University of Leeds

UKRI Gateway to Research · FY 2024 · 2024-08

UK problematic substance use (PSU) is highest in 16-24 year olds with a recent estimate that 6.9% of women consume illegal substances each year. Young women with PSU are a chronically-underserved, under-researched demographic. Women's treatment needs are unique, however there is a dearth of provision and little research on what women with PSU want from services. My mission is to enhance the voice of young women journeying through and beyond PSU. I bring insights from my use of visual methods with a similar demographic in India and will embed women's perspectives in research, UK policy, and service development. This work builds on a partnership with Humankind Charity, one of the UK's largest drug and alcohol treatment providers. Aim 1: To enhance psychological, social and cultural insights into the experience of risk, resilience and recovery with regard to young women with PSU in the UK. This will be achieved through a systematic research review and a research study with a diverse sample of 12-15 women aged 18-30 years on their recovery journey. Data will be generated using visual methods-informed interviews and analysed with Thematic Analysis. Aim 2: To promote young women's voice with respect to PSU to raise public awareness and inform policy in the UK. This will be achieved through creating 5 co-produced films, public engagement, and promoting a policy brief. Aim 3: To adapt visual methods to enhance service provision for young women with PSU. This will be achieved through a placement with Humankind focused on knowledge exchange with service users and providers, and the creation of a training manual on using visual methods with young women with PSU. Scientific impacts include understanding the basis of an innovative solution to supporting the recovery from PSU. Social impacts include interrupting the intergeneration cycle of deprivation. Economic impacts are potentially enormous given that every pound spent on drug treatment saves 2.5 times that in future costs.

UKRI Gateway to Research · FY 2024 · 2024-08

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

UKRI Gateway to Research · FY 2024 · 2024-08

Rapid deforestation is occurring across the tropics with substantial impacts on local and regional climate including increased temperature and reduced precipitation. Whilst there is now strong evidence of the local climate impacts of deforestation, there is very limited understanding of how deforestation alters the climate at distances of tens to hundreds of km from the location of forest loss. These non-local climate impacts are challenging to assess and are poorly constrained, but have important impacts on the lives of millions of people living across tropical forest regions. Our analysis of satellite data has shown that regions of the Brazilian Amazon with both local and regional deforestation have experienced four times greater land-surface warming than regions with only local forest loss, suggesting that non-local impacts are substantial. We will use a novel combination of satellite remote sensing, machine learning and regional climate models to make the first detailed assessment of the non-local impacts of tropical deforestation on climate. We will apply machine learning methods to isolate the local and non-local climate impacts of forest loss in satellite records of temperature and precipitation. We will use a regional climate model with embedded water vapour tracking to assess how deforestation alters water fluxes, regional water budgets and climate. We will quantify the regional climate impacts of policy relevant scenarios and interventions identified through our network of tropical forest stakeholders. This work will transform our understanding of how deforestation alters regional climate and will ensure new results support evidence-based sustainable land use in the tropics.

UKRI Gateway to Research · FY 2024 · 2024-08

Membrane proteins are crucial to cellular function, such as recognition of - and interaction with - the extracellular environment and neighbouring cells, and controlling membrane dynamics, cellular signalling and transport of molecules and ions across membranes. Membrane protein malfunction underlies many diseases and disorders (in humans, animals and plants), and ~60% of current drug targets are membrane proteins. Determination of membrane protein structures, mainly by X-ray crystallography and single-particle cryo-electron microscopy (cryoEM), has provided detailed insights into their function and molecular interactions. However, membrane protein structures are typically determined after purification and stabilisation in non-native environments, hindering determination of physiologically relevant states necessary for understanding mechanism-of-action. The next revolution in membrane protein structural biology will be their structure determination in a native cellular environment by tomography, and many laboratories (including ours) are rapidly investing in tomography facilities for in-situ structural biology research. A major challenge in this field is how to detect and localise the membrane protein(s)-of-interest in a crowded membrane environment, and new technologies for this are urgently needed. Here, we propose to develop DogCatcher-quantum dots (DogDots), which will allow us to rapidly and specifically deliver quantum dots to membrane proteins that incorporate a short peptide (DogTag) within an extracellular loop. As a model system, we will use TRPC5 ion channels, which have important roles in health and disease. We have a strong track record of studying TRPC5 structure (by cryoEM) and have previously shown the feasibility of specifically labelling TRPC5 with DogCatcher. Using a workflow that builds complexity we will demonstrate how DogDots can be used to pinpoint TRPC5 in proteoliposomes, membrane-derived liposomes, and intact cell membrane, by both fluorescent and electron microscopy. Using Leeds' state-of-the-art Astbury Structure Laboratory, we will use DogDots to determine the first structure of TRPC5 in its cellular environment, at sub-nanometre resolution. We will also determine in-situ structures of TRPC5 in the presence of potent and selective activators, which may lead to the first structural insights into TRPC5's open channel state. This technology can be translated to any membrane protein with an extracellular loop, and working with our academic and industrial networks, we will develop DogDots as a versatile technology for structural studies of membrane proteins, thereby transforming our understanding of these important biomolecules.

UKRI Gateway to Research · FY 2024 · 2024-08

This project aims to create a new artificially intelligent continuous flow platform for the development of multistep chemical and biocatalysed reactions. Pharmaceuticals are complex molecules which require multiple transformations to synthesise from readily available starting materials. Traditionally they are produced via batch manufacturing, where after each step intermediates are stored in containers or shipped to other facilities around the world to complete the manufacturing process. This adds a significant amount of processing time, contributes to a large carbon footprint, and is at significant risk of supply chain disruptions. In contrast, continuous manufacturing addresses each of these challenges by enabling end-to-end production within the same facility. Catalysts are substances which are added to reactions which influence the rate and/or outcome of the reaction without been consumed. A well-designed catalyst will minimise the generation of waste by being highly selective, recyclable, and only required in very small quantities, often replacing the use of larger amounts of toxic reagents. Hence, it is economically and environmentally desirable to include multiple catalysed steps in a manufacturing process. Alone, the benefits of catalysis and continuous flow are becoming increasingly relevant due to the drive for decarbonisation, but in combination, they have the potential to truly transform the next generation of sustainable manufacturing. However, combining different types of catalysis into continuous flow processes remains highly challenging, due to poor compatibility between catalysts and the large number of variables that need to be optimised. In this project we will develop a fully autonomous and artificially intelligent multistep continuous flow platform, which is capable of simultaneously optimising interconnected catalytic reactions. New multipoint analysis and automated reconfiguration capabilities will enable the creation of individual feedback loops for each reaction, which will be driven by machine learning algorithms suitable for multiobjective and mixed variable systems. We will then demonstrate this approach for the optimisation of industrially relevant chemoenzymatic cascades in sustainable and mutually compatible reaction media (e.g., deep eutectic solvents), thus combining the versatile reactivity of chemocatalysis with the high selectivity of biocatalysis.

UKRI Gateway to Research · FY 2024 · 2024-08

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

UKRI Gateway to Research · FY 2024 · 2024-08

To secure a continued supply of safe, tasty, affordable and functional/healthy proteins while supporting Net Zero goals and future-proofing UK food security, a phased-transition towards low-emission alternative proteins (APs) with a reduced reliance on animal agriculture is imperative. However, population-level access to and acceptance of APs is hindered by a highly complex marketplace challenged by taste, cost, health and safety concerns for consumers, and the fear of diminished livelihoods by farmers. Furthermore, complex regulatory pathways and limited access to affordable and accessible scale-up infrastructure impose challenges for industry and SMEs in particular. Synergistic bridging of the UK's trailblazing science and innovation strengths in AP with manufacturing power is key to realising the UK's ambitious growth potential in AP of £6.8B annually and could create 25,000 jobs across multiple sectors. The National Alternative Protein Innovation Centre (NAPIC), a cohesive pan-UK centre, will revolutionise the UK's agri-food sector by harnessing our world-leading science base through a co-created AP strategy across the Discovery?Innovation?Commercialisation pipeline to support the transition to a sustainable, high growth, blended protein bioeconomy using a consumer-driven approach, thereby changing the economics for farmers and other stakeholders throughout the supply chain. Built on four interdisciplinary knowledge pillars, PRODUCE, PROCESS, PERFORM and PEOPLE covering the entire value chain of AP, we will enable an efficacious and safe translation of new transformative technologies unlocking the benefits of APs. Partnering with global industry, regulators, investors, academic partners and policymakers, and engaging in an open dialogue with UK citizens, NAPIC will produce a clear roadmap for the development of a National Protein Strategy for the UK. NAPIC will enable us to PRODUCE tasty, nutritious, safe, and affordable AP foods and feedstocks necessary to safeguard present and future generations, while reducing concerns about ultra-processed foods and assisting a just-transition for producers. Our PROCESS Pillar will catalyse bioprocessing at scale, mainstreaming cultivated meat and precision fermentation, and diversify AP sources across the terrestrial and aquatic kingdoms of life, delivering economies of scale. Delivering a just-transition to an AP-rich future, we will ensure AP PERFORM, both pre-consumption, and post-consumption, safeguarding public health. Finally, NAPIC is all about PEOPLE, guiding a consumers' dietary transition, and identifying new business opportunities for farmers, future-proofing the UK's protein supply against reliance on imports. Working with UK industry, the third sector and academia, NAPIC will create a National Knowledge base for AP addressing the unmet scientific, commercial, technical and regulatory needs of the sector, develop new tools and standards for product quality and safety and simplify knowledge transfer by catalysing collaboration. NAPIC will ease access to existing innovation facilities and hubs, accelerating industrial adoption underpinned by informed regulatory pathways. We will develop the future leaders of this rapidly evolving sector with bespoke technical, entrepreneurial, regulatory and policy training, and promote knowledge exchange through our unrivalled international network of partners across multiple continents including Protein Industries Canada and the UK-Irish Co-Centre, SUREFOOD. NAPIC will provide a robust and sustainable platform of open innovation and responsible data exchange that mitigates risks associated with this emerging sector and addresses concerns of consumers and producers. Our vision is to make "alternative proteins mainstream for a sustainable planet" and our ambition is to deliver a world-leading innovation and knowledge centre to put the UK at the forefront of the fights for population health equity and against climate change.

UKRI Gateway to Research · FY 2024 · 2024-08

Across human history, bacteria have been responsible for a huge burden of disease and mortality that only lessened with the discovery of vaccination and antibiotics. We now face a rising tide of antimicrobial resistance, and are experiencing a slow-moving pandemic of hospital-acquired infections by drug-resistant bacteria. Alongside better prevention, control, and surveillance, there is an urgent need to identify new targets against which we can develop new antibiotic drugs. Of particular concern are the Gram-negative group of bacteria. Of the five microorganisms identified as urgent threats by the US Centres for Disease Control, three are Gram-negative bacteria, and while there are worryingly few new antibiotics in trials, even fewer target Gram-negative bacteria. Membranes, and the proteins associated with them, constitute the majority of current drug targets across multiple disease areas, largely because membranes are the basis for much compartmentalisation and communication in and between cells. Gram-negative bacteria have a unique, additional, protective outer membrane (OM) that shields the bacterium from its environment. The OM is a major barrier to toxins and antibiotics, and is critical for bacterial growth, virulence, pathogenesis, and the formation of biofilms (which are important for establishing many infections). All biological membranes have two leaflets of amphipathic lipid molecules (typically phospholipids) that form a bilayer, and the lipids in each leaflet are different (asymmetric). The bacterial OM is perhaps the most striking example of membrane asymmetry in biology, with an inner leaflet dominated by phospholipids (as in normal membranes), and an outer leaflet dominated by lipopolysaccharide molecules (which are unique to the bacterial membrane). Integral outer membrane proteins (OMPs), which all have a barrel-shaped structure, have thus evolved to fold and function in a different environment to proteins in other membranes: they experience a very rigid membrane because the lipopolysaccharide clumps together. Furthermore, they don't move around very much in the membrane, and their conformations and interactions are dictated by interactions with other proteins and lipopolysaccharide that are missing in other membranes, but essential for bacterial growth and survival. The OM is thus a fascinating environment that could provide a rich source of new targets for antibacterial interventions. In this MRC programme grant, we will integrate functional and structural studies on the bacterial OM, with the latest innovations in protein structure (and protein interaction) prediction, and in our ability to design new proteins that can bind target proteins. Working in the test tube and with whole bacterial cells, we will learn how OMPs naturally fold up and become embedded within the outer membrane, how they interact with each other and with LPS molecules when they're in that membrane, and how these interactions affect the ways proteins work and how bacteria grow. Ultimately, we want to use these discoveries to illuminate new ways of killing bacteria, or at least weakening their defences so that other drugs can kill them. A programme grant is essential because it will allow us to build a talented team that can work together to make discoveries at a pace and scale that would be impossible via individual, smaller project grants, and it will allow us to place the UK at the forefront of this vital area of research.

UKRI Gateway to Research · FY 2024 · 2024-07

Monoclonal antibodies (mAb) are medicines that have revolutionised treatment of a broad range of disease states for nearly 3 decades. mAbs are expressed from engineered cells but recently there has been significant effort to enhance their functionality by protein engineering. This next generation of mAb-based therapeutics (NG mAbs) includes bispecifics, mAb-scFv and FC fusions. However, whilst this bring performance gains, the NG mAbs are generally less robust as a result of these modifications. This places a greater emphasis on correctly establishing the stability of potential candidate molecules at an earlier stage in the development cycle, such that "manufacturability" is built into the decision-making process around which candidates to take forward for industrial production. To de-risk the translation from scientific discovery to production, industry uses developability assays (DAs) to infer the likelihood that a potential candidate can be manufactured robustly at scale to give a safe and stable drug. There is an unmet and timely need to establish appropriate developability assays for this next generation of therapeutics. Working with industrial partners has highlighted that long term / accelerated stability (LTAS) is a critical quality attribute for candidate medicines that is costly to determine in terms of both time and resource. Ideally, candidates with good LTAS would be identified through the use of DAs, to identify manufacturable product, and at a stage where only small amounts of sample are available and in a short timeframe. Whilst many assays are available, identifying the optimal subset of DAs that can predict LTAS early on development, would allow resources to be focussed on those sequences likely to be successfully manufactured, reducing time to market and cost-of-goods and increasing sustainability. Here we propose to use a range of industrially-adopted DAs and manufacturing-focussed assays (developed by the applicants or advanced within this proposal), to perform a detailed, statistically robust investigation of the developability of three next generation formats. This will be carried out alongside LTAS studies, in line with industry practice. Working closely with manufacturing partners, this will support establishing a minimum panel of DAs in assessing manufacturability, was well as advancing scientific understanding that will rationalize molecule design. In addition, this data set will allow us to: (1) perform statistical and in silico methods to identify the relationship between each "family" of DAs and stability data for the first time for any format. (2) convolute liabilities identified by distinct assays into a single developability metric, simplifying the integration of often disparate DAs. (3) use statistical methods to identify a minimal set of non-degenerate DAs that predict LTAS using a fraction of the time and sample required. The resulting dataset will be unique in the sector for any format: it will be publicly accessible and contain sequence data, observables from DAs and LTAS data. Any stakeholder will be able to utilise this large dataset for their own analyses, either to generate predictive algorithms or to validate novel manufacturing methods or developability screens, increasing its impact. This study is timely since we are at the start of the manufacturing era of NG mAbs. To address manufacturability through identification of appropriate assays will provide a rationalised and streamlined pathway towards supply of this important class of medicines. It will facilitate the economic and sustainable translation of candidate therapeutics to blockbuster medicines now and in the future.

UKRI Gateway to Research · FY 2024 · 2024-07

Antibiotic resistance is projected to cause 10 million deaths per year by 2050, with gram-negative pathogens comprising 9 of the 12 bacteria that pose the greatest threat to human health, according to the World Health Organisation. These gram-negative pathogens have a unique outer membrane (OM) that acts as a first line of defence against an assault from potentially harmful molecules to the bacteria, such as antibiotics. As a result, the OM is essential for bacterial survival and is one reason why certain bacteria are resistant to different types of antibiotics. Finding ways to prevent correct assembly of the OM may therefore produce new routes to kill gram-negative bacteria, or make them more susceptible to existing antibiotics. However, the mechanism by with the OM is built remains mysterious, making its assembly difficult to target with therapeutics. Here we propose to determine how key proteins of the OM - so-called outer membrane proteins (or OMPs) - are folded into the OM to create the usually impenetrable cell wall. OMPs play essential roles in bacterial virulence and survival, so by understanding how OMPs are assembled into the OM it may be possible to develop new drugs that target this essential process. A key protein involved in ensuring OMPs reach the OM is a chaperone protein called SurA. SurA is an attractive target for the development of new drugs to control gram-negative pathogens because perturbing the chaperone function of SurA results in a loss of bacterial viability and virulence along with increased sensitivity to antibiotics. However, in order to target the chaperone function of SurA, further work is needed to understand its mechanism of action. We have recently discovered that two key sites on SurA are responsible for recognising OMPs. This is exciting, as it suggests that one or both of these sites could make good targets for new drug-like molecules. However, we still do not understand how each of these two binding sites contribute to OMP binding and chaperone function. Here we propose to use information from an array of complementary and cutting-edge experimental methodologies (including NMR spectroscopy, mass spectrometry, single molecular Forster resonance energy transfer, biochemistry/biophysics and bioinformatics) to understand how each of the newly discovered OMP binding sites on SurA recognises specific signals within its OMP clients. Further, we propose to determine how these two binding sites work together to bring about its chaperone function, in particular regarding SurA's role in protecting newly synthesised OMPs from aggregation and facilitating their delivery to the OM. This will uncover the molecular features of SurA that are essential for assisting in OMP biogenesis, which, in the future, could lead to new strategies to develop much-needed antibiotics that target gram-negative pathogens that threaten humans, plants and animals.

UKRI Gateway to Research · FY 2024 · 2024-07

Life's processes depend on the interactions of macromolecules with ligands and other macromolecules, and the resulting conformational and functional changes that occur upon complex formation. While measuring these interactions has yielded key mechanistic insights over recent decades, including parameters such as binding affinity and cooperativity, detailed measurements typically require well-behaved (monodisperse) samples, significant quantities of material, and simple buffer systems, rather than the complex milieu of physiological environments. Studies of intrinsically-disordered proteins (IDPs) and self-assembling systems are particularly challenging, but are involved in fascinating and biologically important mechanisms such as viral assembly, liquid-liquid phase separation (LLPS), protein aggregation and amyloid formation. Here we propose to purchase a Fida-1 instrument which has revolutionised measurements of binding, conformational change and self-assembly of even the most complex systems. Fida-1, supplied by Fidabio, offers real-time, sensitive detection of molecules coupled with rapid microfluidic separation (Flow-Induced Dispersion Analysis) (FIDA). Fida-1 is unique in its capability to resolve size, conformation and binding effects in polydisperse samples, bringing clarity to complex and self-assembling systems that have confounded existing techniques (e.g. dynamic or static light scattering). Fida-1 can resolve mixtures with a broad range of hydrodynamic radii, in ensemble mode for smaller particles and via simultaneous single-particle detection of larger assemblies. Experiments are performed in solution, and can include label-free measurements of virtually any system. It is automated, takes vials or 96-well plates, and has a uniquely broad size range, including small molecules, nucleic acids, proteins/peptides, polysaccharides, fibrils, viruses, biomolecular condensates and other nanoparticles, including membrane vesicles and virus-like particles. Low concentrations can be measured, in minutes, using mL of material, in physiological milieu and without need for purification. Fida-1 will be widely utilised in projects spanning the biosciences and biotechnology, from plants and microbes to man, from biophysics to cell biology, from health to disease. Specifically, we will use the instrument for sample quality control, enhancing efficiency of high-resolution structural analysis, binding-induced conformational changes, especially for dynamic biomolecules in complex environments. Fida-1 will be the first instrument of its type in a UK University, available to users across the Leeds campus, as well as academia and industry from the UK and beyond. Our AIM is to transform our ability to monitor and analyse macromolecular complexes key to life's processes and enhance capability in allied, high-resolution structural methods at the heart of the Astbury Centre for Structural Molecular Biology (ACSMB). Focusing on projects including LLPS, virus assembly, amyloid formation, molecular chaperones, IDPs and polysaccharides, our OBJECTIVE is to bring new capability that will increase fundamental understanding of biological mechanism and its translation. Working closely with the instrument manufacturers, we will run training events and host an annual symposium for Fida-1 users, providing the UK with a hub for exploitation and development of FIDA into the future.

UKRI Gateway to Research · FY 2024 · 2024-07

Transportation is the largest contributor of carbon emissions in the UK (23%). Tackling transport emissions is one of the defining challenges of the UK Government's Net Zero Strategy. The Climate Change Committee consistently finds that lower travel demand futures are necessary to meet our carbon budgets but, as yet, there is a lack of credible solutions in the UK or internationally which can deliver change at scale. Sharing mobility assets, 'right-sizing' of vehicles, and powered light electric mobility could counter the focus on heavier vehicles and accelerate electric vehicle uptake by lowering costs and widening access. New service design options such as demand-responsive transport, service integration across products, radical road space reallocation, and virtual technologies could also improve the attractiveness of non-car-based options. However transport science, has focused only on measuring, predicting, and acting under assumptions of increasing car use. It lacks the data, the models, the methods, and the mandate to inform more radical transformation to new forms of mobility access not predicated on individual ownership. The INFUZE project seeks to address this major gap with a vision: To transform the process of understanding, designing, and implementing transport system interventions to enable and ensure the rapid transition to zero carbon mobility through accessing mobility on demand. INFUZE will develop a ground breaking approach to participatory mobility science to build a unique suite of data-enabled decision tools to identify and galvanise the opportunities for emerging mobility service systems which capture the impact of place, social learning, and tipping points. We will test, evaluate, and learn through a series of ambitious real-world trials how to stimulate a transition from individual ownership to mobility access. The question is not 'can you live without your car?' but 'what would a world where people did not need to own their own cars look like?' INFUZE will answer this question by achieving seven key objectives: Co-design with communities and stakeholders a set of vision-led approaches to building mobility systems which provide a positive alternative to car-ownership Develop new tools and conceptual models to understand the propensity to shift mobility ownership to mobility access taking account of new mobility service characteristics Build a world leading Agent Based Modelling platform which enables the joint modelling of mobility ownership, access and mobility choices Create and deploy new forms of data visualisation to enable stakeholders to engage with, scrutinise and impact our models to build enhanced scientific legitimacy Test, learn, iterate and validate our tools through a transdisciplinary, experimental approach that integrates participatory design science, data science and behavioural science Identify the governance and policy changes which will enable new mobility packages to be scaled up and transferred nationally and beyond Change how mobility transitions are researched, developing a new approach to participatory mobility science for change INFUZE will open up opportunities for researchers to develop new projects and businesses to develop and test algorithms and services. The grant will act as a springboard to a new National Centre of Excellence in Low Carbon Mobility Transitions as a major 'place-based' investment that will enable partners from across the UK, and globally, to design and evaluate interventions building on our unique data assets, models, and whole life carbon assessment tools. Our participatory mobility science will change the way consultancies and governments approach the mobility transition challenge.

UKRI Gateway to Research · FY 2024 · 2024-07

This ambitious R&D project will transform the fractured data infrastructure of the UK’s arts, cultural and heritage (ACH) sectors and create the blueprint for a national Cultural Data Observatory.  Currently, data about the ACH ecosystem is fragmented, incomplete, inconsistent and insufficiently granular. This reflects the anomalous characteristics of a sector dominated by SMEs and a substantial freelance and mobile workforce, financed by a mix of private, public and third sector sources, and divided into specialised sub-sectors. The fluid and multi-agency nature of the sector currently inhibits a holistic data view. This project addresses both of the call’s themes by: (a) scoping a transformational data collection infrastructure (the proposed Cultural Data Observatory); (b) facilitating the development of alternative data collection methods (population surveys, financial analysis of cultural organisations, creative, qualitative and ethnographic methods to capture cultural value and engagement).  The research will be coordinated and disseminated by the Centre for Cultural Value, a national research centre based at the University of Leeds. It will be led by a cultural policy scholar, co-led by a human geographer and a quantitative sociologist, and supported by the Leeds Institute for Data Analytics and by industry data experts sub-contracted from The Audience Agency and MyCake.  The Observatory blueprint will demonstrate the possibilities for data collection, aggregation and analysis. It will incorporate cultural infrastructure and activity, cultural engagement and participation, and the different dimensions of public value that accrue from these – social, economic and environmental. By doing this at unprecedented scale and granularity, the ambition of such an Observatory is to provide a definitive, defensible and trusted evidence base both for ACH sector strategy and for public policy more broadly. It will deliver this evidence base by: Refining the potential opportunities for ACH data to formulate a framework that meets the needs and use values of key stakeholders.  Identifying and evaluating the quality and feasibility of datasets to represent the key elements of the ACH ecosystem in a national observatory. These will range from physical infrastructure, talent and other human resources, and creative knowledge assets to improved health and wellbeing, enhanced education and better work through to positive impacts on leisure, enterprise, tourism and consumption.  Piloting the immediately feasible elements of the resulting data framework within a regional data observatory for Bradford 2025, the next UK City of Culture.   Beneficiaries: Sector: Organisations and freelancers across ACH will benefit from the more joined-up sector strategy and policy design, as will the myriad consultancies, think-tanks, academics and researchers that support them, to help make their case, demonstrate impact and develop their practice.  Public: Public resources are committed to ACH to benefit a variety of publics and communities (including ‘audiences’). National (e.g. DCMS, Arts Council England), regional (combined authorities) and local authorities and policymakers will benefit from more standardised, impactful, consolidated sector data – more focused on people and where they live.  Other sectors: policymakers and public, third sector and private funders/providers operating in health, education, social justice and tourism. The observatory will provide evidence in terms and on a basis that they understand with respect to value, use and investment in culture.  By the end of the project, we will have built a national consortium to develop a major UKRI bid to develop, establish and implement a national observatory for cultural sector data. 

UKRI Gateway to Research · FY 2024 · 2024-07

In order to function, cells need to sense their environment, manipulate their surroundings and move. For example, sperm cells swim using a whip-like tail; the cells lining your airways sweep mucus up into your throat, keeping your lungs clear; rod and cone cells in your retina collect light, allowing you to see; and the cells in your kidneys sense the flow of urine. These diverse functions are all performed by various types of cilia, which are finger-like organelles on the surface of cells. Cilia are found in many different organisms, from single-celled algae, to flies and humans. This shows that they evolved a very long time ago and are so useful that they have been retained and repurposed for a multitude of different biological functions during evolution. This proposal focuses on a protein called CEP290, which is one of the largest proteins in cilia. CEP290 is essential for the correct formation and function of cilia. When this protein is defective or missing from cells entirely cilia do not form correctly, and when they do, they have the wrong composition, which compromises their function. However, we don't understand what this protein actually does. We know very little about its structure, how it interacts with other cellular components, and how its organisation allows it to function. Cells are full of tiny membrane-bound "bubbles", called vesicles, that transport cellular components from one part of the cell to the other. The cell uses vesicles to generate cilia and, once formed, "feed" them with the components they need to function properly. Based on similarities with other proteins in the cell, we think that CEP290 is a "vesicle tether", whose role is to capture vesicles that contain cilium components and guide them to their destination at the cilium base. In this proposal we will investigate this hypothesis by investigating the molecular structure of CEP290, studying its binding to vesicles in vitro and inside cells, and how this function relies on its interactions with membranes and other cilium proteins. This will provide essential new insights into the molecular details of how cilia form and function. Genetic mutations in CEP290 cause a very broad range of inherited disorders. This tells us that CEP290 does something very important in cilia, and hence that we need to know what it does and how it does it to understand how cilia work. As cilia and CEP290 are found in such a wide range of organisms, from algae to humans, this will have wide-ranging implications for biology. Thankfully, human diseases caused by CEP290 mutations are rare in general, since both parents must carry a disease-causing mutation to produce children with a CEP290-related disorder (i.e. these disorders are recessive). However, the incidence of these disorders is much higher in consanguineous communities, which are often experience healthcare inequality and do not benefit fully from research. Thus, understanding how CEP290 mutations cause disease will help improve genetic counselling and develop gene therapies to prevent and treat these conditions, which is an important clinical and societal unmet need.

UKRI Gateway to Research · FY 2024 · 2024-06

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

UKRI Gateway to Research · FY 2024 · 2024-06

Chikungunya virus (CHIKV) is an arbovirus, transmitted by Aedes aegypti and Aedes albopictus mosquitos. Since its re-emergence in 2004, it has caused numerous epidemics across expanding geographical ranges within sub-/tropical areas of Africa, Asia and the Americas and increasingly across temperate regions of Europe, Asian and North America. The main risk factor for spread of CHIKV is change in global mosquito vector distribution - as a consequence of climate change associated seasonal variations and increasing mean temperatures, globalisation and changes in land use. Invasive populations of Ae. albopictus have been identified in the UK and temperature rises are expected to increase their months of activity and range. Chikungunya disease is associated with severe debilitating joint pain for months or years and exacerbation of co-morbidities. High mortality rates are observed among elderly patients with pre-existing conditions, such as hypertension or diabetes. Despite increasing numbers of epidemics and their expanding geographical spread, there remains no specific antiviral therapy or licenced vaccine. The mechanism and interactions by which CHIKV controls translation and replication of its genome are unclear. We have shown that CHIKV requires host protein MSI2 to replicate its genome in human cells. We and others have also shown that host protein DHX9 is required for efficient CHIKV translation, while simultaneously inhibiting replication of the virus genome. We demonstrated that MSI2 and DHX9 interact specifically with the 5' region of the CHIKV genome and identified an MSI2 RNA binding site within this region of the virus genome. We previously published a study demonstrating that the 5' region of the virus genome forms complex RNA structures, essential for CHIKV replication. We have also produced preliminary data consistent these RNA structures regulating the MSI2 binding to the CHIKV genome. Therefore, the scientific objective of the project is to generate a detailed functional and structural model of how these different factors interact, to regulate CHIKV translation and genome replication. We will address the following objectives: (i) We will identify MSI2 and DHX9 RNA binding sites within the CHIKV genome and the role of RNA structure in MSI2 and DHX9 binding. (ii) Confocal imaging will be used to determine changes in localisation, co-localisation, expression and degradation of MSI2, DHX9 and nsPs during CHIKV translation and genome replication. Using the same approach, we will determine the influence of individual RNA structures on these changes and interactions. (iii) Our previously published studies demonstrate that RNA structures in the 5' region of the CHIKV genome are essential for virus genome replication. Therefore, we will use in vitro and in cell approaches to determine the RNA structure of the CHIKV genome following interaction with MSI2 and DHX9. We will also determine the RNA structure specifically associated with CHIKV genome replication and different stages of virus translation. (iv) To complete our understanding of the interactions between MSI2, DHX9 and the 5' region of CHIKV genome we use Cryo Electron Microscopy to generate high-resolution 3D models of unbound and protein-bound RNA tertiary structures. With results from the other aims, this will allow us to produce a detailed model of the regulation of CHIKV translation and genome replication. As well as furthering our understanding of how CHIKV controls translation and replication of its genome, results will provide a model for related human pathogenic viruses. An increased understanding of this fundamental mechanism will provide insight towards novel therapeutic targets and attenuated vaccine design.

UKRI Gateway to Research · FY 2024 · 2024-06

Development of synthesis and optimisation of reactions remain rate-limiting factors in pharmaceutical process development, often relying on resource-intensive trial-and-error approaches that are costly, time-consuming, and wasteful. This highlights the need to develop new digital methods that are capable of rapidly responding to emerging health challenges. To achieve this, we will create a network of digitally coupled reactors across multiple sites capable of high-throughput screening and self-optimising manufacturing processes. This proposal uniquely combines different flow reactor technologies, analytical techniques, and automated workflows to provide enhanced mapping of chemical space and generation of robust high-quality datasets. Robotics will be used to design flexible experimental systems capable of exploring continuous (e.g., time, temperature) and categorical (e.g., catalyst, ligand) variables, as well as different reactor types. Notably, parallelised droplet flow reactors will be developed and combined with intelligent optimisation algorithms to reduce the amount of material required during pharmaceutical development campaigns. A multisite reactor network will be established and driven by next generation machine learning algorithms, which will use knowledge from prior experimental campaigns to increase library synthesis success rates and accelerate the development and optimisation of chemically related processes. Orders of magnitude more experiments are performed during discovery than during process development; the high-quality automated data collected at this early stage will be essential for accelerated, lower cost and sustainable manufacturing. In collaboration with our partners in the pharmaceutical industry, we will leverage this novel workflow to streamline the pathway to future medicines. The capabilities and results generated from our delocalised artificially intelligent network will be transferable across different chemical manufacturing sectors. The objectives of this research are: Development of autonomous high-throughput microfluidic flow reactors for the synthesis of pharmaceutically relevant compound libraries. Library synthesis success rates will be increased by integration of state-of-the-art mixed variable optimisation algorithms. Real-time online analytics will be used to quantify each reaction, thus providing robust and standardised datasets for use in predictive machine learning models, enabling their application towards currently underexplored chemistries. Creation of digitally coupled reactors across multiple sites for the exploration of wide process spaces. To achieve this, complementary analytical techniques and different reactor technologies will be leveraged to generate datasets across different scales. Parallelised optimisations will consider the trade-offs between multiple objectives, enabling the sustainability of manufacturing to be considered from the outset of pharmaceutical development. Combination of different types of data across multiple experimental labs to generate hypotheses for new library synthesis and process optimisation campaigns. Next generation machine learning algorithms will be designed to use prior knowledge of contextually similar chemical systems, with the aim of accelerating the transition from discovery to manufacturing. Demonstration of a pilot-scale manufacturing process. Our network of digitally coupled reactors will be used to perform parallelised library synthesis and self-optimisation of a selected process. Scale-up will be evaluated using the facilities available within the iPRD at Leeds.

UKRI Gateway to Research · FY 2024 · 2024-06

Stroke patients often suffer from sudden and unpredictable muscle spasms during robot-assisted rehabilitation. If not addressed properly, it will put the patient at high risk of secondary injury. Leveraging University of Leeds's and my expertise in musculoskeletal modelling, biomechanical analysis, rehabilitation robotics and robot control, my vision is to address this challenge via building an advanced neuro-musculoskeletal model of spasticity for precise spasm detection and developing an adaptive variable stiffness human-robot interaction control method specifically aimed at providing effective protection against spasms. This approach will help to enhance the safety of robotic rehabilitation training, and it will ultimately benefit millions of individuals recovering from strokes via increasing their chances of successful rehabilitation and leading to improved quality of life for them.

UKRI Gateway to Research · FY 2024 · 2024-06

The Network for sustainable Digital Research Infrastructure Vision and Expertise (NetDRIVE) will provide a forum for managers, software engineers, academics and others to come together to build a common vision for a sustainable future and to incite a transition to sustainable working practices in the DRI communities. In Stage 1, the two co-coordinators will engage with academics, industry, policymakers, DRI users and other stakeholders to build a Stage 2 proposal which is adapted to community and stakeholder needs and expectations. Through an open process we will ensure that the network created in Stage 2 has the visibility and authority necessary to provide UKRI with clear and actionable information. The Stage 1 work has a total budget of £106,382 covering the staff costs of the co-coordinators, with a combined commitment of 0.7 FTE, an additional 0.8 FTE of support staff, travel and event costs (including funds for a specialist facilitator). The support effort includes staff at STFC and Edinburgh to provide local support for two community events, project management and communications support, and finance support for preparation of the Stage 2 budget. We envision a network which will be composed of experts nominated by key stakeholders, community members recruited through an open call in Stage 2, and invited international domain experts. The network will, by design, represent both the technical, organisational, academic, and geographical diversity of the UKRI DRI community and the societal diversity, particularly with respect to age, gender, and ethnicity. The network will provide a forum within which creative thinkers from across the spectrum of DRI users and managers can share and develop ideas to deliver the transition to net zero. Constructive framing of discussion and synthesis of outcomes will be led by four champions to be recruited for Stage 2. Details of the job roles will be finalised, with community input, during Stage 1, but should broadly cover: Machine rooms and computer architecture. Green Software Engineering. Inciting change and supporting transformation. A system level view to ensure progress against global targets and ambitions. A project office providing project management, communication and facilitation support project office will support the work of the network, champions and community projects. The project will also distribute funds for community projects in spring and autumn of 2025. Sandpit events will be held to enable community participation in shaping projects and encourage consortium projects. The first will be for projects running from September 2025 to August 2027, the second for projects from June 2026 to December 2027. Defining the composition, governance and terms of reference for the network will be critical. The network will include both members nominated by Research Councils and members recruited by an open call. Recruitment procedures will ensure that the network includes the necessary technical, managerial, and transformational competences as well as meeting diversity and inclusivity requirements. The Terms of Reference of the network will set out the commitments of Network members and the processes through which the Network will be able to advise UKRI on steps needed to progress towards the Net Zero objective. The central role of ethical considerations planning organisational change will be addressed through a white paper on emerging ethical challenges.

UKRI Gateway to Research · FY 2024 · 2024-06

This fellowship proposal plans to increase our capacity to predict the ways and magnitude in which non-native invasive species will cause damaging ecological impact and under what environmental scenarios. This will drastically enhance the efficiency of conservation interventions and proactive policy making to benefit biodiversity and human livelihoods. Biodiversity loss is occurring rapidly in all ecosystems across the globe. Freshwater systems have the highest extinction rates in any system and are losing populations at an alarming rate. This is due to the interacting effects of climate change, non-native invasive species, and habitat loss. Around 10% of established non-native species populations are thought to cause negative impact, however, this changes under different climatic scenarios as environmental change can trigger benign populations to become damaging. Due to the speed of change it is not practical to wait until a species is present and causing damage in the environment. Pre-emptive action will vastly benefit global biodiversity goals and economies which lose US$162.7 billion annually due to biological invasions. These costs are incurred through damage to infrastructure, flooding, loss of ecosystem services, damage to fisheries, as well as management costs undertaken to control species of concern and mitigate damage. To act pre-emptively to reduce these costs, we need accurate methods to predict which species will cause what negative impact, and under which environmental scenarios. Current methods are insufficient as they do not account for the complexity of natural environments nor the rate of global change. We need to use interdisciplinary approaches to unravel and predict the interacting twin threats of non-native invasive species and climate change at a global scale. Contemporary methods have not yet resolved this level of complexity which makes cohesive management action impossible. Food web interactions determine the structure and composition of biological communities. If interactions in the food web change, this can drastically alter the functioning of the ecosystem and have knock on effects for all levels of biodiversity, as well as human livelihoods. Food web interactions can be measured in a standardised manner across all species. I will use interaction strength as a currency to track change across communities over space and time. Foraging efficiency varies depending on physiology and morphology of both consumer and resource, and the outcomes are governed by of responses of both to environmental characteristics. Multi-disciplinary methods will be paired and tested in the laboratory and then upscaled to field campaigns under natural conditions. This will generate ecologically relevant data which will be used to develop a hypothesis testing model which will be used to predict the conditions in which an invasive species will cause negative ecological impact on native biodiversity regardless of invasion location or time since invasion. This will allow us to find general rules which control invasion dynamics and ecological impact regardless of climate and time, to be able to predict ecological outcome in advance and "future proof" legislation. I am an aquatic ecologist who has developed and pioneered multi-disciplinary impact prediction methodology. The current project builds on my previous innovations and leverages my international partnerships. My vision is that the capacity of my partnerships are built up to function as an International Freshwater Invasions Network to tackle future pressing challenges which can only be solved through global cooperation. This fellowship will provide the foundation for the formation of this network and contribute to guiding more effective legislation and targeted invasive species management approaches which account for global climate change. In doing so, the outcomes of this research will directly combat rapid biodiversity loss in freshwater ecosystems.

UKRI Gateway to Research · FY 2024 · 2024-06

The cement and steel sectors are foundational to the UK, are the largest manufacturing industries (by mass), and are essential to construct our infrastructure. Cement manufacture is intensive in resources, carbon, and energy, and needs radical transformation to achieve sustainability. The steel industry produces up to 1M tonnes of steel making by-products annually, and into the foreseeable future. These waste materials need to be managed properly to improve resource efficiency, and to avoid landfill and subsequent ecotoxicity. Although effective utilisation of steel slags is ~80%, a large portion is unutilised. Moreover, the majority of slag utilisation is for low-value products, e.g. aggregate, but their chemistry and mineralogy are variable, making their effects on material properties unpredictable, in the absence of further processing. Additionally, more than 190 Mt of legacy iron and steel slag are present across the country. The UK's cement industry is set to cut 4.2 MtCO2 emissions per year by 2050, about half of which is to be gained by resource efficiency in cement plants. Every year, the UK cement sector consumes ~12.5 Mt of natural raw materials, which can potentially be substituted with by-products that the steel sector produces. These materials contain the key elements that are essential to cement making, but they also have an unusually high amount of iron. FeRICH aims to replace the natural raw materials used in Portland cement making by valorising and upcycling iron-rich waste materials from the steel industry. This leads to cements containing an unprecedented level of [calcium] ferrites; however, our understanding of ferrite chemistry is still incomplete, and we need to establish what happens to this phase both during cement production and after use. These side streams also constitute other minor elements that are likely to alter the cement chemistry. Therefore, we need to develop the knowledge underpinning the interdependency between the role of minor elements in ferrite chemistry, what controls the reaction of ferrite with water over time alone or in mixture with other phases occurring in cement, and importantly, the long-term durability of ferrite-rich cement. Along with this, we also need to develop modelling tools to be able to predict the relationship between these factors - FeRICH relies on thermodynamics as a powerful technique here. We also recognise that ferrite-rich cements are ferromagnetic, and this property can add functional properties to cement (or subsequently to concrete) which may be exploited throughout the materials lifetime: form manufacturing to both their service life and end of life. FeRICH will develop and validate data-for-manufacturing of ferrite rich Portland cement. From reactions at high temperature in kilns to reaction with water at ambient temperatures, we will establish the best cement making conditions and materials compositions to achieve maximum process, energy and resource efficiency in kilns and cement performance upon reaction with water. For the first time, we will also examine the electromagnetic properties of ferrites related to cement, laying down the foundation for building intelligent systems in the future infrastructure. The findings and data developed in this project will be assimilated into tools that will accelerate the uptake of iron rich wastes in cement making. FeRICH will reduce the environmental burden of the cement industry and drive the steel industry towards zero-waste through implementation of the circular economy strategy. This will help alleviate the current crisis in the UK steel industry whose competitiveness in the global market is inhibited by a higher overhead costs than other countries. The results will allow for the use of other iron-rich materials for cement making, in the UK and worldwide.

UKRI Gateway to Research · FY 2024 · 2024-06

What does it mean to imagine music? Imagining music in one's head is a common experience (Bailes, 2015). Yet relatively little is known about how this aspect of our shared humanity relates to our wider wellbeing. The innovative 'Inner Music and Wellbeing Network' represents the first interdisciplinary collaboration to address this question. 'Musical imagery' (MI) can be defined as a mentally generated representation of musical sound. There has been a tendency for MI research to separately focus on either clinical cases of musical hallucinations (e.g. Coebergh et al., 2015), on everyday 'earworms' (research led by music psychology), or on voluntary MI (e.g. in creative practice). MI has also been a source of inspiration in the arts and literature, while a humanities approach has been adopted by scholars in cultural history (Kennaway, 2015) and philosophy (Priest, 2022). But the challenge of capturing the complexity of MI and wellbeing experience calls for a collaborative response across disciplinary boundaries. An interdisciplinary approach can inform and invigorate research on the intricate question of how human beings relate to the music in their mind's ear, with its consequences and potential for wellbeing. The project aims to develop a set of interdisciplinary approaches to understanding the range and significance of MI and wellbeing experience across contexts and communities. To achieve this, the main objectives are to generate new knowledge about MI and wellbeing by joining across disciplinary boundaries for the first time, and to broaden understanding of the ways in which MI plays a role in the lives of different communities. The network will promote exchange between people researching clinical and non-clinical manifestations of MI and develop knowledge about their inter-relationship. By working together, we can begin to identify cultural differences in perceptions of, and attitudes towards, inner music in diverse contexts. One applied objective is to work collaboratively to identify treatment and prevention ideas for those who experience intrusive MI, and conversely to develop the intentional use of MI as a beneficial intervention (e.g. as a positive distractor, to aid sleep). The network's activity will stimulate discussion from arts, humanities, social science, and clinical perspectives, allow scholars to see how research on inner music and wellbeing can impact on their own work, and facilitate collaborative partnerships in the UK and abroad. It will be driven by questions such as: What cultural differences exist in how we feel about MI? What can MI researchers in different areas learn from and with each other about imagination and wellbeing? What opportunities exist for arts and humanities researchers to collaborate with clinical practitioners to support people who suffer from intrusive MI? Network events (workshop and themed webinars) are designed to progress from 'sandpit' exploration through thematic dialogue (driven by a co-produced set of network research questions) to a final International Symposium, new collaborative funding proposals, and the main academic output of a multidisciplinary edited volume. A website will present the outcomes from the network activities, including a curated collection of examples of musical imagery in the arts and literature, musical imagery testimonials from diverse contributors, and an open-source Bibliography. Project partner Elysium Theatre Company will contribute to the network's activity to inform a public performance of scenes from plays which feature MI, at the International Symposium. In partnership with non-academic participants, the network will enable the co-creation of a new interdisciplinary research agenda to 1) further theoretical understanding of the relationship between MI and wellbeing, and 2) enhance applied research to benefit clinical practice and lead to recommendations for health (e.g., sleep, with project partner The Sleep Charity).

UKRI Gateway to Research · FY 2024 · 2024-06

I will establish the underpinning scientific and technical knowledge to enable the UK cement industry and UK producers of alumina-containing waste to create new supply chains for the manufacture of high-performance low-CO2 cements. I will also develop a user-friendly process model that can optimise cement clinker manufacture from waste. Moreover, I will support the academic and industrial community by creating a much-needed centre for experimental thermodynamics in the UK and will become established and recognised as a leader in low-carbon cement production. Cement is the most manufactured product on the planet and is essential to the development of infrastructure and economy. Cement manufacture is responsible for 2% of the UK's carbon emissions where more than 8 Mt p.a. of, the generally employed, Portland cement (PC) clinker are produced. Globally, the manufacture of 4 Gt of cement p.a. is responsible for 8% of man-made CO2 emissions. Calcium sulfoaluminate (CSA) cements can achieve more than 30% reduction in CO2 emissions compared to PC, on a mass basis, when produced from virgin raw materials. The properties of CSA cements are often superior to those of PC and are therefore used in special applications such as fast-track rehabilitation of highways and airfields. Considering their savings in work-time and their higher performance, CO2 savings from CSA cement, compared to PC, are in fact greater. Moreover, CSA cement can be produced in existing PC plant configurations without major modifications; thus, low industrial capex. CSA cements are normally produced from bauxite, limestone, and clay. However, the use of CSA cements has been limited in the UK due to the lack of a raw alumina source (i.e., bauxite), which is required for CSA manufacture; any CSA cement currently used in the UK is imported. On the other hand, the UK industry produces significant volumes of waste material containing alumina which this Fellowship research aims to valorise. Two major waste streams are potable aluminium water treatment sludge (aWTS), and aluminium oxide residue (AOR) from secondary aluminium production and recycling. The UK produces ~90 kt of aWTS (dry) and ~70 kt of ALS per year which can be used as alumina sources, replacing bauxite, to produce ~1M tonnes of CSA cement p.a., and replacing up to 50% of virgin raw materials with waste. This translational research will create a new subindustry in the UK, by enabling CSA cement manufacture through an innovative process, valorising UK industrial residues, and creating new UK products. However, to develop and establish the manufacturing process for targeted cement clinkers, the presence and fluctuation of impurities in the wastes must be addressed. Industrially, the proportions of cement clinker phases produced through thermal processing of the raw materials are designed using empirical equations. This approach is not suitable to produce CSA clinker, especially when alternative raw materials (containing foreign elements) are used. A more flexible approach is required. Therefore, this Fellowship research will also derive necessary fundamental material data for the phases involved in CSA clinkering from waste and use the data to build a user-friendly pyro-processing simulator that will allow for rapid raw material mix and process design, optimisation, and troubleshooting. This simulator will also enable identification of other potentially useful feed sources for clinker manufacture; thus, a reduction in future experimental clinkering tests. As part of this Fellowship, I will also establish the first centre for experimental thermodynamics in the UK. I will leverage the successful completion of the Fellowship to lead research in low-carbon cement production and specialising in thermochemistry. I also aim to become an ambassador for CSA cement and concrete in the UK and to be involved in influencing policy and writing standards for CSA cement and concrete.