IMPERIAL COLLEGE LONDON

UKRI Gateway to Research · FY 2025 · 2025-12

Mitochondria are cellular organelles that produce most of the energy of the cell. The dysfunction of mitochondria contributes to a wide range of diseases, from heart failure to cancer, and is a hallmark of ageing. Mitochondria, have their own DNA (mtDNA) that encodes key components of the bioenergetic and mitochondrial translation machinery. Mutations in the mtDNA causes mitochondrial diseases that affect ~1 in 4,300 of the population, and have variable phenotypes, with the most predominant involving the nervous system. How these mutations affect development of the embryo is poorly understood. During early mammalian development there are multiple mechanisms that reduce the mtDNA mutation load. These promote tissue fitness as well as reduce the contribution of mutant mtDNAs to the germline. In humans, these mechanisms include the bottleneck effect, that results in a reduction in mtDNA copy number and the asymmetric segregation of mutant and wild-type mtDNAs, and purifying selection against pathogenic mtDNA mutations. How these mechanisms act at the molecular and cellular level is still poorly understood. We have shown that in the early mouse embryo a novel form of purifying selection eliminates cells with dysfunctional mitochondria and mtDNA mutations. To model this elimination in humans we have generated human embryonic stem cell (hESC) lines carrying different types of mtDNA mutations. Importantly, we have found that those mutations associated with pathogenic phenotypes in humans, reduce oxygen consumption rates and disrupt the patterning of the embryonic lineages in stem cells models of early human embryogenesis. In this proposal we aim to determine how these mtDNA mutation cause these bioenergetic and patterning defects observed. For this we will do three things. First, we will characterise the impact of different types of mtDNA mutations on the metabolic and signalling pathways that regulate pluripotent stem cell fitness. Second, we will study how those metabolic and signalling pathways that are affected by mtDNA mutations cause aberrant embryonic patterning. Finally, given that the nervous system is frequently affected in mitochondrial disorders, we will differentiate our mutant mtDNA hESCs into motor neurons and study the phenotypes arising and their causes. Our work will provide an understanding of the impact of mtDNA mutations on early human development.  We anticipate that this knowledge will help us in the to develop therapeutic targets for reducing the transmission of heteroplasmic mtDNA disease.

UKRI Gateway to Research · FY 2025 · 2025-12

Photosynthesis uses sunlight to provide the energy for life. It takes CO2 from the atmosphere to make the polymers that are the fuels and building blocks of living things. The electrons required are taken from water and the oxygen released energizes the atmosphere. The appearance of “oxygenic” photosynthesis allowed complex life to evolve and changed the face of planet itself. In the history of life much of the biomass produced, either directly or indirectly by photosynthesis, was sequestered in rocks, lowering atmospheric CO2 concentrations, and establishing a climate appropriate for the current inhabitants. Mankind has caused the climate crisis by reversing photosynthesis due to an inordinate enthusiasm for combustion. Because of the poor efficiency of photosynthesis, biofuels cannot (at present) replace fossil fuels. We need the food as food and the trees as trees. However, by understanding photosynthesis, we can modify it for more efficient food production, for more efficient photosynthesis-based biotechnologies, and we can learn lessons from nature to improve technologies such as solar cells. In recent years, improvements in understanding photosynthesis and new genetic tools have allowed desirable traits to be put into crops, resulting in marked yield improvements. One approach, much discussed but not yet implemented, is to extend the solar spectrum useable by plants by engineering the chlorophyll pigments to collect light at longer wavelengths: to shift from the red light to far-red and even the near-infrared. Evolution has already done this engineering job at least twice in cyanobacteria, blue-green photosynthetic bacteria, in which oxygenic photosynthesis evolved. These two low-energy long-wavelength photosynthetic modes were a surprise to many scientists as it was thought that red light was the low energy limit for the energy-demanding process of oxygenic photosynthesis and yet biology had found two distinct ways of breaking this red limit. One has the usual chlorophyll-a pigments replaced by long-wavelength chlorophylls-d. The other has only 10% of the chlorophyll-a molecules replaced by another even longer wavelength pigment, chlorophyll-f. Both systems are as active as the conventional photosynthesis but use less energy. The team members are leading experts on far-red photosynthesis and have made many breakthroughs in this field. Here they have joined forces and brought in other specialists to make a team and project unmatched in the world. We will use genetic, biochemical, and biophysical (spectroscopic, structural, and computational) approaches to study and compare the three types of photosynthesis, the two long wavelength kinds and the conventional visible light kind. We will do experiments many of which are not possible with conventional photosynthesis. They will provide an in-depth knowledge-base for this new field, required to achieve three main aims:  to understand how these systems manage do the same difficult chemistry (split water and make the reactive chemicals needed to fix CO2) with less energy; to provide new insights to better understand the near-universal conventional photosynthesis; finally, to judge the feasibility of, and then to prepare the ground for, future engineering programs to put these traits into crops for more efficient food production.        

UKRI Gateway to Research · FY 2025 · 2025-12

Medical imaging is essential for diagnosing and monitoring diseases, but current technologies such as X-rays, CT scans, and MRI present significant limitations. X-rays and CT scans expose patients to ionising radiation, which carries health risks, particularly for those who require repeated scans. MRI, while producing highly detailed images, is costly, non-portable, is contraindicated for patients with ferromagnetic implants and often involves long wait times. These challenges limit the accessibility and practicality of these imaging methods, particularly in time-sensitive cases like stroke, or in regions with limited medical infrastructure. This research aims to further develop and validate a portable, cost-effective ultrasound-based imaging device that integrates full-waveform inversion (FWI) to deliver high-resolution, non-invasive images of the brain, and extend it to image the abdomen and the limbs, offering a safer, faster alternative to current methods. Ultrasound is widely valued in healthcare for its safety, portability, and cost-effectiveness, but traditional methods struggle with producing sufficiently detailed images of complex internal structures, such as the brain, especially in the presence of high-impedance contrasts such as the skull or air-filled tissues. FWI, though well stablished in geophysics, can overcome these limitations by utilising the full waveform of the recorded data and accurate algorithms that model wave propagation through the body, but it has not yet been fully exploited in clinical settings. This project will bridge that gap by refining and integrating FWI algorithms into an advanced and clinically ready ultrasound device that utilises optimally arranged low-frequency transducers to achieve the high resolution and accuracy needed for brain and abdomen imaging. The primary application of this device will be brain imaging. In this phase, the project will consolidate the technology developed to date and validated in a laboratory environment by addressing different challenges that hinder the translation to a clinical setting (e.g. patient movement, lack of low frequencies and flat bandwidth, contact medium). In parallel, the device will be repurposed for abdominal imaging, where current techniques struggle with early detection of conditions like pancreatic cancer by adapting the design of the device, type of sensors and reconstruction algorithms. In its final stage, the system will be optimised for imaging limbs, offering a safer alternative to X-rays and CT scans for musculoskeletal conditions. The impact of this research extends beyond improving image quality. For instance, the ability to detect strokes quickly and accurately with non-ionising ultrasound technology could significantly improve patient outcomes by enabling faster intervention, particularly in emergency settings. Similarly, earlier detection of cancers, such as those affecting the pancreas, could lead to earlier diagnosis, more effective treatments and better survival rates. For musculoskeletal imaging, a portable, affordable, and safer alternative to X-rays would reduce radiation exposure for vulnerable patients and those who require frequent imaging, such as athletes or patients with chronic conditions, reducing their exposure to ionising radiation. Moreover, this technology’s affordability and portability would expand access to advanced imaging capabilities in underserved or remote areas, where traditional imaging infrastructure may be unavailable. In conclusion, this research aims to develop a groundbreaking ultrasound-based system integrating FWI to offer a powerful, portable, and safer alternative to current imaging technologies by addressing the key limitations of MRI, X-rays, and CT scans and delivering faster, more accurate, and more accessible imaging solutions with the potential to significantly improve healthcare outcomes.

UKRI Gateway to Research · FY 2025 · 2025-12

Light microscopy forms a bedrock of modern research in bioscience and medicine, allowing processes to be examined across scales from individual molecules up to living organisms. We propose to establish an imaging platform with a highly advanced confocal and multiphoton microscope to allow the study of events in cellular ensembles, tissues and in intravital preparations with unparalleled precision and penetration depth. The equipment will permit MRC-funded and other researchers to drive research projects understanding the fundamental mechanisms driven by molecules its interactions and dynamics. Ultimately, we aim to translate cutting-edge research  findings into benefits for society. This proposal is to provide a new state-of-the-art microscope for Imperial's Facility for Imaging by Light Microscopy (FILM) at the Hammersmith Hospital/White City campus (HH/WCC). After consulting with the Facility Steering committee and asking the users, we realised the need for a high-end multiphoton with confocal (single-photon) capabilities and time-resolved fluorescence lifetime imaging and fluorescence spectroscopy. From the quotes provided by Zeiss, Nikon and Leica, we favour, for technical reasons, capabilities, and FILM facility know-how, the Leica STELLARIS 8 DIVE FALCON multiphoton and confocal with a software-based superresolution microscope. This system allows time-resolved fluorescence imaging and single-molecule spectroscopy dynamics deep inside cellular ensembles, tissue and intravital, and single cellular and subcellular levels. The system will enable us to resolve functional molecular events spatiotemporally in thick specimens, as we will be able to image deep inside the specimens at levels we are currently unable to achieve with other equipment at FILM. Moreover, we will be able to image events without the need to use a fluorescence probe by employing autofluorescence imaging and second harmonic generation signals, ultimately allowing us to gather quantitative metabolic information without using fluorophores. This will all be quantified by employing the phasor analysis and time-resolved fluorescence (FLIM). This microscope will enhance Imperial College research in several MRC strategic priority areas: collaborative research with users, population and systems medicine, molecular and cellular medicine, infections and immunity, neurosciences and mental health, global health research, translational research and methodology development, better methods, better research. Technically, the objectives of this proposal will be to 1) establish a multiuser facility for multiphoton  fluorescence and label-free imaging in thick specimens with time-resolved fluorescence imaging and single-molecule fluorescence spectroscopy open to all researchers at Imperial College and external academics or industrial collaborators run and managed by the FILM at Hammersmith Campus. 2) Enhance the research outputs, drive scientific discovery, and advance knowledge in current and future research within MRC remit. 3) Increase the usage of multiphoton imaging by enabling applications of less experienced microscopists by providing expert technical support. 4) Nurture the establishment of collaborations within Imperial College London and with external users in multidisciplinary research, benefiting from multiphoton and time-resolved microscopy. 5) Train new users, including students, research staff, academics and external users, in the application of multiphoton microscopy, label-free imaging, time-resolved fluorescence microscopy and single-molecule fluorescence spectroscopy.

UKRI Gateway to Research · FY 2025 · 2025-12

Many bacteria need to swim to cause disease, and understanding how they do so is essential for therapeutics development. Bacteria swim using helical propellers called flagella that are rotated by molecular motors embedded in the cell surface. Although understanding flagellar motility has focused on Escherichia coil and Salmonella enterica, whose flagella are dotted over their cell surface, many bacteria polarly-localize their flagella. These polarly-localised flagella are not just differently-positioned versions of those from E. coli and Salmonella: while E. coli and Salmonella rotate all of their flagella counterclockwise to swim forward, polar flagella spin in either direction equally, and—in species with a flagellum at each end—coordinate to rotate in opposite directions. And while E. coli and Salmonella search for new directions by transiently switching to spin clockwise, polar flagella toggle in either direction to reorient their swimming. This proposal seeks to understand the mechanisms behind these differences. We wish to understand how the apparatus that both generates rotation and chooses between clockwise and counterclockwise rotation works—and how it differs from its counterpart in E. coli and Salmonella. We use bacterial genetics to alter characteristics of the motor, and electron cryo-microscopy to visualise molecular structures and understand their mechanisms and the impact of our genetic changes. We focus on polar flagellate Campylobacter jejuni because we can easily genetically manipulate it, and it is well-suited for the structural techniques we use. First, we would like to understand how the polar flagellar motor is not biased to spin counterclockwise. We recently discovered that individual C. jejuni motors spend approximately equal time spinning clockwise and counterclockwise, echoing other studies of polar flagella from Vibrio and Pseudomonas species. We will to determine the structures of purified C. jejuni motors engineered to spin exclusively clockwise or counterclockwise using electron cryo-microscopy. We will compare our structures those already published from Salmonella to understand how polar motors behave differently. Second, we would like to understand how the cell influences the polar flagellar motor’s switching frequency. Recent findings indicate that signalling molecules trigger increased bidirectional switching in polar flagellates, in contrast to E. coli and Salmonella, whose signalling molecules trigger a unidirectional switch to clockwise. To understand how the signalling molecule modulates switching frequency, I will image the signalling molecule bound to flagellar motors in situ using electron cryo-tomography and subtomogram averaging to sufficient resolution to build molecular models of how its binding modulates the switching ability of the motor. Third, we would like to understand how this fits into coordination between two apparently opposed flagella. First we must understand how switching is powered – most likely, this is intrinsic to motor rotation, with forces involved in rotating the motor being harnessed to switch rotation direction. We will first image the motor proteins in action driving rotation. We will build on this knowledge by subsequently assessing how two opposed motors coordinate; we suspect that there is explicit signal to coordinate; rather, we hypothesise that the excessive resistance felt by a motor if it opposes the other motor inherently trigger it to switch rotation. We will test this with mutants and my observing motor switching using light microscopic techniques. This work is relevant to the MRC as basic research into a common feature of many pathogens including Campylobacter jejuni, Helicobacter pylori, Vibrio cholerae, and Pseudomonas aeruginosa.

UKRI Gateway to Research · FY 2025 · 2025-12

We are requesting funding for the purchase of a Bruker Skyscan 1276 CMOS In Vivo Micro-CT Scanner (SKYSCAN). SKYSCAN is a ground-breaking imaging system currently not available in the UK that offers high resolution combined with a significant reduction in radiation exposure. This reduction in radiation means that it the tool is ideal for longitudinal studies, meaning that researchers can conduct repeated imaging on the same animals without compromising animal welfare or altering the biological processes being measured. This is a non-invasive technology which provides an ethical and scientifically robust method for tracking disease progression and treatment outcomes over time. The SKYSCAN will be a transformative addition to biomedical research, enabling the detailed study of disease mechanisms and therapeutic responses in live small animal models. Its enhanced capabilities are critical for addressing challenges in fields such as osteoarthritis (a severe joint disease present in almost 50% of people over the age of 65), trauma, cancer metastasis, bone regeneration and growth, cardiovascular health, and tissue engineering. By offering superior image quality and reducing the radiation impact, this equipment will improve data reliability, minimise variability, and set new standards for preclinical research. SKYSCAN will be incorporated in the Core Facilities of the Department of Bioengineering at Imperial College, ensuring accessibility for academic researchers, industry partners, and collaborators across the UK in a sustainable and responsible way. Training programs will be developed to support skill-building and encourage interdisciplinary use, fostering a wider adoption of these advanced imaging techniques. Additionally, this technology aligns with the 3Rs principles of animal research (Replacement, Reduction, and Refinement), particularly enhancing refinement by reducing stress and harm to animal models and reducing the total number of animals needed thanks to the fast low radiation scans. It ensures reduction of animal use by enabling a single animal to be measured over many time points; other technologies require animal sacrifice at each time point. The SKYSCAN will have far-reaching applications and benefits. It will support cutting-edge research that advances understanding of disease, accelerates the development of precision medicine, and promotes sustainable scientific practices. The incorporation of SKYSCAN in the fully managed state of the art facilities of the Department of Bioengineering will support and drive existing and new collaborations to the benefit of the UK wide community delivering a significant step forward for the UK research community and the global pursuit of ethical, high-impact biomedical science towards impactful innovation in healthcare.

UKRI Gateway to Research · FY 2025 · 2025-11

This proposal combines innovations in previously parallel fields of organic electronics to build a new groundbreaking electrically driven quantum microwave amplifier at room temperature with unprecedented performance. This new hybrid optoelectronic device represents a major advance in masers, which amplify microwaves in the way that lasers amplify light. So far, masers have required expensive and large external light sources that prevent their widespread deployment in modern applications. In our design, the maser materials will be interleaved with thin layers of powerful organic light-emitting diodes (OLEDs) that efficiently excite the maser gain media directly in situ, thereby eliminating the need for external lasers. This will enable a new generation of masers ten times smaller and lighter than existing devices, enabling their widespread use. Robust and sensitive detection of microwave radiation is technically very important because microwaves are widely used in communications technologies, space monitoring, and healthcare. Detecting weak microwave signals at room temperature has been very challenging due to thermal noise. So far, this challenge has been met by cooling microwave detectors to near absolute zero, using high and potentially hazardous microwave signal powers, or accumulating data for a long time to average away the thermal noise. Ultimately, however, this limits the sensitivity, speed, and efficiency of vital technologies such as magnetic resonance imaging, radar, space imaging, and even the development of quantum computing. In this project, we will offer a transformative solution to high-precision microwave measurement by using “microwave amplification by stimulated emission of radiation” (maser). Room-temperature solid-state masers were first demonstrated in 2012 and are capable of amplifying, detecting, and thereby sensing extremely weak microwave signals. By capitalising on new developments in OLED technology, our new compact OLED-pumped maser will combine electrical efficiency, high sensitivity, and unprecedented signal-to-noise performance to transform a plethora of microwave precision measurement applications. We will work with our industrial partners to assess their performance compared to state-of-the-art conventional microwave amplifiers and explore real-world use cases relevant to materials science, space exploration, quantum technologies and healthcare to deliver genuine benefit to society. This project will lead to advances in the physical sciences of organic semiconductors and optoelectronic devices and significantly contribute to the UK’s leading position in quantum science.

UKRI Gateway to Research · FY 2025 · 2025-11

We are requesting funding for an ultrafast volumetric ultrasound imaging system (Ultrafast3DUS). Objectives: 1) To generate novel basic, translational, and clinical research discoveries within MRC remit, including in the fields of heart disease, gastrointestinal disease, metabolic diseases , infertility, neurodegenerative disease and cancer. 2) To promote collaboration locally and nationally on Ultrafast3DUS projects. 3) To drive innovative and ambitious new local and national research programmes within MRC remit. The circulation of blood through blood vessels is a crucial indicator of tissue health and of diseases including those of the heart, gastrointestinal tract, reproductive organs and brain. However, current approaches such as Magnetic Resonance Imaging or X-Ray Computed Tomography are unable to accurately visualise small blood vessels or to record the very rapid changes in blood flow that occur in these biological processes and diseases. Contrast enhanced ultrasound (CEUS) is a fast and sensitive research tool for visualising blood flow. Combined with recently developed genetic techniques, CEUS can non-invasively visualise specific cell types and even measure signalling inside individual cells of the body. Until recently, CEUS was largely limited to taking two dimensional (2D) pictures of tissues, or slow and limited 3D imaging. This meant it couldn’t be used to easily visualise the relevant blood flow in tissues that move a lot, such as the gut and heart, or in the smallest blood vessels, which are crucial to, for example, brain health and disease. The requested Ultrafast3DUS is a state-of-the-art system which can image tissue and organs at high resolution in 3D.  This will allow us to see the smallest of blood vessels and even individual cells in large 3D volumes, allowing precise mapping of the changes that occur in disease. It will be the first such system in the UK; equivalent systems are currently only available to a few research groups in the USA, France, and China. We thus have a number of engineers, biomedical scientists and clinicians at Imperial College and partners at external universities and research organisations who are highly supportive of this application and keen to use the equipment. The Ultrafast3DUS will therefore greatly increase national imaging capabilities, promote collaboration amongst scientists and clinicians across the UK, and provide the infrastructure necessary to help push this kind of UK biomedical research to the forefront of the international stage. The involvement of both basic scientists and clinicians, and the ability of the Ultrafast3DUS to image a wide variety of cells and tissues in both animal models and humans, will encourage and support the translation of scientific findings into work that directly benefits human health. The work initially planned will use the Ultrafast3DUS to investigate heart disease, gastrointestinal disease, metabolic diseases such as diabetes, infertility, neurodegenerative disease, cancer, and novel ways of targeting drugs to specific regions of the body. However, we expect beyond these initial studies that the equipment will support work in many other fields of biomedical research, from basic science through translation to clinical studies. The Ultrafast3DUS will therefore enable a wide range of world-class biomedical research and innovation to accelerate improvements in human health.

UKRI Gateway to Research · FY 2025 · 2025-11

Our older population is growing at a faster rate than ever before, with 2 out of 3 of us experiencing cognitive decline as we age. Our brain’s immune cells play a critical role in this decline by triggering abnormal inflammatory responses when activated for extended periods, leading to neuronal damage. With this fellowship, I will pioneer an innovative non-invasive approach to modulate the brain’s immune cells using therapeutic ultrasound, aiming to preserve cognitive function as we age and thus enhance our overall quality of life. Ultrasound is a powerful technology, used for both imaging and therapy, that can change how cells behave and either increase or decrease inflammation in the body. In the brain, increasing inflammation can promote repair and clearance of unwanted compounds, while decreasing excessive inflammation can protect brain cells from stress and neurotoxic substances. Inducing these effects in a controlled manner could therefore have neuroprotective roles at different stages of many diseases. My preliminary data show that ultrasound can influence the inflammatory response of the brain’s immune cells, offering the potential as a therapeutic tool to improve cognitive functions. This technology is non-invasive, portable, safe, and can deliver both region-specific and brain-wide treatments. Could this technology also delay the onset of cognitive decline? During this fellowship, I will first determine the range and duration of effects ultrasound can exert on the brain’s immune cells to understand the level of control this technology can achieve. Secondly, I will investigate which genes and proteins are impacted and whether ultrasound is affecting these immune cells directly or through neuronal stimulation. This mechanistic understanding will help identify directions for future investigation and improve these treatments further. Thirdly, I will develop ultrasound regimens to delay cognitive decline by performing preventive ultrasound treatments in naturally ageing mice, followed by clinically-relevant touchscreen-based behavioural testing. These ultrasound treatments will be compared and combined with other anti-ageing interventions. After the first four years, I will leverage the new understanding of how ultrasound affects brain cells in health and ageing, to develop ultrasound technologies aimed at delaying cognitive decline in Alzheimer’s disease and restoring brain function in those already affected by this disease. My research will investigate the use of ultrasound as a preventive strategy against cognitive decline. It will provide the neuroscience field with a non-invasive tool to modulate the brain’s immune cells, revealing new targets for drug development and complementary therapeutic interventions. In the long term, this technology could be developed to treat conditions ranging from other neurodegenerative diseases to skin inflammatory disorders and cancer, with significant societal, economic and scientific impact. Demonstrating that ultrasound can delay brain ageing and disease progression will introduce a new avenue for safe therapeutic intervention against cognitive decline. Its non-invasiveness, portability, safety and cost-effectiveness mean that this technology will be widely accessible. Such a technology could potentially impact millions of people globally, improving our quality of life and reducing the burden on patients, families, carers and the healthcare system. This ambitious anti brain ageing programme will position the UK at the forefront of advancements in therapeutic ultrasound for ageing, helping us meet the nation’s target for people to enjoy at least five extra healthy, independent years of life by 2035.

UKRI Gateway to Research · FY 2025 · 2025-11

Context: Climate change and new technologies like AI are having unprecedented impacts on the performance of critical engineered systems like infrastructures. For example, surges in the demand for electric power can exacerbate the impact of devasting floods and storms that can then wreck power grids. Coastal erosion disrupts railroads and impact transport and supply chains. The UN SDGs stress the urgent need for next generation infrastructures to make better use of resources, sustain economic activities, and recover readily from major disruptions. These are essential to face global societal challenges like climate change and transition to net zero. Challenge: Standard tools for designing and planning complex engineered systems (electrified transports, renewable energy systems, space-based remote-sensing) are poorly suited to deal with uncertainty in environmental conditions, markets, technologies and societal needs. Tools and measures of performance like optimization and benefit-cost analysis typically rely on deterministic forecasts that cannot deal with uncertainty or the value of strategic adaptation in the face of unforeseen conditions. They often lead to rigid systems that are insufficiently resilient, inefficient in terms of resource use, or cannot provide the originally intended societal value for money. Our ability to address complex global challenges like climate change is at risk if upcoming investment decision-making continues to rely on existing approaches. Aims & objectives: This OTG will push further the development of an emerging paradigm called Strategic Engineering, which promotes design & planning of complex systems like infrastructures to dynamically adapt and reconfigure to deal with uncertainty and risks. Many years of research show that strategic engineering produces systems with improved economic value for society, better sustainability, and resilience in the long run. This OTG will support travels to enable in-person meetings and workshops with colleagues in the US and Europe who have contributed to the development of this emerging paradigm. The objectives are to 1) continue development of an educational eBook presenting concepts and theories underlying strategic engineering and how to apply the methods and measure benefits in sectors like aerospace, defence, energy, transport, 2) research and co-develop new data-driven and AI technologies to better disseminate knowledge in engineering education and practice, and 3) contribute to grow a global community of researchers and practitioners to maximise impact and momentum in view of a follow-on EPSRC Network Plus proposal. Potential applications & benefits: Latest research shows that strategic engineering produces engineered systems with improved economic value for society (20-30% routinely compared to standard tools, significant for infrastructures typically requiring >£100 million investments). Strategic engineering is a unifying paradigm promoting sustainable use of economic and material resources via dynamic adaptation, as well as resilience in the face of uncertainty. As such, it supports global business and policy aspirations for a cleaner and greener future. The tools, methods and technologies developed over the years are, however, not widely accessible to engineering students, academics and practitioners. This is because the knowledge is highly cross-disciplinary and fragmented, and our community spread out across many institutions. This OTG will help consolidate our efforts to produce innovative, open access and accessible educational and research material for future engineering and system leaders. Crucially, it will support society’s ability to adapt to a changing world at a time when it is most needed.

UKRI Gateway to Research · FY 2025 · 2025-11

Introduction According to the UK Biomass Strategy published by the Department for Energy Security and Net Zero in 2023, sustainable biomass use across the economy plays a vital role in achieving the ambitious target of net zero carbon emission by 2050. Aligned with The Biomass Strategy Policy Statement, widespread biomass use in the industrial sector provides a low-carbon alternative to conventional chemical synthesis, significantly reducing greenhouse gas emissions. Sugar beet pulp (SBP), a major waste stream from sugar industries in the UK/Europe is currently sold as animal feed and its valorisation into more value-added products is essential to establish profitable SBP-based biorefineries. The proposal aims to design Yarrowia lipolytica-based cell factories to produce value-added chemicals [zeaxanthin and 1,4-butanediol (BDO)] from SBP, providing a sustainable route for the UK’s nascent bio-based industry. BDO, a tetracarbon diol, is an industrially important large-volume commodity with applications in the food, chemical, medical and pharmaceutical industries. BDO is used as a starting material for manufacturing different products including polybutylene terephthalate, tetrahydrofuran, ?-butyrolactone (GBL), and polybutylene succinate. Zeaxanthin is a naturally occurring carotenoid pigment and a potent antioxidant found in yellow vegetables and fruits, including corn, orange peppers, mangoes, pink grapefruit, apricots, etc. It has a wide range of applications, from colorants and antioxidants in the food industry to dietary food supplements and cosmetics. The consortium brings together the expertise of esteemed academics (Dr Rodrigo Ledesma-Amaro, and Dr Razieh Rafieenia, Imperial College, London, Dr Vinod Kumar, Cranfield University and Dr Ahsan Islam, Loughborough University) and industrial partners (C-Source Renewables, and FRUU Cosmetics) who will provide in-kind support. The project will apply systems/synthetic biology, metabolic and bioprocess engineering approaches coupled with machine learning algorithms to ensure industrial scale production of zeaxanthin and BDO. The proposed research is part of a wider vision to enable efficient use of all major monosaccharides in lignocellulosic-based waste streams with a circular biorefining approach. Research Aim & Objectives The overall aim of the proposed research is to design and construct Y. lipolytica-based cell factories by rewiring its metabolic network to enable the sustainable biomanufacturing of zeaxanthin and BDO from SBP. This involves achieving specific and measurable milestones: I) Machine learning-based design of optimised strain engineering strategies, II) Construction of L-arabinose and D-galacturonic metabolising Y. lipolytica strains, III) Bioconversion of L-arabinose and D-galacturonic acid into zeaxanthin and BDO by the engineered Y. lipolytica strains, IV) Scaled-up production of target chemicals. The potential direct or indirect benefits: The project outcomes will hugely benefit the current, unsustainable, fossil fuel-based chemical industries, as these are identified as the key and direct beneficiaries of the work through the availability of environmentally friendly products. The profound research investigation and investment in this area will strengthen the bioeconomy, improve the economic viability of bio-based industries including pharmaceuticals, and polymer industries, and create new employment opportunities in the UK from researchers to engineers and operators. The efficient bioconversion of lignocellulosic-based wastes into value-added chemicals will benefit the polymer and pharmaceutical industries by contributing to circular biorefining, leading to more sustainable and environmentally friendly bioprocesses. Additionally, the use of wastes as inexpensive raw material will result in reduced process costs and, subsequently, lower market price of the final products.

UKRI Gateway to Research · FY 2025 · 2025-11

Context and the challenge the project addresses Over 45% of women of reproductive age in the UK are overweight or obese. Maternal obesity has a significant impact on the cardiometabolic risk of offspring. Lifestyle interventions for obesity during pregnancy are ineffective. The prevalence of surgical and pharmacological interventions for managing obesity before pregnancy is increasing. However, their effects on offspring’s cardiometabolic risk remain poorly understood, creating a knowledge gap that has substantial implications for the lifelong health of these children. Bariatric surgery (BS) is the most effective treatment for morbid obesity. Limited evidence suggests that pre-pregnancy maternal BS affects offspring cardiometabolic risk factors, but the data are inconsistent. To better understand the impact of maternal BS on offspring health, we initiated a post-BS pregnancy cohort in 2015, which is currently ongoing. From this cohort, we have observed significant associations between maternal serum and urine metabolic changes and offspring birth weight, indicating a potential biological link between these maternal metabolites and offspring growth. However, comprehensive investigations into the nature of these associations have not yet been undertaken and further research into the short- and long-term transgenerational effects of BS is crucial. In contrast to invasive surgical interventions, new pharmacological obesity treatments, such as Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which induce significant weight loss with health benefits, are becoming popular for many people living with obesity. Since many women with obesity may become pregnant soon after stopping or even while taking these medications, it is important to investigate the transgenerational impact of GLP-1RAs and evaluate the effects of both BS and GLP-1RAs maternal weight loss strategies on the offspring cardiometabolic risk factors.   Aims and objectives We aim to study the effects of pre-pregnancy maternal BS and GLP-1RA therapy on the offspring cardiometabolic risk factors, and to investigate associations between these effects and maternal metabolic changes resulting from pre-pregnancy obesity treatment. To address these aims, we will study two cohorts: (1) We will establish a cohort of pregnant participants with a history of pre-pregnancy BS or GLP-1RA therapy, for weight loss, and their offspring. We will compare the cardiometabolic risk factors of those offspring (in utero and birth to 12-18 months) to control groups without maternal BS or GLP-1RA therapy. (2) We will use our existing post-BS cohort, initiated in 2015, to study the longer-term impact of BS on the cardiometabolic risk factors of offspring (5-9 years old). In both cohorts, metabolic phenotyping approaches will be applied to investigate weight loss strategies-associated metabolic changes during pregnancy. Subsequently, machine learning methods will be used to explore associations between these metabolic changes and offspring cardiometabolic risk factors.   Potential applications and benefits This study has significant clinical implications. The knowledge gained will benefit pregnant people living with obesity and those planning for pregnancy by providing evidence on the transgenerational impacts of different obesity management strategies. The study has the potential to improve pre-conception and pregnancy care for obese women, promote better health outcomes of their children, and may contribute to early childhood obesity prevention.

UKRI Gateway to Research · FY 2025 · 2025-11

The rapid expansion of the wind energy sector has led to increasingly large and clustered wind farms, sitting at close proximity to each other. Often new wind farms are built upstream of already existing ones, reducing the power production of the farms that were installed first, together with the turbine lifespan due to increased loads. Examples of that are the clustered farms in the North Sea, and the US great planes. The wind turbines in a farm generate wakes which coalesce, forming a massive turbulent air flow at the outlet of the farm, with significant mean wind speed deficits and enhanced turbulence. This "combined" flow propagates downstream for tens of kilometres, reaching subsequent farms. Therefore, farm-to-farm aerodynamic interactions are expected to become a major challenge in the wind industry, with wind farms "stealing the wind" from each other, lowering the overall power production. To prevent this, proper planning guidelines need to be developed. These should ensure that the wind farm spacing is adequate, so that the reduced kinetic energy of the wind at the wake of a farm has had sufficient time to recover, before reaching subsequent farms, and new wind turbine and wind farm arrangements are developed that minimize the production of very large wind wake deficits. However, at present, the wind farm-to-farm wake production and interaction is poorly understood, and thus there is a critical need for developing new knowledge. To address this issue, the proposed research will investigate the problem of successive wind farm wake interactions and develop reduced-order representations of use to industry and national laboratories. Specifically, we will quantify and develop models for (i) the production and recovery of momentum deficit that a single farm generates at its outflow, and (ii) its interaction with downstream farms. A combination of four research teams in three countries will perform detailed large- and small-scale laboratory experiments and high-fidelity numerical simulations that will be used to consider a multitude of real-world conditions, including changes in ground surface roughness, the Coriolis force, thermal stratification, global blockage and entrainment between the atmospheric boundary layer and the wind farm wake. The results will be complemented by wind farm field data, provided from industrial partners. The datasets will be used to develop and test new wind farm flow models that are able to capture the important flow physics, yet are computationally inexpensive, i.e. designed to run in laptop computers of use to industry when developing preliminary analyses in future wind farm projects.

UKRI Gateway to Research · FY 2025 · 2025-11

Modern society abounds with applications where data is constantly being recorded. As the amount of data increases, the computational efficiency of any algorithms processing this data becomes important. For many applications, it may be important to know if a process being monitored changes in some way. The area of statistics that studies these methods is known as changepoint detection, and applications for this methodology are as diverse as finance, cybersecurity, meteorology and medicine. In finance, one can use this methodology to detect changes in a collection of financial instruments. In cybersecurity, changepoint detection can be used to monitor a computer network to detect intrusions. In medicine, it can be used to monitor the condition of patients in an intensive care unit and provide alerts for when their condition changes.   The goal of this work is to develop a computationally-efficient nonparametric changepoint method for use with multivariate data. A nonparametric method makes very few assumptions on the observed data and seeks to detect any type of change. This allows the methodology to be used in a variety of settings, from detecting a change in the average value of the data or detecting a change in an increase in the data's volatility or variance, or other changes in the distribution of the data. However, while nonparametric methods are more versatile, they can be more computationally intensive. Moreover, instead of monitoring a single stream of values, the goal is to monitor multiple parallel streams of data.   To achieve this, the first objective will be to extend recently published work, which developed an efficient algorithm for a nonparametric two-sample test in the univariate setting, to the multivariate setting. In essence, a two-sample testing method compares two datasets and attempts to determine if there is a statistically significant difference between them. One could view two-sample testing as a simpler version of the changepoint detection problem, since in changepoint detection we are given a single dataset with the goal of partitioning it into adjacent, significantly different, datasets. We shall start with the bivariate case of two data streams since this already presents significant challenges. The second step will be to create an efficient changepoint detection algorithm in the bivariate case using this two-sample test. If possible, we would then extend this to higher dimensions.   The main motivating application for this work is the medical setting. Patients in an intensive care unit can have tens of sensors monitoring their vital signs such as blood pressure, body temperature and blood oxygenation levels. Often, some of these measurements are displayed on screens for medical staff to monitor visually. Experienced staff can interpret these visualisations and determine when a patient’s condition is deteriorating, for example, if the patient is at risk of circulatory failure. The goal of this work is to create an algorithm that can provide a basis for monitoring such data and provide timely alerts for medical staff in this environment.

UKRI Gateway to Research · FY 2025 · 2025-10

The magnetic signals recorded by rocks provide information about the Earth’s evolution. For example, magnetic anomalies on the ocean sea floor were key to theory of plate tectonics, and more recently palaeomagnetic recordings suggest that the Earth’s magnetic field has existed for nearly four billion years; the geomagnetic field protects the Earth making it habitable. However, there is one key process in the Earth Sciences for which we do not understand the magnetic response. That process is stress. This is important, as much of the Earth’s surface is characterised by stress, with stress being integral to dramatic processes like earthquakes, eruptions and impacts, as well as slower processes like mountain building. Yet, we have no comprehensive model for the effect of stress on the magnetic response of minerals. Why have the effects of stress on the magnetic signal of minerals been largely ignored? We know that most rocks have been subjected to stresses from a variety of mechanisms including faulting, burial and in more extreme cases impacts. Historically, however, these stresses were thought to be too small (<1 GPa) to alter or reset existing “stable” magnetic recordings (remanent magnetisations) in all but the most extreme impacts. However, in a recently published paper, we demonstrate this assumption is incorrect. Our numerical models predict that stresses of only ~0.1 GPa are sufficient to affect geologically “stable” magnetic recordings. Whilst 0.1 G Pa is still a high pressure, such stresses are very common in areas such as seismically active fault zones and mountain building. The aim of this proposal is to formulate the first accurate predictive model for stress-induced magnetisation in rocks. To do this, experimental measurements are critical to the development, refinement and extension of our existing numerical model to a wider range of mineralogies and grain morphologies, and to provide detailed experimental validation. We have already undertaken some preliminary experimental measurement on bulk samples – presented in this proposal, which encouragingly support our numerical predictions. However, to build the first accurate, predictive model, we need to experimentally verify and quantify the processes on nanometric scale. To do this we will use state-of-the-art in-situ nanometric magnetic images using the world’s most advanced transmission electron microscopy methods. We will test this new theory on natural rocks through a comprehensive set of bulk measurements. If our numerical prediction is correct and stresses of only ~0.1 GPa can alter magnetic recordings in rocks, this will have significant consequences for many palaeomagnetic studies; however, the real potential breakthrough is in new areas of study and application. One breakthrough area, we are keen to develop, is earthquake hazard quantification. Key to this is knowledge of peak palaeo-stress fields due to previous earthquakes over recent geological history, i.e., ~10 kyr.  Currently, palaeo-stress fields are hard to quantify as rocks directly in the fault are heavily altered due to heating, and rocks distal to the fault, which experience limited heating and stresses < 0.2 GPa, display elastic behaviour leaving no detectable microstructural damage. However, that magnetizations are altered by stresses of only ~0.1 GPa, means that rocks have the potential to magnetically record palaeo-stress fields and to retain this information over geological timescales. We plan to use our new knowledge refined in this proposal, to develop methods of quantifying palaeo-stress fields, leading to a step-change in earthquake-hazard risk quantification.

UKRI Gateway to Research · FY 2025 · 2025-10

Knee osteoarthritis (KOA) is one of the most common causes of pain and disability, affecting over 367 million people globally. In the UK, KOA leads to more than £2.5 billion in annual healthcare costs. Detecting the disease early is essential to delay or avoid invasive treatments like joint replacement surgery. However, the current diagnostic process is often slow and uncertain, especially in the early stages of the disease. A key issue is the communication loop between general practitioners (GPs) and radiologists. The way referrals are written can influence the wording of radiology reports, sometimes reinforcing assumptions rather than identifying disease with accuracy. At the same time, GPs rely on these reports to guide treatment decisions. This mutual dependence can introduce diagnostic bias and uncertainty, especially when early-stage signs of KOA are subtle. These challenges are made worse by a national shortage of experienced clinicians, contributing to delays in diagnosis and treatment. The first imaging step for most patients is a 2D X-ray, which is quick and accessible but often lacks the detail needed to detect early joint degeneration. CT scans provide more accurate 3D information but are costly, expose patients to more radiation, and are not routinely used for KOA diagnosis. MRI offers excellent soft tissue detail but is expensive and not always available in the global healthcare system. This creates a gap between what standard screening imaging can provide and what clinicians need to make timely, accurate decisions. This project aims to bridge that gap by validating a new artificial intelligence (AI) approach that reconstructs 3D images of the knee joint from just two standard X-rays. The system uses a generative AI model trained on real-world examples of matched 2D radiographs and 3D CT scans to produce detailed images that replicate CT-like bone structure. Preliminary studies show that the model can reconstruct healthy anatomy with high accuracy. However, it is not yet known whether it can reliably capture disease-specific features such as joint space narrowing or osteophytes—key indicators used in KOA diagnosis. This project will generate the critical evidence needed to answer that question. We will test the AI-generated 3D images using anonymised datasets of patients across different KOA severity levels. Clinical experts will assess the synthetic images alongside the real CT scans to judge how well the AI captures relevant disease features. This evaluation will provide essential data on the model’s accuracy and potential to support clinical decision-making earlier in the patient pathway. If successful, this approach could improve the accuracy and speed of KOA diagnosis, reduce the need for advanced imaging, and support clinicians—particularly in primary and secondary care settings—with a more accessible diagnostic tool. By generating robust clinical evidence, this project will enable future development toward regulatory approval, NHS integration, and wider application across musculoskeletal care pathways.

UKRI Gateway to Research · FY 2025 · 2025-09

Catalysis is an enabling technology that improves our quality of life. Catalysis is involved in around 85% of chemical manufacturing processes and contributes £ 50 billion per year to the UK economy. Catalysis science in the UK is recognised as a national strength. This field is facing several challenges however, not least how to provide for a growing population with increasingly limited resources. Catalytic processes typically rely on expensive, toxic, and limited supply elements such as Rh, Ir, Pd, Pt. Replacing these elements with more sustainable and widely available alternatives is crucial for the future of the catalysis sector. Hydrogenation is a key technology that underpins production of commodity and fine chemicals, pharmaceuticals, agrochemicals, fuels, and polymers. Controlling selectivity (e.g. chemoselectivity or stereoselectivity) in hydrogenation can be challenging. Our team recently described a breakthrough discovery in selective catalytic hydrogenation using a simple and cost-effective homogeneous catalyst based on zinc (J. Am. Chem. Soc. 2023, 145,7667). In this project, we will develop next generation zinc catalysts for selective hydrogenation. We will develop a detailed understanding of mechanism and structure-activity relationships in zinc hydrogenation catalysis, constructing a knowledge base that will inform catalyst design. We will apply the next generation catalysts to the chemoselective hydrogenation of a wide range of functional groups along with the enantioselective hydrogenation of alkenes. Our aim is to develop catalytic technologies that meet the requirements for commercial applications, allowing translation of our discovery from the lab into the UK fine chemicals manufacturing sector.

UKRI Gateway to Research · FY 2025 · 2025-09

The R Epidemics Consortium (RECON) builds and maintains a collection of interconnected software tools focused on actionable analyses to be used in disease outbreak response. These include several kinds of tools written in the widely used R language. "Building block" software defines data structures and processing steps that can be used by a wide set of other tools and epidemiological pipelines, e.g., epicontacts, for contact tracing data, or distcrete for working with discrete distributions in disease simulations. There is also "turnkey" software for low-effort, rapid implementation of common analyses required in outbreak response, e.g.  EpiEstim, for calculation of reproductive numbers, and epiflows for travel-based risk assessment. RECON also build tools for analytical support to low-resource environments such as deployer, a framework for bootstrapping tools without internet access, and reportfactory, for rapidly generating standard epidemiological reports. Developed since 2016, and deployed and tested through multiple Ebola outbreaks and the COVID-19 pandemic, RECON tools are essential components of rapid response analytics. RECON software has been built by a loose coalition of volunteer developers with a mix of software design approaches. As the R epidemiological toolset has expanded and developed, other ecosystems have been built using RECON packages as essential dependencies, while other specialty epidemiological tools have developed parallel but incompatible data structures. This project aims to bring RECON packages in line with each other and peer tools in terms of package design standards so as to ensure dependability and maintainability. We will bring the core RECON suite of packages up to common set of standards in testing, documentation, and maintainability in design following standards for R and epidemiological software, as defined by the rOpenSci development guide and Epiverse-TRACE blueprints. Core RECON packages with significant reverse dependencies and user bases will be the priority, including EpiEstim, outbreaks, epicontacts, distcrete, incidence2 and i2extras.  Priority maintenance within these include updating core algorithms with updated methods (distcrete), improving API for interoperability with emerging popular packages (epicontacts, incidence2, EpiEstim), and refactoring code to facilitate further expansion (EpiEstim).  All will receive updates to improve test coverage and developer documentation on package internals and roadmap to improve maintainability, facilitate regular release cycles to dissemination platforms such a the Comprehensive R Archive Network (CRAN) and R-Universe,  and expand the contributor base. We expect to responsibly deprecate several packages that have low usage and have been superceded by new tools. As part of this effort, we will coordinate with Epiverse, a peer project using RECON tools, to align on standards and establishing broad, long-term maintenance priorities. To improve both internal and external transparency into package maintenance status, we will implement monitoring for all RECON packages using the Community Health Analytics in Open Source Software (CHAOSS) framework.  A CHAOSS dashboard will provide insight into RECON package development cadence, developer responsiveness, and package cross-dependencies with the broader software ecosystem.  The RECON developer board will use the CHAOSS dashboard to target packages for additional developer support when falling behind on maintenance.  

UKRI Gateway to Research · FY 2025 · 2025-09

Hardware engineers rely on several "EDA tools" in the design and manufacture of semiconductor devices, and one of the most critical is the equivalence checker. The equivalence checker is responsible for checking that two hardware designs -- usually a "spec" and an "implementation" -- are functionally identical. The equivalence checker is highly trusted -- if it reports that the implementation does agree with the spec, then fabrication can go ahead. But our recent work casts doubt on how trustworthy current equivalence checkers actually are: we identified multiple soundness bugs in all the main commercial equivalence checkers through a fuzz-testing campaign. Bugs in EDA tools can waste time and resources, but worse: they can be systematically exploited by malicious actors to circumvent security guarantees that have been established at higher levels of the stack (as will be demonstrated in a USENIX Security paper being presented next month). In response, we have started building a new equivalence checker  that is programmed and proven correct inside a proof assistant. This means that it comes with a computer-checked mathematical proof that it never gives the wrong result. We propose now to shift our focus from correctness to efficiency. Our prototype equivalence checker is guaranteed to be correct, but its performance is poor. Our plan is to collaborate with Prof Adam Chlipala at MIT, who is probably the world leader in "mathematical proof applied to hardware design", to make our equivalence checker faster and more useful. We will develop better underlying data structures that balance performance and ease-of-verification, new optimisations, and wider support of the Verilog language as input. Our overall goal is to set a new bar for how rigorously engineered EDA tools can be, and ultimately contribute to a safer and more secure world.    

UKRI Gateway to Research · FY 2025 · 2025-09

We propose the creation of AIRTUK, a national centre of excellence dedicated to pioneering artificial intelligence (AI) techniques for the analysis, prediction, and control of turbulent flows. This hub will unite the UK's foremost experts in turbulence, fluid dynamics, high-performance computing, and machine learning to address one of the most complex and enduring challenges in physics, with far-reaching implications for aerospace, energy & environmental sciences. It will be created in close partnership with the Alan Turing institute. AIRTUK will position the UK at the global forefront of AI-enhanced turbulence research, creating a sustainable ecosystem that drives innovation across disciplines while addressing critical industrial challenges and environmental concerns. The objectives of the hub are (1) Research Excellence: Deliver groundbreaking research that fundamentally transforms how turbulent flows are studied, modelled, and understood by integrating cutting-edge AI methodologies with classical fluid dynamics approaches, (2) Data Infrastructure: Develop and maintain a comprehensive national infrastructure for curating large-scale datasets (in collaboration with the National Wind Tunnel Facility), creating an invaluable resource accessible to the entire UK research community, (3) AI Innovation: Drive forward UK's AI capabilities by developing novel techniques, algorithms, and analytical approaches with applications extending beyond turbulence research into diverse scientific and industrial domains, (4) Environmental Sustainability: Pioneer environmentally sustainable approaches to turbulence research through energy-efficient computing techniques (sharing best practice and latest developments in on-the-fly post processing), and applications focused on reducing carbon footprints, (5) Diversity & Inclusion: Address diversity challenges through targeted knowledge exchange activities, and various outreach activities; share ideas/tools required for a broader up-skill of the UK high education landscape.

UKRI Gateway to Research · FY 2025 · 2025-09

This proposal is an invited resubmission to provide Longitudinal Population Studies (LPS) infrastructure support for data curation/archiving, and continued maintenance and upkeep of the data and samples collected by the Airwave Study of 50,000 police officers and staff across Great Britain. Airwave is unique worldwide in both scope and depth concerning study of a frontline workforce. It is by far the largest occupational cohort in the MRC cohort directory, includes both men and women, a range of educational attainment from school leavers to graduates and covers a broad age range at baseline from 18 to 65+ years. The cohort is ideally placed for the study of various lifestyle, environmental and occupational exposures and stressors affecting health, disease risk and wellbeing. Potential applications span cancer risk, cognitive effects from TETRA radio use, and occupational exposures such as noise-induced hearing loss, traumatic brain injury, shiftwork, and workplace stress and trauma, which impact mental and physical health. In addition, clinical, genetic and molecular data are available to study biological pathways linked to genetic variants, to clinical phenotypes and disease. We hold the data in a secure ISO27001 certified and NHS Data Security and Protection Toolkit (DSPT) compliant environment and have in place strong governance procedures to maintain and manage the data and stored biological samples. We will continue to work to the highest standards to store, maintain and make available the data, and ensure data security and confidentiality. Airwave is an enthusiastic LPS partner in the UK cohort portfolio and contributes over 15% of the participants included in the UK Longitudinal Linkage Collaboration (UKLLC). As a founder member, we will work closely with UKLLC as well as Population Research UK (PRUK) to further embed Airwave as a critical and central resource in the MRC cohort portfolio. We will curate, check, quality control and link our data across the multiple datasets collected to date, creating a readily navigable research database supported by an updated, enhanced and user-friendly data dictionary. This will provide researchers with the tools to readily interrogate the comprehensive participant (row-level) data, linked across multiple datasets, and identify potential sets of candidates for data analysis and further studies. All datasets will be made available with full metadata and description of relevant data collection methods. We will ensure our data are widely accessible to the research community with ready access through UKLLC and Dementias Platform UK (DPUK), as well as continuing to signpost the study and availability of data through portals such as the Health Data Research UK (HDRUK) Innovation Gateway. As well as linkage to NHS records, our membership of UKLLC provides opportunities to link to other centrally held data such as education and pensions, which will support analyses of the impact of occupational stressors on workforce retention, retirement and drawing benefits. Working with UKLLC and PRUK, we will be at the vanguard of efforts to implement a common ontology, so that researchers can work seamlessly to combine analyses across cohorts. We will continue to engage and involve our participants in the research process and to inform them of progress through the website and newsletters.

UKRI Gateway to Research · FY 2025 · 2025-09

Almost 15,000 different per- and poly-fluoroalkyl substances (PFAS) are currently estimated to exist. In total, 63 PFAS have been detected in the environment globally, which is likely a major underestimate, given the size of this chemical class. For humans, these chemicals have already been linked to several health issues but the risk for environmental health remains poorly understood. Importantly, the C-F bond chemistry confers significant and molecule-specific recalcitrance to natural degradation, as well as concerning potential for accumulation and toxicity in aquatic organisms. For one substance alone, perfluoro-octanoic acid, over 90% of all receiving waters downstream of wastewater treatment plants tested in the UK exceeded the environmental quality standard. The aim of UNSaFE is to rapidly close the significant knowledge gaps that exist regarding the scale of exposure, sources, fate, and biological effects of large numbers of PFAS in UK waters.  In order to meet the aim, our objectives include: (a) to combine and integrate qualitative and quantitative analytical approaches for biota and water field monitoring for large numbers of PFAS; (b) to co-develop and co-deliver large a 'catchment-to-country' PFAS monitoring programme with academia, government (Environment Agency) and large-scale organised citizen science initiatives (Earthwatch); (c) to establish and predict how PFAS structure governs their environmental behaviour (i.e., persistence, bioaccumulation, mobility and fate); (d) to more fully understand PFAS Modes of Action (MoA) using multi-omics data across species; and (e) to establish evidence-driven and ecologically-relevant thresholds for sensitive species. This project directly addresses the scope of Highlight Topic D. Importantly, and given the number of PFAS that may potentially exist in water, the project aligns closely with the NERC Digital Strategy 2021-2030 by focusing specifically on integrating and applying new, scalable and fit-for-purpose technologies to generate multidimensional data to better understand the environmental impacts of PFAS. This is embedded and integrated across environmental data acquisition and new advanced computing approaches towards building a readily scalable and unique capacity for assessment of PFAS on a national scale. We have a unique opportunity in UNSaFE to engage >150 community groups through UK-wide "Water Blitz" activities to evaluate the opportunities and robustness of citizen science-led monitoring. Several benefits exist for national capability enhancement including: the integration of novel low-cost 3D-printed multifunctional passive samplers with untargeted analytical methods using high resolution mass spectrometry as well as the total organic fluorine assay and advanced in silico identification tools that are enhanced specifically for PFAS; application of new approach methodologies (NAMs); molecular profiling through comparative systems biology approaches;  Artificial Intelligence (AI)-enforced quantitative structure-activity relationships (QSAR) models to quantify both exposure and hazard; and development and validation of novel source apportionment tools such as inverse modelling to identify and estimate how much and exactly where PFAS enter the aquatic environment. Most importantly, this project will involve critical comparisons between new technologies and standard regulatory risk assessment strategies to ensure more rapid and reliable translation for regulators. When used together, the tools and technologies in UNSaFE will rapidly enhance the prioritisation of PFAS-related compounds for risk assessment, monitoring capability and direct future mitigation strategies. By bringing together these key academic and research institutions with the Environment Agency and the general public to this field, we envisage a step-change in ability to assess how PFAS can impact our environment and inform proactive management of further uses to limit further impacts.

UKRI Gateway to Research · FY 2025 · 2025-09

Diamond-Blackfan anaemia (DBA) syndrome is a rare genetic disease affecting about 1 in 100,000 people of all ethnicities. The main problems are severe anaemia (low red blood cells), often starting in childhood, birth defects that need surgery, short height and a high risk of cancer (1-in-7  people by age 45). DBA disrupts children and families’ lives, with missed school and work, financial stress, and social isolation due to having a rare disease. Steroids are the only drug that can help DBA, but high doses are needed, causing serious side effects. Because of this, over half of DBA patients cannot tolerate steroids in the long-term and need to stop them. The only alternative treatments are lifelong red blood cell transfusions or bone marrow transplantation, which are risky and can cause major health problems. DBA is caused by a genetic change in one of several ribosomal protein genes, leading to impaired ribosomes, the structures in every cell that produce proteins. Limited treatment options for DBA is due to our poor understanding of how anaemia develops. Most DBA research focuses on red blood cells alone, but these are impacted by many other cells and signals in the bone marrow, like trees in an orchard influenced by the weather conditions. I discovered high levels of inflammation, including a molecule called tumour necrosis factor alpha (TNFalpha), in the bone marrow of patients with DBA. The aim of my proposal is to better understand the cellular and molecular basis of inflammation in DBA and use this knowledge to develop new treatment avenues. First, I will identify which cells in DBA marrow cause inflammation. Then, I will study how steroids help DBA by defining how they change gene expression and inflammatory signals in marrow. Finally, I will test if reducing inflammation, for example by blocking TNFalpha, could lead to new treatments that help more people with DBA, with fewer side effects than steroids. I am the right person to deliver this work as I am a physician-scientist, motivated to improve the care of my patients with DBA. I have a strong track-record in DBA research and have established unique resources over the last 10 years: the National UK DBA Patient Registry (a database of clinical and laboratory data from 205 patients) and the largest repository worldwide of precious bone marrow cells from children with DBA, who have donated their samples to research. I will study these cells from patients and collaborate with experts to create new "mini marrow" models of DBA (called organoids). This recent scientific advancement mimics the marrow ‘orchard’, allowing patient cells to be studied outside of the human body but in a lifelike context. Developing treatments that target the pathways causing DBA would transform DBA patient care. Unique data from patients and their precious samples will be useful for other researchers in the field.  My research also has the potential to improve the treatment of other anaemias, since anaemia is a very common complication of many inflammatory diseases. Finally, other blood diseases, cancers and autism have been linked to ribosomes. Though these are essential for all cells, ribosomal disorders affect only some cell types. Understanding why DBA affects mainly red blood cells, will provide broader scientific insight into how diseases characterised by insufficient ribosomes impair some cells, but spare others.

UKRI Gateway to Research · FY 2025 · 2025-09

This grant is to continue the group's programme of investigation into the properties of elementary particles and the fundamental forces of nature, encoded in the so-called “Standard Model” (SM). One of the main objectives of this grant will be to support our experimental programme at the LHC. The CMS experiment will continue to characterize the Higgs boson, which provides a unique window onto new physics. It will also be possible to extend our searches for SUSY, dark matter, long-lived particles and other new phenomena. The LHCb experiment will offer complementary tests of the SM and beyond with the ability to look for extremely rare decays in flavour physics that are sensitive to contributions from new physics. Measurements led by the group have revealed deviations from the SM. The group is also very active in preparing the next generation of CMS and LHCb detectors for the high luminosity upgrade of the LHC. The CMS upgrades will be completed, installed and commissioning over the coming grant period. The T2K long baseline neutrino experiment will allow us to expand our understanding of the masses and mixings in the neutrino sector, and leptonic CP violation. Future running, and combination with other experiments, will shed further light.  To fully characterize this CP violation and its role in the observed matter-antimatter asymmetry will require the next generation detectors, DUNE and Hyper-K, in which we are also involved, with development underway. Hyper-K will start taking data during this grant. We are also involved in the SBN programme at Fermilab. Heavy neutrino-like particles are predicted in several new physics models and the SHiP experiment is designed to search for these new particles and other feebly interacting new particles. Around a quarter of the Universe is composed of dark matter and its nature is unknown. This has so far remained undetected in the laboratory and the group will continue its activity in searching for direct evidence of a dark matter candidate through the LUX-ZEPLIN experiment, along with preparations for the next generation detector, XLZD. The AION experiment will use novel quantum technologies to probe for ultra-light dark matter, and, in time, gravitational waves. Direct conversion of muons to electrons is heavily suppressed in the SM so any observation of this process would be a major discovery. The COMET experiment is searching for this process and will take data during the grant. Similarly, a measurable electric dipole moment for the electron could only arise through new physics and the eEDM experiment will continue to push down the limits for such an effect. Whilst the output is primarily furthering our understanding of fundamental physics, the techniques and technologies developed have wider societal benefit and we have an associated impact programme.

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.