University of Cambridge

UKRI Gateway to Research · FY 2025 · 2025-09

From renewable energy to transport electrification, every watt is converted multiple times by power electronic converters from generation to end-use. Achieving high efficiency, high reliability, low cost, and miniaturization in power converters is crucial for energy savings and decarbonization. The development of individually structured components has been isolated, with interactions between entities often overlooked. This lack of integrated design beyond individual components has largely restricted the full potential of emerging wide bandgap (WBG) power electronic devices. Consequently, improvements in power converters have been incremental, and technological demarcations continue to stifle innovation in power electronics. The development of power electronics products and technologies typically prioritizes efficiency, power density, affordability, and reliability, often neglecting reusability and waste management after consumption. Conventional power electronics converter design is linear, beginning with raw materials, progressing through the composition of individually structured components, and ending with disposal. Power electronic packages are challenging to reuse, repair, and recycle due to the inseparable physical connections of parts within the package. Significant resources and residual values inherent in power electronics are wasted through standard disposal methods such as landfilling and incineration, leading to environmental concerns. The lack of focus on reusability, reparability, and recyclability in power electronics undermines sustainability and the principles of a Circular Economy. In our quest for high performance and sustainability in power electronics, we aim to demonstrate a new design paradigm for power electronic packages and converters through structural and functional integration, with a focus on circularity from the design stage. We will cohesively design novel and high-performance power electronic device packages where parts can be separated and replaced. This innovative packaging concept and design incorporate new structures of ceramic embedding die chips, a new bonding method using liquid metal, and new assembling and disassembling processes for power electronics packages. We will explore the fundamental sciences and engineering implementations necessary to enable the reusability, repairability, and recyclability of all parts in the device package, ensuring their 'another life' and 'after life'. This approach is expected to deliver unprecedented performance and enable circular power electronics. We aim to achieve an advanced system for high-performance and circular power electronics through the following objectives. 1) Develop a ceramic-embedded power electronic package for scalable power converters with ultra-fast switching and excellent thermal management; 2) Innovate a floating die structure for power electronics packaging using liquid metal fluidic joints to address thermomechanical issues; 3) Create an integrated design and fabrication process for reusable, repairable, and recyclable power electronics using floating die structures enabled by liquid metal. The team from the University of Cambridge (CAM) and the Compound Semiconductor Applications Catapult (CSAC) will collaborate closely throughout the project. Transformative ideas and theoretical analyses from CAM are well complemented by the fabrication and testing expertise and facilities at CSAC. The project enjoys strong support from leading industrial partners, STMicroelectronics for SiC bare dies, MacDermid Alpha for packaging bonding materials, and Semikron Danfoss for thermal and packaging design. We believe this combined effort will derisk the fundamental research and accelerate the impact. The technology and knowledge generated from this project will inspire the academic community to explore more interdisciplinary research between Electrical Engineering, Material Science, and Economics. Research and training activities from this project will benefit the UK’s Power Electronics and Machine Drives (PEMD) industry with more assets contributing UK’s PEMD supply chain.

UKRI Gateway to Research · FY 2025 · 2025-09

Despite being the epitome of strength, the solid rocks below Earth’s surface can flow surprisingly rapidly over human timescales, impacting processes of societal relevance. This project aims to deliver new equations describing this flow based on the underlying processes operating in the rocks. Major earthquakes and the melting of ice sheets cause deflections of Earth’s surface that are facilitated by viscous flow of the hot rocks below. This deformation creates important feedbacks. During the seismic cycle, earthquakes induce viscous flow of rocks beneath the fault zone that impacts the spatial and temporal distribution of future earthquakes. During the glacial cycle, viscous flow of rocks beneath melting ice sheets causes ground uplift that impacts sea-level change. Therefore, modelling these systems requires knowledge of the viscosity of rocks in Earth’s lower crust and upper mantle. During the first phase of this project, experimental data and observations of the microstructures of deformed rocks provided the basis for a new framework of equations describing how the viscosity of rocks evolves as they flow. However, this work also highlighted important knowledge gaps regarding the fundamental microphysics of flow and how key processes should be mathematically described. At a time when populations exposed to seismic risk are rapidly expanding and when the modelling of ice-sheet dynamics is of unprecedented importance, it is critical to delve deeper into the microscopic processes of viscosity evolution in the rocks that underpin these systems. Deciphering the microphysical processes that control the viscosity evolution of rocks requires an ambitious multidisciplinary approach. Each element of the research will be centred on the novel adaptation of techniques from the forefront of the materials sciences to analyse key geological minerals. Experiments will be conducted at temperatures up to 1600 degrees Celsius and will induce viscosity evolution by imposing instantaneous changes in the applied forces, analogous to those imposed by earthquakes. At the same time, we will monitor sound waves emitted by defects in the crystals to characterise the fundamentals of their behaviour during flow. Using a new approach pioneered in the first phase of the project, a subset of the experiments will be performed inside a scanning electron microscope allowing the samples to be directly imaged during the tests. The microstructures of the samples will be analysed using state-of-the-art microscopy techniques, pioneered by our group, to measure distortions of the crystal lattices and the forces trapped within them. The combined mechanical data and microstructural observations will provide the new insights necessary to determine what controls key effects, such as the rate of viscosity evolution. Using the refined equations describing viscosity evolution, we will begin to explore the impacts of our work for the behaviour of fault zones over the earthquake cycle and rebound of underlying rocks as ice sheets melt. To build understanding of how the relevant materials and systems behave, we will take a multilevel modelling approach. First, we will analyse simplified scenarios designed to capture the key aspects of the flow of deep, hot rocks in the aftermath of major earthquakes or melting ice sheets to gain intuition of the most important effects. Second, we will integrate our new equations into three-dimensional models of Earth’s crust and mantle to simulate specific earthquakes and melting ice sheets to understand how these systems are likely to behave into the future.

UKRI Gateway to Research · FY 2025 · 2025-09

Lactation is a cornerstone of mammalian life, playing a pivotal role in the growth and development of offspring. Breastfeeding offers a wealth of benefits for mothers and infants. For mothers, it reduces the risks of breast and ovarian cancer, lowers the likelihood of postpartum depression, and strengthens the bond with their infants. For babies, breastmilk provides tailored nutrition and immune protection, reducing the risk of infectious diseases and fostering healthy development. In the long term, breastfed infants have a reduced risk for diabetes and obesity. The successful establishment of breastfeeding depends on the accurate and timely development of the mammary gland, a process driven by complex hormonal and transcriptional signals. Despite its importance, much remains unknown about the mechanisms underlying lactation, particularly the links between early postnatal nutrition and the origins of health and disease. This knowledge gap is particularly concerning given the increasing incidence of these conditions in an ageing global population. Breastfeeding is vital not only physiologically, but also culturally and evolutionarily across all mammals. Disparities in breastfeeding rates between developed and developing countries, and across socioeconomic groups, create inequalities for mothers and babies. Breastmilk is economically and environmentally advantageous compared to formula. It offers sustainability and lower health risks, yet breastfeeding is often overlooked in global health policies. Climate change further threatens maternal and infant nutrition, especially during disasters, when safe formula feeding becomes challenging due to disruptions in water, electricity and supply chains. This highlights the need to enhance our understanding of lactation biology to safeguard maternal and infant health in a changing world. The overarching aim of my research is to expand our knowledge of early postnatal nutrition and the biological mechanisms that govern lactation. Unlike traditional studies, my approach explores the mother, offspring, and milk as an integrated system, providing a holistic view of lactation biology. A significant focus of this work is on imprinted genes, which are crucial for embryonic and placental development but remain largely unexplored in relation to mammary gland function. Another novel aspect of this study is exploring inter-organ communication involving the mammary gland, both sending and receiving signals. Specifically, my objectives are: Investigate the function of candidate imprinted genes on mammary gland development, lactation and offspring growth. Study imprinted gene protein products in human breastmilk. Explore maternal inter-organ communication between the mammary gland and other maternal organs, to understand how these signals influence lactation and maternal health. By uncovering the fundamental processes that regulate lactation, this research has the potential to revolutionise our understanding of early postnatal nutrition, improve formula for infants, identify genetic factors that enhance milk supply, and shape public health strategies. Leveraging advanced genetic and molecular tools and integrating data from both mouse models and human breastmilk, my pioneering approach could uncover new pathways that drive infant growth. Ultimately, these discoveries have the potential to transform the lives of pre-term infants, those facing feeding challenges, and mothers unable to breastfeed, addressing critical global health issues and advancing the field of lactation science.

UKRI Gateway to Research · FY 2025 · 2025-09

This project seeks to understand the processes through which non-elite homes were decorated in the seventeenth and eighteenth centuries and in doing so tell the story of the rise of the painter decorator (as opposed to elite painters, stainers, and plasterers) in Britain. The story of interior decoration in this period has generally been told about upper-class houses, whereas this doctorate will establish the identity of people who painted, whitewashed, plastered, and applied wallpaper to the walls of lower-middle and lower-class homes. It will also explore the degree to which the lodging and boarding houses used by low-income people were painted or decorated, and also look at DIY traditions before the nineteenth century. The resulting thesis will transform our understanding of painting and decorating before the nineteenth century and put non-elite domestic interiors at the forefront. The research will also be central to the museum’s upcoming remodelling of the early modern period rooms to reflect a more diverse range of interiors from the period.

UKRI Gateway to Research · FY 2025 · 2025-09

The land carbon sink depends on the persistence of giant tropical trees. The largest 1% of trees store half the carbon in tropical forests and their deaths release this carbon back to the atmosphere, but we do not know what kills these trees because their deaths are rarely described. A novel sampling strategy is needed to effectively monitor the life and death of giant tropical trees. Gigante will integrate remote sensing and frequent field surveys to answer: (1) What kills giant trees and how do their mortality rates vary over space and time? (2) What are the risk factors underlying variation in giant tree mortality rates? and (3) How does giant tree mortality risk influence pantropical carbon stocks? We will locate giant tree mortality events using multi-platform, high-frequency remote sensing of 7,500 ha across five tropical forest super sites. These data will facilitate targeted field surveys using detailed state-of-the art protocols to assign proximate agents of mortality to recently dead trees in an unprecedently large field study. We will integrate these data with information about climate, topography, canopy structure, and tree traits to validate mechanistic models of tree mortality risk. Finally, combining these risk models with forest plots and satellite LiDAR, we will evaluate how drivers of giant tree death predict spatial variation in forest dynamics, structure, and carbon storage. The validation of geospatial relationships will allow us estimate the contributions of giant tree mortality to pantropical forest carbon stocks.

UKRI Gateway to Research · FY 2025 · 2025-08

Modern scientific experiments are built on dreams of disaggregating the world into separate variables. They crucially depend on creating controlled spaces in which the object of study is perfectly separated from surrounding sources of noise and dirt. But while scientists strive to keep environmental interferences out of their laboratories, these laboratories inevitably interfere with their environments. Laboratories are resource-intensive, take up land, and produce waste. Using historical and ethnographic methods, the proposed project investigates how scientific experiments materially depend upon and impact their earthly surroundings. Tracing and comparing the resources and waste of three experiments meant to detect the hypothetical dark matter particle, it aims to develop a new theoretical vocabulary that helps articulate the complex relation between experimental research and its various fragile environments. In doing so, the project presents the first detailed history of the experimental search for dark matter and provides critical impetus to an emerging field of research - the Environmental History of Physics. Its results will aid in advancing urgent discussions on the environmental impact of scientific research.

UKRI Gateway to Research · FY 2025 · 2025-08

Programmable nucleic acid-dependant therapies (NADTs) including siRNAs, antisense oligonucleotides (ASOs), CRISPR-cas 9 based editing systems, and modified in vitro transcribed mRNAs have the potential to transform healthcare. There have been considerable successes in NADT development, including the FDA/MHRA approved therapies Givosiran (siRNA) for acute hepatic porphyria and Nusinersen (ASO) for spinal muscular atrophy.  However there have also been notable failures such as the ASOs Tominersin for Huntington’s Disease treatment and SRP-5051-201 for Duchenne’s Muscular Dystrophy.  The emerging clinical toxicities which have resulted in withdrawal of NADTs from phase II/III clinical trials are hepato-, renal- and immuno-toxicity.  There are 3 major factors which contribute to the general failures of NATDs namely, an incomplete understanding of mechanisms of toxicity associated with the on- and off-target binding of NADTs, insufficient predictability of preclinical cell/animal models and an inability to predict which chemistries/sequences trigger adverse outcome pathways (AOPs). The ability to address these challenges requires a broad range of expertise and multidisciplinary partnership between academia and industry. This proposed partnership between the MRC Toxicology Unit (MRC-TU/UoC), Astra Zeneca (AZ), Mary Lyon Centre (MLC) and CRUK Scotland Institute (CRUK-SI) brings together individuals with unique skill sets and our combined efforts, working closely in the precompetitive space, will provide solutions to these major challenges. We will investigate ASOs, siRNAs and CRISPR-based editing systems.  The nucleic acids that form a key part of these therapies and the AOPs that they trigger are conserved and by studying these 3 modalities we will gain essential information about the commonalities and distinctions of on- and off-target toxicities of NADTs. Four work-packages are proposed where the combined outputs will improve the safety profiles of NADTs. WP1: We will gain mechanistic understanding of the toxicities associated with NADTs, identify ways in which to improve their safety profiles, and generate new assays that predict adverse outcome. WP2: To develop novel, advanced humanised preclinical models to predict NADT toxicity in vitro.  We will develop an advanced humanised model that is able to recapitulate kidney toxicity, since trial failure is frequently due to renal toxicity. WP3: To generate algorithms that are predictive of toxic NADTs to inform the safe-by-design agenda.  To achieve this aim we will use multi-omic data sets provided by AZ in parallel with machine learning and AI. WP4: Translation of research outputs for stakeholder benefit. In this WP, the assays/tools (WP1) and the advanced humanised models (WP2) will be made available through the MLC which will run assays and screens, accessible and affordable to the wider biomedical community. The algorithms that predict safe ASO design (WP3) will be made available through open-access repositories. We will collaborate with regulatory bodies (MHRA, EMA, FDA) and contribute to new regulatory guidelines. Our approaches will be informed by clinical data obtained from patient cohorts, and interaction with patient interest groups, via UpNAT.  Finally, the training provided in the partnership will build a diverse workforce with capacity and capability in safety science, ensuring the UK has a world-leading position in the development of advanced therapeutics for socioeconomic benefit.

UKRI Gateway to Research · FY 2025 · 2025-08

The human genome is believed to contain approximately 20,000 protein-coding genes, originally annotated based on criteria for predicting synthesis of stable proteins, including an arbitrary size threshold of 100 amino acids. Technological advances such as Ribosome footprinting (RiboSeq), which reveals the position of every translating ribosome, have abruptly challenged these assumptions, revealing widespread translation of thousands of previously unannotated, non-canonical, small open reading frames (smORFs) located in “untranslated” regions or “non-coding” RNAs. The biological impact of non-canonical translation is beginning to emerge, revealing smORFs that encode novel microproteins with potent biological functions. However, the vast majority of smORFs remain completely uncharacterised at a functional level. This suggests the potential for an entire layer of bioactive molecules that remains almost entirely unexplored. Initial studies were constrained by limited depth of RiboSeq data (often from a single tissue type or cell line), variation in the ORF-calling pipelines used, and the imperfections of current experimental technologies to screen bioactive microproteins. These constraints are evident from the minimal overlap in smORFs identified across studies, the diverse estimates of predicted smORF numbers, and the comparatively low number of microproteins to which biological function has been attributed. Our collaborative study will leverage the largest collection of pooled RiboSeq data ever analysed, spanning multiple tissue types. Our preliminary findings have already revealed thousands of smORFs, many with evidence of stable expression and apparent cell-essential function. We will deploy optimised and standardised analytical pipelines that incorporate innovative approaches such as translation factor binding data and tissue specific isoform usage to improve smORF calling precision. To overcome CRIPSR-associated limitations, we will exploit our optimised protocols for base-editor mutagenesis, generating a comprehensive base editor library targeting the start codon of every predicted smORF in the human translatome. We will perform start codon mutagenesis screens using cell lines and primary cells. These data will be integrated with ultrasensitive, deep proteomic profiling, single cell perturbational transcriptomics and co-expression network analysis to reveal stably-expressed microproteins, and resolve molecular functions for hundreds of bioactive smORFs. We will establish disease relevance of smORFs by integrating with variant data from thousands of cancer whole genomes and from 0.5million UK Biobank participants. We will develop deep mechanistic understanding of the function of selected microproteins to identify their contribution to cell biology and disease and to identify exploitable therapeutic vulnerabilities. Our computational analysis will encompass a broad, multi-tissue platform. However, our mechanistic investigation will focus onto non-Hodgkin lymphoma (NHL), where we can leverage strong RiboSeq data and the most advanced, already-optimised model systems for functional genomic screening. NHL is the 5th commonest human cancer and a significant cause of global morbidity and mortality. The slow progress in developing effective new therapies suggests gaps in our understanding of lymphoma biology. Whilst previous research has predominantly focused on the classical protein-coding genome, we propose that crucial insights into NHL biology may lie within the unexplored, non-canonical proteome. Ultimately, our study will provide a comprehensive functional compendium of non-canonical translation across the human genome, elucidating novel mechanisms that will reshape future research direction in fundamental cell biology and lead to novel therapeutic approaches in NHL. The computational and experimental tools developed through this study, including pan-start codon base editor library, will prove valuable resources for researchers as this emerging field of non-canonical translation continues to expand rapidly.

UKRI Gateway to Research · FY 2025 · 2025-08

The gastrointestinal (GI) tract is an attractive route for therapeutic delivery. However, targeting across the mucosal barrier is highly challenging, and evidence shows that therapeutics may be metabolised in the GI tract altering bioavailability[1] or even inducing toxicity.[2]  The standard for assessing efficacy and safety of novel therapeutics has been a combination of (2D) in vitro cell assays followed by animal testing, and human clinical trials. However, the drug discovery pipeline is inefficient (~90% attrition[3]), expensive (£2Bn++)[4] and lengthy (10-12 years). There are strong economic and humanitarian arguments for improving the efficiency of therapeutic screening. Animal models can provide useful information on therapeutic effectiveness, however, many late-stage failures in pre-clinical testing are related to species differences between rodents and humans. Recent awareness of the power of in vitro models to answer specific questions in drug discovery, has prompted a new wave of interest in Organ on chip technologies, with new legislation encouraging the use of alternatives to animal testing in the USA. This aligns with the NC3Rs work on new approach methodologies, recently debated in parliament.[7] Some failure points have been identified, including the inability of current in vitro testing to predict how physicochemical interactions of compounds of interest with specific tissues will impact human health. The consensus is that 2D models do not recapitulate the in vivo situation, as gene/protein expression and cell function is inherently different.[5] In addition, failure to consider the microbiota resident in the gut, is increasingly being identified as problematic, as it is now known to significantly alter therapeutic bioavailability and function.[1,6] 3D, engineered in vitro models of human tissues represent a solution to more accurately recapitulate in vivo biology, overcoming these challenges. We propose to develop tissue-scale, human, multicellular 3D models of the GI tract with embedded electronics, using dynamic in situ monitoring to evaluate the health of the tissue with subsequent monitoring of the effects of model therapeutics, taking into account the additional parameter of host-microbiota interplay. Advanced materials engineering will ensure accurate mimicry of the tissue, crucial to understanding initial interactions with tissues, and barriers to entry or effectiveness. The goal is to provide a medium-high throughput method to screen for therapeutics. The team’s expertise ranges from engineering biology (the PI is a leader in Organ-on-chips (OoC) with integrated electronic monitoring, a disruptive sensing technology), metabolomics of the gut microbiome (Patil), and clinical expertise on gastrointestinal disorders and derivation of human intestinal organoids from tissue biopsies (Zilbauer). This multi-disciplinary scientific expertise is complemented by the team at AZ, leaders in development and testing of therapeutics. The success of this proposal will result in faster, more accurate early screening of promising drug candidates, and enhanced understanding of host microbe interactions in the gastrointestinal tract. This work will not only solidify the strength of the UK in therapeutics development (particularly gut-directed biologics together with our partner AZ), but it will also contribute to our understanding of the basic biology behind gut disease. Our team’s combined expertise will complement existing knowhow, injecting increased strength and breadth, bringing in engineers and physical scientists to enhance the technology component, e.g. by incorporation of highly sensitive bioelectronic devices for efficient and accurate readouts in complex biological models. This project will contribute to strengthening engineering biology capabilities, applying engineering principles to the development of advanced tools for therapeutic screening.

UKRI Gateway to Research · FY 2025 · 2025-08

Alternative splicing (AS) is an important post-transcriptional process that allows individual genes to generate multiple mRNA variants encoding functionally distinct protein isoforms. Cell-type specific regulation of AS is principally achieved by the action of RNA Binding Proteins (RBPs). By binding to specific control sequences in pre-mRNA, these RBPs can either promote or inhibit assembly of splicing complexes at regulated splice sites. Many of the RBPs that regulate AS are widely expressed in different cell types, but a smaller number show more restricted expression and can act as “master regulators” that switch on specific AS programmes. Regulatory RBPs usually contain one or more structured RNA binding domains (RBDs) that allow them to recognise and bind to specific sequences in RNA. Their activity often requires additional regions without well defined structure – so called Intrinsically Disordered Regions (IDRs). In recent years it has become apparent that many of these RBPs are able to assemble into large structures that can be directly viewed by microscopy in cells. The assembly of these “biomolecular condensates” is driven by interactions between their IDRs and by multiple interactions between the RBPs and RNA. The importance of properly controlled assembly of biomolecular condensates is illustrated by the diseases that can arise from mutations in RBPs, leading to the normally liquid condensates becoming solid aggregates. The principles underlying regulation of AS by RBPs have been investigated by a number of experimental approaches, mostly using live cells (in vivo). A rigorous understanding of the physical principles underpinning the action of RBPs in regulating AS would ideally use cell-free (in vitro) approaches, but reconstituting cell-specific AS in vitro has rarely been achieved. This collaborative interdisciplinary project builds upon our recent discovery of the RBP RBPMS as a master regulator of AS in smooth muscle cells (SMCs), and the demonstration that it can confer SMC-regulation upon AS in vitro, acting as a specific repressor or activator of different target exons. RBPMS has an RBD that recognises CAC motifs in RNA and an IDR that is essential for function and confers the ability to form assemblies at different length scales, from >20 subunits (at endogenous concentrations) to microscopically visible condensates (at higher concentrations), in vitro. Our project will harness an array of state of the art approaches (a number of which were developed by the BBSRC SpliceSelect sLoLa) to address the following questions: What is the “molecular grammar” — the amino acid composition determinants — that enables splicing regulation by the IDR of RBPMS? How does the IDR mediate and control self-assembly at different length scales, and on individual RNA substrates? How does the IDR mediate interactions with other RBPs and splicing factors? How do IDR-mediated interactions orchestrate regulated splicing on individual pre-mRNA molecules? The outcome of our research will be a deep understanding of how the types of interactions that enable RBPs to assemble condensates can, in a more restrained way, allow the assembly of much smaller defined regulatory complexes on individual RNA molecules to direct regulated patterns of AS. Given the central role of RNA in normal cell function and the opportunities for development of RNA-based therapeutics, our project aligns with the Understanding the Rules of Life, Transformative Technologies and Bioscience for Health themes in BBSRC’s 2022-25 Strategic Delivery Plan.

UKRI Gateway to Research · FY 2025 · 2025-08

RMIT EU spearheads the Driving Climate Positive Futures (DREAM+PLAN), a truly interdisciplinary, international and intersectoral PhD program, uniting European and Australian research via 32 doctoral positions for double degree. DREAM+PLAN brings together a community of visionary changemakers, leaders, who dream big and develop tangible pathways for solving local and global climate-related challenges, all united by a mission to create a positive impact, towards a more sustainable, fair, inclusive and thriving planet for future generations. The need for 1. resilience (ability to withstand and recover from disruptions), 2. restoration (ability to repair or rehabilitate degraded ecosystems) and 3. regeneration (fostering the renewal, revitalization and replenishment of ecosystems, communities) research is more acute than ever. The overarching objectives of DREAM+PLAN research training program is to create and deliver, legacy-worthy, novel, cutting-edge, 3i-centric training through best-practice multi-faceted, multi-modal group and individual training options for DCs. This will ultimately breed the next generation of high-performing ESRs, equipped with a unique set of skills and capabilities to fully comprehend and address the multifaceted nature and scale of climate change, across sectors. DREAM+PLAN’s training program is aligned to contribute to EU Missions, the European Green Deal and supporting RIS3 strategies and includes 3 annual doctoral schools, adopting a novel scaffolding approach. DREAM+PLAN will fully embrace diversity and through its ecosystem approach, develop pathways for ESRs towards new mindsets, behaviours, technologies, policies supporting the transition to more sustainable, fairer, and productive futures.

UKRI Gateway to Research · FY 2025 · 2025-08

Because of their high energy density, Lithium-ion batteries are currently the dominating technology for powering electric vehicles and portable consumer electronics. However, their high costs, flammability, and the scarcity of elements such as Li, Co and Ni used in these batteries, have motivated the search for alternative energy storage solutions. This is particularly true for applications such as renewable energy storage where cost-efficiency, safety and sustainability are more important than energy density. This work focuses on aqueous Zinc-Ion Batteries (ZIBs), which are an exciting new battery technology where a Zn metal anode is cycled against a cathode typically made out of a transition metal oxide such as MnO2. These batteries do not rely on any rare or toxic materials, they use non-flammable aqueous electrolytes and are easy to recycle. However, ZIBs suffer from two major challenges that prevent their commercial adoption, the first is the growth of Zn dendrites and the second is hydrogen evolution reactions. Our project aims to address these issues by using new asymmetric separators that are rationally designed to cater for the different chemical processes taking place on the anode (plating and stripping) and the cathode (intercallation). These separators allow for a better distribution of the Zn-Ion flux, which addresses dendrite issues, and they will be paired with artificial solid-electrolyte interphase coatings to suppress hydrogen evolution reactions. Finally, a key goal of this project is to ensure that the proposed membranes can be manufactured at scale using a continuous Roll-to-Roll (R2R) process. Along with addressing the two challenges discussed above, this is critical for ensuring that the technology proposed in this project can have a tangible real-world impact. The two institutes working on this project (UCL and Cambridge) are equipped with state of the art scale-up manufacturing tools, including Roll-to-Roll coating, automated large area spray coating and pouch cell assembly lines. We will use these facilities to fabricate 5 Ah pouch cells with a lean anode design to demonstrate the capabilities of the proposed technology to industrial stakeholders and help the UK advancing towards it net-zero goals.

UKRI Gateway to Research · FY 2025 · 2025-08

Embedded Artificial Intelligence (AI) has emerged as a transformative technology with immense potential to revolutionise various domains, spanning from robotics and healthcare to environmental monitoring and the Internet of Things. This Doctoral Network (DN) project ANT aims to train a network of 15 excellent Doctoral Candidates (DCs) by addressing the fundamental challenges of Embedded AI and accelerating the development of Embedded AI systems and applications through an innovative and interdisciplinary research and training program. ANT consists of four interconnected Work Packages (WPs) that encompass different aspects of Embedded AI. WP1 tackles the challenges in designing low-footprint standalone Embedded AI models under resource constraints and with diverse contexts and evolving environments. WP2 goes beyond standalone Embedded AI and designs innovative distributed and scalable learning solutions for heterogeneous Embedded AI networks under energy and bandwidth constraints. WP3 enhances the trustworthiness of Embedded AI with explainability, robustness, security, and privacy. ANT concludes in WP4 with a concerted effort to transfer fundamental research contributions to industry-relevant applications in autonomous robotics, underwater IoT, mobile healthcare, and smart farming, boosting Europe's position in the global AI market both from a talent and a technological perspective. These interdisciplinary and inter-domain research training, along with the comprehensive soft-skills training (spanning from presentation skills to intellectual property, marketing, and economics, etc.) will make ANT's 15 DCs highly employable in various industries, academia, or public government bodies, and will position the EU at the forefront of the emerging revolution of Embedded AI on Things.

UKRI Gateway to Research · FY 2025 · 2025-08

We represent thirty research groups from the East of England region, including co-investigators from the University of Cambridge, the University of East Anglia, and from three major NHS trusts (Cambridge University Hospitals, Cambridge and Peterborough, and Royal Papworth Hospital). We rely on an ultra-high field 7T Terra MRI scanner which is the only imaging modality able to probe the brain of patients at sub-millimetre resolutions directly in vivo. This is essential for clinical research in dementia, epilepsy, stroke, traumatic brain injury and psychiatry and for neuroscience research because it shows vitally-important but subtle changes in brain morphology, microstructure, metabolism and blood supply. Our 7T MRI has been used for >4,900 scans in 58 studies so far: investigating mechanisms of disease, monitoring the effectiveness of new treatments, and revealing the role of the brain’s mesoscopic laminar/columnar circuit functional units. However, progress in research is increasingly being held back by technical and regulatory limitations from our 8-year-old “Terra” scanner. To enable the next decade of 7T MRI health research, we request a comprehensive hardware and software upgrade to the new “Terra.X” scanner which enables high-fidelity whole-brain imaging rather than being limited to studying cortical areas and which enables diagnostic imaging as a certified medical device unlike our current research-only Terra scanner. This will particularly benefit active programmes for: Dementia research: Rowe, O’Brien, Su, Lambon-Ralph study the causes and treatment potential for Alzheimer’s disease, Lewy Body disease including Parkinson’s disease, and frontotemporal dementias. Terra.X will increase our power to study the small but critical pathology of brainstem nuclei such as locus coeruleus and substantia nigra, as well as cortical pathology including early loss of mid cortical layers. Terra.X will enable whole-brain quantitative multi-parametric mapping (MPM of T1, T2* and MT contrasts) without the artefacts seen on the current Terra MRI. Epilepsy research: Cope aims to improve access to curative neurosurgery for severe epilepsy. We have shown that parallel transmit 7T MRI (7T-pTx) is ten times more cost effective per epilepsy-causing abnormality detected than the current NHS standard-of-care approach using invasive depth-electrode recordings, besides being substantially safer and more comfortable. This is already helping patients from East Anglia, London, and Liverpool. Terra.X will improve the quality of our whole-brain sub-millimetre 3D-EDGE, FLAIR and TSE protocols to better screen for epilepsy-causing abnormalities. These can occur in cortex, temporal lobes or elsewhere, and are often invisible to hospital 3T MRIs. Terra.X’s medical device certification means that we will be able to offer this innovative screening to NHS patients and not only to research participants as at present. Stroke research: Markus studies the causes of cerebral small vessel disease to design new/better treatments. Terra.X will improve imaging of the lenticulostriate arteries and their walls to differentiate between clotting, haemorrhage, and/or inflammation as causes of lacunar stroke. Traumatic brain injury (TBI) research: Newcombe, Stamatakis and Menon lead the UK-wide TBI-REPORTER consortium probing the mechanisms of injury and creating a platform to test emerging therapies. Terra.X will enable high-fidelity whole-brain susceptibility and diffusion imaging including in temporal lobes and brainstem which are important sites of injury but obscured on current Terra MRI. The Terra.X will be accessible to any funded UK research team: from the NHS, academia or industry. This investment will help the MRC meet its strategic ambition to develop cutting-edge infrastructure for research into human health.

UKRI Gateway to Research · FY 2025 · 2025-08

Reactive oxygen species (ROS) are vital for host defence and immuno-regulation. Although reactive oxygen species such as hydrogen peroxide are often considered damaging to cells through oxidative stress, humans have several dedicated systems for the production of ROS. In the immune system, the phagocyte NADPH oxidase (NOX2) generates ROS. Its importance is underlined by the fact that mutations in the genes encoding subunits of this protein complex lead to chronic granulomatous disease (CGD)[1]. CGD is an inherited inborn error of immunity (IEI), characterised by severe recurrent opportunistic infections as well as autoinflammation and autoimmunity [2]. Furthermore, genome-wide association studies demonstrate that hypomorphic coding polymorphisms in genes encoding phagocyte NADPH oxidase subunits lead to an increased risk of several autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis and inflammatory bowel disease [4][5] The propensity towards autoinflammatory manifestations in the absence of ROS arises because some ROS must be made for normal immunity, for example in the degradation of dead cells and the control of cell signalling. This latter effect is via the reversible oxidation of cysteine residues in proteins that are central to the immune response [6]. It is therefore crucial that the production of ROS is tightly regulated: both too much and too little are bad. The Thomas lab identified the Essential for Reactive Oxygen Species protein (EROS) as necessary for the generation of ROS. It is a chaperone for gp91phox, the key transmembrane protein of the phagocyte NADPH oxidase [3]. EROS is essential for host defence in both mouse and humans and homozygous mutations in EROS have been identified as a novel cause of CGD [7][8][9][13]. When EROS was first described it was a completely uncharacterised protein giving us very few clues to how its actions are regulated. My preliminary work, using multiple orthologous techniques, has identified TMEM128, another uncharacterised transmembrane protein, as forming a stable interaction with EROS. We have also demonstrated its functional relevance. TMEM128 can bind directly to EROS and physically sequester it away from gp91phox, thus regulating its ability to act as a chaperone for this protein. This is an exciting development because we believe that we have now found another crucial regulator of the ancient and conserved process of ROS production in the immune system. I will characterise the role of TMEM128 in regulating ROS production. I will focus on immune and endothelial cells as our preliminary data has shown high expression of TMEM128 (and EROS) in these cell types. I will use NanoBiT technology to dissect the nature of the interaction between TMEM128 and EROS by deciphering how this protein-protein interaction takes place. I will use our alpha-fold prediction of the EROS-TMEM128 complex, together with site-directed mutagenesis to understand the TMEM128-EROS interface. Yeast two hybrid and immunoprecipitation will also be used to further characterise the interaction. I will also determine what controls TMEM128 production physiologically. The functional relevance of TMEM128 will be addressed by knockout/knockdown using CRISPR-Cas9/siRNA and lentiviral overexpression followed by evaluation of NOX2 component expression and ROS production. Following this, I will phenotype TMEM128 knock-out mice and inoculate them with bacterial and viral challenges to understand the role of TMEM128 in host defence. I will therefore define the role of this novel ROS regulator in the immune system and vascular biology.

UKRI Gateway to Research · FY 2025 · 2025-07

The war in Ukraine has escalated discussions of ethnic identity and belonging among non-ethnic-Russian populations in the Russian Federation. Many are redefining what it means to be an ethnic minority in Russia and their place in the country's social and political fabric. Existing research in social sciences and humanities demonstrates that in a wide range of contexts, racialisation is highly relevant during war. Citizens' experience of racialisation shapes the relationship between ethnic minorities and the state, but shifts in racialisation also occur at times of war and in post-war settings. Therefore, in light of Russia's war against Ukraine, "Minority Russia" (MinRus) investigates shifting forms of belonging and identity amongst racialised ethnic minorities from Russia. More specifically, it looks at Inner Asian ethnic minority members who have fled Russia in light of the war in Ukraine and military conscription in Russia. First, it focuses on the ways in which the war facilitates alternative social imaginaries and alliances, analysing their conceptual and practical manifestations. This is investigated by providing a detailed case study of one minority group - the Buryats - and their relationship to Russia, as well as exploring their alternative visions of belonging. Second, it explores how racialised ethnic minorities negotiate belonging in Russia, focusing on how the war fosters interethnic alliances amongst Russia's ethnic minorities in diaspora. Third, it contributes to the comprehension of how ethnic minority racialisation is affected by war. MinRus aims to achieve this through an ethnographically-grounded investigation and an interdisciplinary theoretical framework drawing on anthropology, critical race theory, and decolonial studies. The project aims to contribute to anthropology, critical race theory, decolonial studies, and post-Soviet and Russian area studies through this endeavour.

UKRI Gateway to Research · FY 2025 · 2025-07

Understanding how melt aggregates in our planet's deep interior, i.e. its mantle, during melting remains a critical and fundamental open question in the Earth Sciences. This has important impliactions for topics as diverse as geodynamics and volcano science. Although the transport of melt in the mantle has been typically modelled as being a diffuse process, a variety of geological, geochemical, experimental and theoretical results suggest that this might occur via a network of channels that are 10s of m to km in width during long-distance (100s of km) lateral melt transport. However, it has been challenging to validate these theoretical models via natural observations and assess the importance of melt channelisation in the mantle across different tectonic settings. One geodynamic setting that provides an ideal natural laboratory to understand this channelised transport of melt is the interaction of mantle plumes with nearby mid-ocean ridges (< 1000 km distance). This is because melts derived from a mantle plume provide a distinct geochemical tracer for tracking melt transport processes. The key observed characteristic of this type of interaction is the presence of linear chains of volcanoes (volcanic lineaments). A classic example is the Wolf-Darwin Lineament in Galápagos, a ~ 200 km long volcanic feature extending from above a region where there is currently melting taking place within a mantle plume located ~ 250 km south of the Galápagos Spreading Centre. In our previous work we find that a variety of geophysical and geochemical observations for the Galápagos lineaments are naturally explained in a model where they overlie a network of volatile- and melt-rich channels connecting the Galápagos plume to the Galápagos Spreading Centre. Such volcanic lineaments are found in other plume-ridge interaction settings worldwide (e.g. Reunion, Easter, and Discovery). We propose to use a combination of newly collected geophysical data and novel geochemical observations of the Galápagos lineaments and the Galápagos Spreading Centre. Specifically, we propose to use an array of ~ 60 state-of-the-art broadband marine instruments, dropped overboard from the research ship, to measure electrical conductivity in sections at depths of ~60 to 100 km along and across the volcanic lineaments and the plume-affected ridge segments. Synthetic modelling demonstrates that the conductivity signals associated with the melt channels that we hypothesize are very likely to be detectable. We will couple the results from the geophysical survey with geodynamical models for Galápagos plume flow towards the ridge in order to test our findings and discern among the different possible melt channelisation mechanisms. Finally, while the geophysical instruments are recording data, we propose to dredge samples of igneous rocks along both the northern Galápagos volcanic lineaments and the lineament-spreading ridge intersections. We will analyse these for their geochemistry in order to constrain the contribution of melts from the mantle plume. This work will lead to significant, if not transformative, advances in our understanding of how mantle plumes generated near Earth's core-mantle boundary interact with 'shallow' tectonic features (mid-ocean ridges), and mantle melt transport processes in general. Furthermore, our work will shed important light on the interaction of deep Earth processes on surface systems. This is because the volcanic lineaments that we believe represent the surface expressions of melt transport in the mantle in the Galapagos are fundamental to the migration of marine species in the eastern Pacific (e.g. whale sharks). Our study will provide important constraints on how these topographic features form on the ocean floor and also their potential long-term influence on marine ecosystems.

UKRI Gateway to Research · FY 2025 · 2025-07

Context The Cambridge Centre for Proteomics (CCP) is a highly regarded proteomics facility at the University of Cambridge. The CCP facility has grown steadily over 24 years in both user access and research capabilities. Currently it provides core mass spectrometry and proteomics services for multiple departments across the university, including those within the Schools of the Biological Sciences, Clinical Medicine, and Technology. The centre's services extend beyond local academic boundaries, offering experienced proteomics support and expertise to pharmaceutical companies, small and medium-sized enterprises, and additional national and international research groups in a broad range of scientific research. The facility runs alongside the proteomics technology development research group, led by Kathryn Lilley. Interactions with this group ensures the facility can access and build expertise in cutting-edge technology and advanced informatics pipelines, making sophisticated proteomics capabilities available to a broad research community. Despite processing thousands of samples annually, CCP operates with only three mass spectrometry instruments: a Thermo Fisher Fusion Lumos, a Bruker timsTof HT, and an aging Thermo Fisher QExactive mass spectrometer. The QExactive, which has been the facility's primary instrument for 11 years, is now notably less sensitive and slower compared to newer models. This application outlines the critical replacement of this instrument with the Thermo Fisher Orbitrap Exploris 480 (OE480) which will sustain high-quality services for CCP’s existing and expanding user base well into the future. Objectives Our first objective is to purchase and install the OE480 mass spectrometer to increase our capacity and meet growing demand. We aim to enhance mass spectrometry capabilities by accessing a faster instrument and leveraging advanced multiplexing techniques, such as 35-plex TMT. The OE480 will significantly improve our research efficiency, enabling the identification and quantification of a greater number of peptides and proteins in a shorter time. Compared to our current QExactive, the OE480 offers superior sensitivity and speed. With extensive experience in mass spectrometer installations—having successfully implemented numerous instruments over the years—we are well-prepared for this upgrade. Post-installation, our second objective will be to conduct comprehensive user training through on-site sessions and targeted courses for students and staff, validating the instrument using standard protocols, and revising and maintaining our cost recovery model. Over 15 years, CCP has recovered all facility costs through recharging fees, and the OE480 will further support this financial sustainability while enabling continued expansion to meet evolving research demands. Potential application and benefits The OE480 offers high sensitivity and fast data acquisition, enabling more comprehensive protein coverage from complex samples. The instrument's advanced capabilities will expand the range of proteomics experiments, particularly those with limited sample quantities. Studies will thus be enabled where only low cell numbers, smaller tissue amounts or reduced volumes of biofluids are available. Furthermore, efficient experimental designs combining multiple samples per experiment will increase experimental throughput. Moreover, the OE480 is particularly well-suited for experiments requiring precise measurement of absolute protein and peptide quantities. Its increased scan speed when compared to our current instrument will reduce overall run times, thereby improving facility capacity and minimising user queues. A new pricing policy will leverage this increased capacity to reduce access charges. Its capabilities will not only support the specific research needs of co-investigators but will benefit researchers working within the BBSRC's research framework.

UKRI Gateway to Research · FY 2025 · 2025-07

The United Kingdom Chemistry and Aerosols (UKCA) model is a community atmospheric composition model developed by the National Centre for Atmospheric Science (NCAS) in collaboration with the UK Met Office and is a core component of the UK Earth System Model (UKESM). UKCA contains state-of-the-art schemes for whole atmosphere chemistry together with the GLOMAP aerosol microphysics scheme. These are large and complicated models, with a complex workflow and user interface, and training for new users is essential. The number of UKESM and UKCA users nationally and internationally has grown considerably over time. UKCA is open-source and provides standalone box-model configurations which mirror those used within large climate and air quality models. This training will not only prepare new researchers but will also support existing users of UKCA to keep up to date with new capabilities. Students will learn to use the box-model as well as the 3-dimensional model implementation of UKCA as used in UKESM to add new chemical reactions and diagnostics alongside associated chemical and aerosol processes, and to process, analyse, and visualise UKESM output alongside observational data. The content of this training course has been developed and refined over time following feedback from previous participants. Over 160 people have attended the annual UKCA training courses since 2013. All previous NERC-funded UKCA training courses have had applications up to, or exceeding, the 20 places available. Feedback from previous years has been positive, for example: “It's an excellent workshop that I would certainly recommend to future UK-based PhD candidates and post-docs having an interest in chemistry and aerosol.” “The practicals are tough but that's a good thing. The notes require you to think for yourself, but again that's a good thing.” “I find the work-flow of the practical very well designed.” “This was probably the best workshop I have attended” For previous workshops, 90% of attendees rated the practicals as good (28%) or excellent (62%). As the course content has grown over time, it is no longer possible to complete the training in a single week. We therefore split the training provision into introductory and advanced courses. The 2-day in-person introductory course covers basics such as making up new emissions files and analysing data, thereby teaching key skills that benefit all users of UKESM. The advanced course will be delivered as an online, on-demand course and will cover more complex code and diagnostic changes, with students encouraged to progress through the course material in their own time over three weeks. Students will be able to attend both courses, benefitting from the networking and interactive elements of an in-person course, whilst also having the flexibility to complete the advanced content at their own pace. Additional places will also be available on the advanced course for those unable to attend the in-person training. At the end of these courses the students will not only be confident in using UKCA for their own research, they will also have an understanding of where their work fits within the future directions for UKCA development and the opportunities this will bring. The advanced course is also well-suited for those who are considering coupling the UKCA model component to their own dynamical models, as they will gain an understanding of how to interface the standalone code with a larger parent model.

UKRI Gateway to Research · FY 2025 · 2025-07

AGRDEMAND seeks to understand determinants of long-run agricultural change and its relation to wider economic progress. It focuses on the pre-industrial Eastern Mediterranean, a region that has been conspicuously absent from the discussions around global divergence in agricultural development. Firstly, using a large original dataset from Ottoman tax registers, the study provides the first comprehensive picture of various regional agricultural production systems in the Balkans, Anatolia, and the Levant, and examines how these evolved during a period of demographic expansion in the 16th century. Secondly, through quantitative and comparative analysis, the study explores the role of market forces in shaping the geography and trajectory of pre-industrial agriculture. The project also produces maps of key indicators and provides a compelling visual representation of the relationships between these variables. The study breaks new ground in quantitatively investigating the impact of market forces beyond core Europe for the first time. Doing so, it addresses two vital aspects of global divergence. Was pre-industrial growth driven by the agricultural sector or urban economies and trade? Can a unified, dynamic, and non-Eurocentric framework explain agricultural change and its uneven diffusion both in and outside Europe? The interdisciplinary research utilizes quantitative methods and Geographical Information Systems while integrating historical geography to study pre-industrial agricultural economies. It yields new empirical evidence and high-quality knowledge in an understudied field, also bolstering EU's and UK's social science with unique expertise. By exploring the historical drivers of agricultural innovation and change, AGRDEMAND integrates historical perspectives into contemporary discussions about transforming agriculture into a sustainable sector that can meet rising food demand and enriches both theory and policy considerations.

UKRI Gateway to Research · FY 2025 · 2025-07

This project will demonstrate a proof-of-concept prototype of a novel synthesis of green ammonia using water directly as a hydrogen source, and nitrogen (from air) building on previous EPSRC-funded research outcomes (EP/X016757/1). The main disruptive aspect of the technology is that it is driven by solar concentrated energy or efficient electricity-to-heat, negating the need of capital-intensive electrolysers. In addition, the new process will be inherently efficient, intermittent to align to the production of renewable energy, low-capital cost and modular, facilitating distributed manufacturing. The intended prototype will de-risk the technology to accelerate its future implementation. The use of ammonia as an energy vector will accelerate the achievement of UK Net Zero goals by resolving one of the key challenges: alignment of the production of renewable energy with our energy demands through a carbon-free, easy to liquify and store energy vector. Indeed, ammonia is a readily competitive energy carrier due to its high energy density, existing global transportation and storage infrastructure. However, as all other e-fuels (e.g. methanol, sustainable aviation fuels), their synthesis through conventional thermocatalytic processes require the use of capital-intensive and energy-inefficient electrolysers. Considering the UK’s overseas dependency on electrolyser manufacturing capacity and their high capital cost, the chances of achieving the UK Government’s target of 10 GW of electrolyser capacity by 2030 seem elusive, making the project particularly timely and opportune.

UKRI Gateway to Research · FY 2025 · 2025-07

Quantum effects play a fundamental role in chemistry, yet the potential for chemical systems to carry out quantum information science (QIS) tasks remains largely unexplored. Of particular interest is entanglement—one of the key quantum resources in QIS – which remains difficult to measure and control in chemical systems. This project aims to change that by developing new experimental techniques to probe quantum correlations in the electron spins of molecular systems at room temperature. Our approach leverages nanophotonic cavities, specifically a metallic nanogap structure known as the nanoparticle-on-mirror (NPoM) platform , to enhance single-molecule optical measurements. This self-assembled structure provides extreme light confinement, amplifying optical signals and allowing for unprecedented sensitivity in detecting and manipulating molecular spins. Using this platform, we will achieve the first room-temperature optically-detected magnetic resonance (ODMR) at the single-molecule level, a critical milestone toward using organic molecules for quantum information science. By uniting nanophotonics, quantum optics, and spin photophysics, this project will open new frontiers in molecular quantum science. The ability to probe and manipulate spin entanglement at room temperature could impact a wide range of fields, from quantum computing and sensing to novel optoelectronic materials and chemically-inspired quantum processes.   The project is structured into three key work packages: Single-molecule ODMR with nanophotonics: We will harness NPoM-enhanced optical fields to detect and control electron spins in individual molecules. By using fluctuation spectroscopy and single-photon detection, we will overcome traditional limitations of ODMR, which has previously only been possible at cryogenic temperatures for single organic molecules. These advancements will enable high-fidelity readout of spin states, a crucial step for quantum networks based on molecular qubits. Probing quantum correlations in molecular processes: We will explore how spin-entangled triplet states evolve in processes like singlet fission (SF) and triplet-triplet annihilation (TTA). By embedding SF and TTA-active molecules in the NPoM platform, we will measure their quantum coherence in real time using single-molecule photon correlation spectroscopy. This will reveal how quantum entanglement persists or degrades in molecular systems, offering new insights into fundamental quantum chemistry. Demonstrating chemical Bell inequalities: Building on our ODMR and SF/TTA studies, we will design an experiment to demonstrate Bell inequality violations in a chemical system—something never before achieved. By manipulating molecular spin states with microwave pulses and detecting the resulting photon correlations, we will provide direct evidence of nonlocal quantum behavior in organic molecules. This result would mark a major breakthrough, positioning molecular spins as viable architectures for quantum technologies.

UKRI Gateway to Research · FY 2025 · 2025-06

Context and challenge The ability of human cells to sense and respond to nucleic acids is essential for antiviral immunity, but also underlies a broad range of diseases. DNA is a potent inflammatory trigger, ubiquitous inside nuclei and mitochondria, and present in pathogens such as DNA viruses and bacteria. Human cells can sense microbial DNA and self-DNA that has leaked from damaged organelles into the cytoplasm, causing an inflammatory response. Intracellular pattern recognition receptors (PRRs) bind foreign or mis-localised DNA and drive multiple signalling outputs required to restore tissue homeostasis. Dysregulation of these intracellular DNA sensing mechanisms therefore results in susceptibility either to infection or to autoinflammatory and autoimmune diseases. Indeed, there is an extensive and growing list of inflammatory pathologies and interferonopathies where DNA sensing PRRs are implicated, including Aicardi-Goutieres syndrome (AGS), Systemic Lupus Erythematosus (SLE), Sjögren's syndrome and neurodegenerative diseases. The DNA sensing PRRs cyclic GMP-AMP synthase (cGAS), DNA-dependent protein kinase (DNA-PK) and interferon gamma inducible protein 16 (IFI16) all bind cytosolic DNA and are required for the initiation of antiviral immune responses. It is not clear, however, how these proteins biochemically and functionally interact in different contexts to ensure appropriate signalling following infection or tissue damage. Viral genomic DNA and damaged self-DNA from the nucleus or mitochondria activate these cytoplasmic DNA sensing PRRs, but how these different triggers result in the generation of different signals is not well defined. For example, DNA-PK is indispensable in antiviral responses to poxviruses while IFI16 is essential for sensing herpesvirus infections and nuclear DNA damage. Further, we have now shown that different DNA structures can differentially stabilise DNA PRR co-complexes. As such we hypothesise that DNA sensing is context specific so we will define the specific molecular complexes that determine cGAS/STING activation and signalling outputs in response to DNA virus infection and DNA damage. To fully explore this hypothesis requires an integrated structural, biochemical and cellular approach to define the nature of these protein complexes in vitro, in cells, and in the context of virus infection. Aims and Objectives Aim 1: Define the molecular structures of DNA PRR complexes and their interactions with different DNA substrates Aim 2: Determine the context-dependent mechanisms of intracellular DNA sensing in human cells Aim 3: Define how human disease-associated variants in DNA-PK modify intracellular DNA sensing responses Potential applications and benefits There are broad therapeutic applications for pharmaceutical modulation of DNA sensing PRRs either for enhancing antiviral immunity or reducing the excessive auto-inflammation they can cause. Activation enhances adaptive immune responses and so these PRRs are key targets for vaccine adjuvants and neoadjuvant cancer therapies. Understanding how different triggers are linked to different signalling outputs will help to understand the disparate clinical phenotypes caused by inborn errors of immunity (IEIs) in different components of DNA sensing pathways. Specifically, in this study, we will define the impact of novel SLE-associated mutations in DNA-PK. Therefore, we will make key fundamental advancements in antiviral immunity, in keeping with the UKRI’s strategic priority ‘Tackling Infections’, whilst identifying specific mechanisms underlying SLE.

UKRI Gateway to Research · FY 2025 · 2025-06

Planets intermediate in mass between Earth and Neptune, sub-Neptunes, represent the frontier in our search for life in the Universe.  These worlds have no analogue in the solar system, yet occur frequently around other stars.  Their size and occurrence rate make them primary targets for characterisation with current observational facilities.  It has been hypothesised these sub-Neptunes could harbour life: with a layer of liquid water beneath their hydrogen-rich atmospheres and above deeper water ice layers.  Planet's with such a structure have been termed 'Hyceans', hydrogen atmospheres with liquid water oceans.  However, whether such planets exist is intensely debated.  On the one hand, early James Webb Space Telescope (JWST) observations of the atmosphere of the archetypal Hycean K2-18b, specifically the ammonia depletion of its atmosphere, have been used to argue for it having a liquid water ocean.  In contrast, climate modelling suggests sub-Neptunes like K2-18b receive too high an instellation flux to have water oceans, and our recent work shows that ammonia depletion in the atmosphere of K2-18b is equally consistent with a magma ocean at its surface.  New tracers of the climate and interior structure of this important class of planet are required to test climate models and the Hycean habitability hypothesis. We will develop observable tracers of sub-Neptunes being in a Hycean, magma ocean, or Neptune-like regime, by modelling how the differential dissolution of sulfur in sub-Neptune interiors leaves detectable atmospheric fingerprints. Sulfur is a key tracer of planetary processes, with its atmospheric abundance and chemistry sensitive to the presence and depth of a magma ocean.  Critically, atmospheric sulfur species strongly affect observations we can make today: emission/transmission spectroscopy (e.g., H2S absorption) and planetary bond albedos (through sulfur-haze formation). This opens the possibility of distinguishing between Hycean, magma ocean, and Neptune-like interiors on sub-Neptunes. We will develop diagnostics of sub-Neptune interior structure by extending self-consistent magma-ocean climate models to include sulfur for the first time: this is possible because of our team's significant experience of coupled climate-interior modelling, the thermochemistry of sulfur in magmas, and atmospheric sulfur chemistry.  A large ensemble of simulations will be run across key parameters of atmospheric mass, composition and instellation, self-consistently with predicted sub-Neptune interior structures. From these atmospheres synthetic transmission and emission spectra will be generated.   These predictions will be used to interpret present JWST observations of K2-18b, and inform future observing strategies to understand the habitability of this enigmatic class of planet.

UKRI Gateway to Research · FY 2025 · 2025-06

This project seeks to develop a high-sensitivity, low-cost sensor platform with a wide range of uses. To bring focus to the work, we will target for point-of-care bio-sensing, and specifically will use as an exemplar the detection of the circulating tumor DNA (ctDNA) due to the well matched requirements for ultra-high sensitivity, rapid results and portable system which cannot be currently addressed by other means. Optical micro-ring resonators hold great potential for sensing. Their ability to produce very high quality resonance with light circulating around a loop many times before being lost enables very high sensitivity between the circulating light and the external influences. However, as well as being highly sensitive this process is hard to control. To achieve the best sensitivity, the amount of light lost per circulation has to be extremely low, and can only be achieved with complex manufacturing processes. At the same time, the readout system typically relies on expensive and bulky tuneable wavelength lasers. We seek to overcome both problems using a combination of low-cost polymer (plastic) resonators and a readout scheme method where a microwave frequency sweep modulated on an optical carrier is used rather than an optical wavelength sweep. Typically the achieved tolerances of polymer waveguides are less good than other material systems (e.g. silicon) resulting in lower Q factors, we will overcome this by refining the nano imprint fabrication process and also leveraging the readout scheme which allows the signals used for the readout to be tailored to the specific imperfections of an individual micro-ring resonator. By overcoming the difficulties associated with the use of polymer micro-rings, we expect to realise many benefits. Polymers are low cost, and particularly well suited to functionalisation with biomolecules which do not stick well to other surfaces, so we expect to find a wide range of applications in healthcare diagnostics as well as wider sensing applications. Our ultimate aim within this project is to demonstrate the ability to detect low levels of ctDNA of actionable mutations in human subjects with non-small cell lung cancer. The use of genomic and molecular information is now standard in the treatment of lung cancer though routine testing still requires several weeks for the results to return to the ordering clinician. A rapid point of care detection and classification of ctDNA will accelerate this process and likely lead to improved patient outcomes