future will be very different. A simple injection of AITs will not meet the needs of a highly dynamic and rapidly changing energy sector. Key AI challenges in this project are both to drive wide adaption of AI and to develop new generation of AIT developments fit for a rapidly changing system.  The objectives of this project are: 1. To lay the foundation to build the critical interdisciplinary collaborations to drive cutting edge research at the intersection of energy networks and AI, to drive wider adoption of AI capabilities and identify fundamental development in novel AITs that are required to address rising complexity, scalability and uncertainty in network operation and investment. 2. To develop research infrastructure to speed up the embedding of AI as a research tool in a fair, collaborative and inclusive way, complementing UKRI’s ongoing work in cutting-edge energy network research.  3. To develop a data sharing infrastructure for increasing the use, access, and awareness of data sets for use with AITs, that come with detailed provenance records to support frontier AI progress and greater use of AI in a broad spectrum of energy network research.  4. To drive the application for agile network operation and investment across local, regional and national scales and over operation and investment time frames. This project will position the UK to be the world leaders in agile network operation and development through bringing together AI Community, laying the foundation for the community to come together to build our strong foundation, transforming  energy networks’ efficiency whilst substantially enhancing its ability to withstand future risks and shocks. 

UKRI Gateway to Research · FY 2025 · 2025-09

Ketogenic diets, which limit digestible carbohydrate intake to less than 50g per day, induce ketosis by producing ketone bodies from the breakdown of fatty acids and amino acids. While recognised as a therapy for epilepsy and increasingly used for various neurological disorders and conditions like type 2 diabetes, ketogenic diets have also gained popularity among healthy adults. However, one of the negative consequences from consuming a ketogenic diet is an increase in circulating LDL cholesterol (LDL-C) concentrations, which increases the risk of cardiovascular disease. One potential explanation for the rise in LDL-C during nutritional ketosis is changes to the gut microbiome. Our preliminary data indicate that ketogenic diets, which are typically low in fibre, reduce the diversity of gut microorganisms and decrease the abundance of specific genera, such as Bifidobacterium. Animal studies have demonstrated the crucial role of gut microbiota in host cholesterol metabolism, and thus changes in gut microbial composition and activity could explain the increase in LDL-C in humans consuming a ketogenic diet. Dietary supplementation with prebiotics and probiotics can modulate gut microbial composition and activity. Prebiotics are substrates that selectively support the growth of beneficial microorganisms, whereas probiotics are live microorganisms. When pre- and probiotics are consumed in combination, these are referred to as synbiotics. In mice fed a high fat diet, treatment with prebiotic fibre and probiotics maintains gut microbial composition and reduces cholesterol concentrations. In humans with chronically elevated cholesterol on a non-ketogenic diet, treatment with a synbiotic reduced LDL-C. Thus, we hypothesise that synbiotic supplementation will maintain gut microbial composition and mitigate against the negative effects of a ketogenic diet on LDL-C. To investigate this hypothesis, we will conduct a 12-week randomised controlled trial (RCT) in men and women (Synbiotic versus Placebo, N=64). We will examine the effect of synbiotic treatment (Polydextrose & Bifidobacterium animalis subsp. lactis B420) on LDL-C concentrations and lipoprotein profile using NMR spectroscopy. Gut microbial composition will be characterised using metagenomic analysis. We will use validated biomarkers to assess cholesterol and bile acid synthesis, and stable isotope techniques to examine cholesterol absorption. To examine dynamic changes, including metabolic handling of the prebiotic (polydextrose), we will examine postprandial fermentation (expired H2/CH4) and circulating concentrations of short chain fatty acids (SCFAs) and bile acids, including interconversion of 13C-labelled polydextrose into systemic SCFAs. We will examine distal effects of synbiotic treatment in adipose tissue biopsies taken in basal conditions and 6h after meal ingestion, and we will use in vitro approaches to interrogate key pathways, including experiments using media conditioned with ex vivo serum from our human RCT (e.g., fasted/fed). This collaboration is an Industrial Partnership Award (IPA) that arose from activities coordinated by the BBSRC-funded ORIC hub INFORM. The industrial partner (IFF) has agreed to make a £107,000 cash contribution. They will also make a substantial £120,000 in-kind contribution through (i) the provision of pre- and probiotic supplements, (ii) the manufacture of isotopically-labelled polydextrose, and (iii) access to their laboratories and technical platforms to measure short chain fatty acids and bile acids. This project will establish whether synbiotic treatment prevents a ketogenic diet from increasing LDL-C. In addition to characterising key mechanisms and distal effects on host metabolism, this research will lay the foundation for new strategies and products to help people to get the benefits of ketogenic diets more safely.  

UKRI Gateway to Research · FY 2025 · 2025-09

Appropriate preservation of historic buildings is essential to ensure resistance to deterioration from the changing climate and pollution.  Repair approaches must support net zero and carbon savings, in line with policy across local and national government, ensuring historic places retain a sustainable future.  Understanding moisture movement is paramount as both vapour and liquid water may detrimentally affect the condition and durability of natural organic, metallic, stone, and lime (mortars and renders) to weathering. The exterior envelope protects the masonry and a range of traditional and modern finishes – paints and coatings – are marketed for conservation, all claiming to offer vapour permeability, aesthetic appeal, and waterproofing.  Empirical evidence of early failure, or even increased deterioration of the fabric, suggest that these parameters may not identify what defines a coating that will preserve historic substrates effectively, and their performance is not well understood. The urgency for research is highlighted by the large number of historic buildings suffering from damp problems and associated deterioration, further exacerbated by inappropriate interventions, and changing climate patterns. We propose to address the substantial gap in knowledge through multidisciplinary PhD research between Historic England and University of Bath.  The strong track record of collaboration spanning over 14 years, outstanding supervision, state-of-the-art laboratory facilities, and links to industry stakeholders, will ensure effective dissemination and high impact.  Historic use of paints and coatings will be investigated to provide practical recommendations based on historical knowledge and robust experimental data. Through five interlinked work packages, including clear research questions, the student will investigate methods for assessing moisture transfer, establishing new methodologies for the study of durability and performance of paints and coatings on masonry and render, and their impact on the rate of building substrate deterioration.  These will form the foundation on which to investigate how the paint impacts on moisture transfer or buffering, and this in turn affects thermal properties which are essential in keeping a building warm.  Investigations will then be extended to the effect on the fabric of paint removal and repainting, layer compatibility and performance as a system, and paint application and drying processes which are commonly encountered by practitioners on site. The research will entail a close collaboration with built heritage professionals and craft practitioners, involving heritage sites with field tests; the outcomes will directly support Historic England policy and technical guidance on the topic, and benefit the wider conservation industry.

UKRI Gateway to Research · FY 2025 · 2025-09

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

UKRI Gateway to Research · FY 2025 · 2025-09

The FINTRANS-UK project tackles one of the most pressing issues of our time: financing the Green Transition. This transition involves significant changes to housing, mobility, infrastructure, and our consumption and production patterns. While we have a broad understanding of the technical steps needed, the crucial question remains: how do we finance these changes? Historically, the British state has used off-balance-sheet fiscal agencies (OBFAs) to fund large-scale transformations, such as wars and post-war reconstruction. These agencies, which include national development banks and government-sponsored enterprises, operate outside the government’s main balance sheet, providing the necessary fiscal flexibility without directly impacting national debt or budget deficits. Despite their importance, OBFAs are often overlooked or misunderstood in academic literature. The FINTRANS-UK project aims to shed light on the historical use of OBFAs and explore how these mechanisms can be applied to the current challenge of decarbonising the UK economy. By examining past instances where OBFAs were used to finance significant transformations, the project seeks to develop a comprehensive understanding of their role and effectiveness. The project has three main objectives. First, it will map and analyse the historical use of OBFAs in the UK over the past century, focusing on their role in financing large-scale transformations. This includes creating a detailed database and visual representations of these agencies and their impact on the UK’s monetary and financial systems. Second, the project will explore how the introduction of OBFAs has altered the UK’s monetary architecture. By understanding these changes, the project aims to provide insights into how similar mechanisms can be used today to support the Green Transition. Finally, the project will develop a policy proposal for using OBFAs to finance the Green Transition in the UK. This proposal will be based on historical insights and contemporary needs, offering practical tools for policymakers in finance ministries and treasuries, financial market participants working in the climate finance field, as well as the wider audience interested in or concerned by the challenges posed by the Green Transition. The potential benefits of this project are significant. For policymakers, it provides both a historical context and actionable strategies for leveraging OBFAs to finance decarbonisation efforts, addressing the need to achieve environmental targets while managing fiscal constraints. For financial institutions, it offers insights into the potential of OBFAs to mobilise private capital for sustainability goals. For the public and research communities, it enhances understanding of innovative financial mechanisms and their ability to drive large-scale societal transformations. In summary, the FINTRANS-UK project is highly relevant for stakeholders in economic policy, financial markets, and environmental sustainability. By offering a novel approach to financing the Green Transition, the project draws on historical lessons to develop practical, forward-looking solutions that address contemporary challenges in policy and practice.  

UKRI Gateway to Research · FY 2025 · 2025-09

This research lies in the area of probability theory, specifically discrete probability, and the main focus is on the development of rigorous mathematical tools to analyse spin models, which arise in mathematical physics. Spin models are primarily used to explain the observed phenomenon whereby the strength of magnets gradually decreases as the temperature increases, eventually dissipating when a critical temperature is reached. Mathematically, spin models are defined as complex systems comprising multiple microscopic magnetic components known as spins, which interact with one another. Each spin has a random orientation and magnitude whose values are constrained by a potential. Despite the wide range in the choice of the potential, these models often exhibit similar large-scale behaviour, and are, therefore, said to belong to the same Universality Class. The Ising model, the most prominent among spin models where spins have only orientation, is considered universal for a wide class of models. Its study has flourished over the last few decades due to its fundamental link with the seemingly unrelated area of percolation theory, which models how fluids flow through a porous medium. This link allows relating important objects of interest in the study of the Ising model, such as its correlation functions, to geometric percolation objects, and has led to several recent breakthroughs in the understanding of its critical behaviour. The proposed research programme will make a major contribution to solving the long-standing problem of establishing that the large-scale behaviour of the Ising model is universal. Despite the impressive progress mentioned above, existing results rely to a large extent on delicate properties of the Ising model specifically, and therefore showing their universality remains elusive. Our strategy will be to focus on some of the most fundamental examples of spin models, which share essential similarities with the Ising model, but lack some of the particular properties that facilitated many of the results on its critical phenomena: the f4 and Blume-Capel models. Their study poses new challenges due to the presence of spins that have both orientation and magnitude. This leads to exciting new features which are observed by a wide variety of spin models. More specifically, the concrete objectives, all tied together by the overarching goal of determining the large-scale behaviour of spin models, are outlined as follows: - I will prove the exponential decay of truncated correlations at large scales in the whole supercritical phase. - I will show the large-scale decay of correlations at the critical temperature in dimension 2 and deduce that the magnets lose their magnetisation. This extends the result obtained in my recent work in dimensions 3 and above. - I will establish that the Pfaffian structure of the correlations of the planar Ising model is universal at large scales. A key tool for accomplishing these objectives will be the novel percolation representations introduced in my recent works, which lay the foundations for analysing these models. These representations enable the use of well-established percolation machinery in new contexts. Furthermore, the proposed approach will utilise the close connection with the Ising model to import cutting-edge techniques pivotal for the recent developments in its study.

UKRI Gateway to Research · FY 2025 · 2025-09

This research aims to develop a new type of material that can store hydrogen in a safe and efficient way at near-room temperature. Hydrogen is a clean and renewable energy source, but currently, it is difficult to store and transport in large amounts. By using a combination of two different materials, we aim to create a high-capacity storage material that can be used in hydrogen fuel cell systems, which are a type of clean energy technology. We will use advanced techniques to understand how this new material works and how to improve it. The goal of this research is to make hydrogen a more practical and accessible energy source, which would have a positive impact on the environment and energy system. This project has the potential to create significant advancements in the hydrogen value chain and have global implications for the future energy system.

UKRI Gateway to Research · FY 2025 · 2025-08

Context: Developmental Language Disorder (DLD) is one of the most common neurodevelopmental conditions, but it is relatively unknown and often goes undiagnosed. DLD results in significant functional communication challenges across the lifespan in the face of no known biomedical condition (e.g., hearing loss or Autism) [1], and has been consistently estimated to affect 7% of the population [2, 3]. However, only 39% of children with DLD (identified via population screening methodology) had been referred to speech and language therapy (SLT) for diagnosis and support [2]. Consequently, a substantial proportion of individuals with DLD reach adulthood without diagnosis, not receiving the necessary access to support, resources, and reasonable adjustments needed to thrive. Accordingly, undiagnosed language disorders are associated with significantly higher rates of academic underachievement, difficulties in accessing further education, mental health conditions, emotional and behavioural disorders, criminal behaviour, and unemployment [4-8]. Opportunity: Accommodating and supporting individuals with neurodevelopmental conditions (including those with DLD) is increasingly important in further education (FE) institutions and is mandated by law [9]. However, effective support can only be provided if disability services can accurately and efficiently identify DLD in students, which may have previously gone unrecognised. While FE institutions regularly recognise and accommodate dyslexia, ADHD, and Autism diagnoses, awareness of DLD within these institutions is often lower. Our project will address this challenge, through developing tools and guidance that will enable effective identification and support of FE students with undiagnosed DLD. Objectives: We will evaluate and validate a short screening tool to effectively identify students with undiagnosed DLD in FE institutions. We will determine whether the screening tool can differentiate adults with DLD from adults without DLD, as well as autistic adults and adults with dyslexia. We will also establish whether the screening tool can identify previously undiagnosed DLD in FE students seeking disability assessments. We will then explore the experiences and support needs of FE students newly diagnosed with DLD, and the current knowledge of DLD and support available within FE disability services. This will support our final objective of co-creating video and printed materials with students with DLD to guide both students with DLD and disability services. These materials will provide support at the point of diagnosis and help disability services determine the optimal support for students with DLD. Applications and Benefits: Validating a screening tool to identify missed cases of DLD in adulthood has important applications and benefits for both individuals and educational institutions. For instance, individuals may benefit simply from having much clearer insights into their own strengths and weaknesses. They may also be empowered to seek reasonable adjustments in future contexts (e.g., workplaces). This research has practical applications through the creation of FE education guidance for how best to support and provide reasonable adjustments for adults with DLD. This would facilitate a better understand of DLD in adult education institutions, helping adults with DLD to thrive by acknowledging and adjusting for their neurodivergent needs. However, the applications and benefits of this research go far beyond the FE sector. The adult DLD screening tool could be validated and used with other adult populations, such as individuals with mental health conditions, individuals in prisons and the unemployed, where identifying undiagnosed DLD is particularly important, as well as in research as an efficient method for identifying adult DLD samples.

UKRI Gateway to Research · FY 2025 · 2025-08

Peer review is at the core of the scientific process, where manuscripts are typically written up and submitted for publication once the results are known and the study completed. Decisions of authors, reviewers, and editors at each stage of the review process have been shown to favour positive results, erroneously conflating positive results with scientific merit. This publication bias is pervasive and corrosive. It skews the evidence base, undermines trust in science, and distorts policy decisions. We propose to address this by evaluating an alternative model of scholarly peer review. We have proposed a two-stage peer review process, results-free peer review (RFPR), where manuscripts are initially reviewed, and a decision to publish is made, based on their introduction and methods without the results. In the second stage, the results and discussion are reviewed for revisions only. This approach aims to reduce bias by focusing decisions of whether to publish on the study's scientific merit de-coupled from the results, incentivising authors to publish high-quality null studies. Working in partnership with diverse publishers (commercial, non-profit, learned society), we aim to test the hypothesis that RFPR will increase methodological quality and null studies in the published literature. A further aim is to investigate the feasibility and acceptance of RFPR among authors, reviewers, editors, and journals, to develop actionable policy recommendations.  We will achieve these aims through the following objectives: In partnership with several leading academic journals, we will conduct a randomized controlled trial (RCT) to determine the effectiveness of RFPR as compared to standard review for reducing publication bias. We will also assess how acceptable it is to reviewers, editors, and authors, and how easy/hard it is for journals to implement. In a controlled experiment, we will investigate the cognitive mechanisms underlying biased decision-making during peer review, manipulating the presentation of methods and results and tracking the reviewer’s attention via their eye movements. We will generate actionable policy recommendations and instructional resources engaging with publishers, editors, reviewers, and authors. The PRIME project is international in its ambition; peer review is universal. This work would provide much-needed direct causal evidence of whether RFPR can reduce publication bias in practice. It will directly inform journal publication policies. If our hypotheses are supported, it could pave the way for standard review to be replaced with RFPR review. If not, then we can rule out RFPR as an easy solution to publication bias and use the uniquely rich datasets the PRIME project will provide to unpick why. Basing publication decisions on the quality of the scientific methods aligns the incentives for the researchers’ career advancement with those for rigorous research, getting at the very heart of the reproducibility problem.

UKRI Gateway to Research · FY 2025 · 2025-06

Protein-protein interactions (PPI) govern essential biochemical processes in all living organisms, and dysregulation of PPIs are linked to numerous diseases including cancer, autoimmune and neurodegenerative disorders. Consequently, modulating the interactions between proteins is essential for unlocking new therapeutics. However, 85% of all proteins are currently considered “undruggable” by the two major classes of therapeutics: Small molecule drugs are cheap to produce, can enter cells, but have limited ability to influence PPIs due to their small size. On the other hand, antibodies show excellent engagement to target proteins, but its large molecular size limits entry to cells preventing access to many therapeutically relevant targets. Cyclic peptides are strings of amino acids arranged in a circular pattern. Relative to most drugs, they have an intermediate molecular size (1-3 kDa) which allows entry into cells while showing strong target engagement. Cyclisation also confers structure and resistance to biological breakdown, and therefore cyclic peptides are an emerging class of therapeutics offering access to the undruggable 85%, attracting significant interest from researchers in academia and the pharmaceutical industry. However, cyclic peptide production is challenging. Existing methods employ toxic and unsustainable chemicals which limits development of cyclic peptide drugs. Machinery to produce cyclic peptides exist in nature, in tropical flowering plants such as the Butterfly Pea, which produces cyclic peptides as a defence mechanism against pests. During my fellowship, I will reprogram a harmless gut bacterium to mimic nature and produce cyclic peptides inside live cells, and therefore create a bio-based technology to generate a step change towards a high yielding, clean and green cyclic peptide production methodology that shifts away from toxic and unsustainable chemicals. Additionally, the bacteria will be programmed to rapidly sift through millions of cyclic peptide sequences to select the one that is best at engaging the drug target. I will use the engineered bacteria to identify cyclic peptides that target cancer causing proteins which are historically considered “undruggable” and deliver several leads with the long-term goal of developing into new cancer therapeutics.

UKRI Gateway to Research · FY 2025 · 2025-06

Context: Antimicrobial resistance (AMR) is a prevalent and increasing global health threat; 1.3 million deaths were directly attributed to AMR in 2019, with 4.95 million deaths associated with resistance. Klebsiella pneumoniae (Kp) is a Gram-negative pathogen classed by the World Health Organisation as critical priority, responsible for severe global infections and a top 3 pathogen for AMR-related deaths worldwide. ß-Lactams, the most prescribed antibiotic class worldwide, kill bacteria by binding and inhibiting Penicillin Binding Proteins (PBPs). ß-Lactam resistance can be conferred by ß-lactamases (BLAs), enzymes evolutionarily related to PBPs that inactivate the antibiotics, threatening their continued clinical efficacy. Challenge: We require new antibiotics and BLA inhibitors. Discovery, development and optimisation of new antimicrobial therapies is guided through understanding the complex ß-lactam action and resistance landscape. ß-Lactam:BLA inhibitor combinations are validated routes to overcome AMR through successful inhibition of PBPs and BLAs. However, old drug combinations are failing in clinic due to the rise in AMR, requiring informed new approaches to outsmart resistance. PBPs are a large enzyme family with myriad roles in cell wall biosynthesis to include glycan chain polymerisation and cross-linking. They differ in affinity, structure and function across and within bacterial species. Kp PBPs are poorly characterised and of clear importance to understand at a fundamental biochemical level to develop efficacious Kp treatments (antimicrobial developments). Aims and objectives: I will utilise an interdisciplinary suite of approaches in microbiology, biochemistry, structure, and computational simulation on Kp PBPs, BLAs (and variants) to: Identify key factors governing ß-lactam antibiotic affinity, selectivity, and resistance. I will visualise protein structures of PBPs bound to antibiotics (X-ray crystallography and cryo-EM) and link this to activity (enzyme kinetic) data to highlight important structural features required for potent binding, guiding strategies to develop and improve current drugs. Understand how PBPs interact with their natural substrates. I will produce soluble fragments of natural substrates to understand, using structure and kinetics, how PBPs catalyse peptidoglycan synthesis. Data will extend our understanding of essential cell wall synthesis and remodelling in Kp and other bacteria. Test novel compounds as dual PBP and BLA inhibitors. I will evaluate the efficacy and potency of new inhibitors) and antibiotics (collaborations across Oxford, Ljubljana and SMU) against target Kp PBPs and BLAs. Utilise the latest developments in dynamic structural biology and computational simulation to further explore PBP and BLA reactions. New, powerful, X-ray free electron lasers (XFELs) seek to visualise a moving picture of enzyme activity by capturing time-resolved snapshots along the reaction pathway. These dynamic data will feed into high-level quantum simulations to explore and model chemistry inaccessible in the laboratory. Together, these methods can create molecular movies of PBP and BLA reactions, predict impacts of sequence variants and novel antibiotics on enzyme activity, providing mechanistic insights into antibiotic efficacy and resistance. Optimise current and newly-developed antibacterials to treat Kp. Microbiological assays with current/new inhibitors alongside antibiotic partners will be tested against a range of clinical Kp strains. These minimal inhibitory concentration data will inform antibiotic synergy (combinations) in Kp, identifying new routes to effective treatments. Applications and benefits: I will advance the understanding of PBP/BLA mechanisms and inhibition in Kp.  This work will identify new candidate inhibitors, elucidate trends in antibiotic resistance and guide developments of more potent antibiotics or synergistic drug combinations which improve the clinical treatment of multi-drug resistant Kp.

UKRI Gateway to Research · FY 2025 · 2025-06

Chiral nanoparticles (NPs) can serve as components of vaccines and antibacterial agents, drug formulations against cancer and neurodegeneration. However, the methods for discovery and safety assessment of NPs as drugs are growing inadequate. Here, we aim to drastically accelerate discovery of NP-based medicines taking advantage of their chirality and of novel nonlinear optical effects that are compatible with data-rich high-throughput chemistry processes. Chirality (i.e. mirror asymmetry) is in most building blocks of life –DNA, proteins, etc. Mimicking proteins, chiral inorganic NPs can strongly interact with biomacromolecules forming sophisticated biological complexes with nanoscale dimensions and high biological activity; e.g. triggering an enhanced immune response [NAK, Nature2022, 601, 366] or killing viruses [NAK, Nat. Catalysis 2022, 5, 694]. The parameter space for such complex NPs is vast and its exploration requires novel high-throughput methods. Current drug discovery protocols rely on libraries of drug candidates but they do not exist for. Instead, we will take advantage of (a) versatile and rapid in-situ synthesis of chiral NPs with amino acids from the US team and (b) breakthrough observations of the UK team who reported the first experimental observation of NPs’ strong chiroptical nonlinearities [VKV, Phys Rev. X 2019, 9, 011024]; these will enable detection of Protein complexes in tiny microliter wells of microplates. NAK and VKV demonstrated a new form of this effect that has a maximum of emission in forward direction, which makes it most suitable for the microplates [NAK & VKV, Nat. Photonics 2022, 16, 126]. Our aims:1) Establish the broad applicability of our methodology to chiral NPs. We will synthesize biocompatible chiral NPs from metals, ceramics, and nanocarbons with broad optical properties (plasmonic, excitonic, dielectric). We will then reveal their nonlinear chiroptical properties. 2) Realize the new chiroptical effects in microwell optical systems. We will build dedicated optical rigs for high-throughput optical systems with robotic microwell positioning. The 2nd and 3rd harmonic scattering from NPs will be measured, revealing a previously unknown chiroptical spectroscopy in data-rich format, informing us about multispectral nonlinearities that are specific to NP interactions with biomolecules. 3) NP binding with proteins: The NPs will be tested with model proteins from bacterial biofilms, viral capsids, and immune cell membranes. The data obtained will be cross-checked in parallel tests with nuclear magnetic resonance, mass spectrometry, etc. providing independent data on formation of NP-protein complexes. The binding sites and constants will be also evaluated computationally using our recently developed models (NAK, 2022 Nature Computational Sci). 4) Apply our new technology, based on Renishaw’s inVia platform: With Renishaw’s active assistance, we will modify our inVia Raman microscope for operation with ultrafast lasers, add polarisation control and a highly sensitive detector, and use the high-throughput microplate scanning hardware and software developed by Renishaw.