University of Manchester

UKRI Gateway to Research · FY 2024 · 2024-12

Automated, data-driven, and high-throughput experimentation is already revolutionising materials exploration and optimization. While great strides have been made in using this approach to optimize bulk properties of materials, functional nanomaterials remain poorly understood due to the complex and often non-linear relationship between material quality, geometry, and performance. In the first part of my fellowship, I have developed and demonstrated a unique experimental and statistical methodology to study individual nanomaterial performance at huge scale, with tens of thousands to millions of measurements. This has provided unique insight, robust statistical evidence, and industrially useful yield analysis. In the renewal period I will lead a world-class team to tackle urgent challenges in nanotechnology, namely scale-up for quantum photonic technologies, and ultra-high-throughput for novel materials. My program will draw on the expertise and capability of 10 international academic and industrial partners to maximise the impact of the research.

UKRI Gateway to Research · FY 2024 · 2024-12

Basement membranes are thin, layered meshes of networked proteins (such as collagen IV and laminin) that serve as crucial barriers between tissues in many organs. In skin, a basement membrane anchors the cell-rich epidermis to the collagen-rich dermis. In filtering units within the kidney (glomeruli), basement membranes play a critical role in filtering small molecule waste from blood into urine, and in lung (alveoli), where they enable exchange of oxygen and carbon dioxide between air spaces and blood. Basement membranes in these tissues undergo profound changes in ageing, becoming flatter, thinner and patchier, leading to tearing and ulceration in skin of older people, a 5-10% fall in kidney filtration per decade of people aged over 35 years, and a decrease in lung elasticity. Despite these impacts on organ function, little is known about how basement membrane proteins are damaged during ageing and whether these changes are shared between organs. Since basement membrane proteins are long-lived, they are thought to accumulate structural damage by ageing processes like oxidation, which unravels proteins, and exposure to protease enzymes, which cleave proteins. Using a new analysis technique we pioneered (peptide location fingerprinting), this work aims to identify key basement membrane proteins with age-related structural damage in skin, kidney and lung. Microscopic areas containing basement membranes will be cut out of mouse and human tissues (laser capture microdissection) and peptide location fingerprinting used to identify potential biomarker proteins with structural differences between young and aged. These will be compared between skin, kidney and lung to reveal overlapping signatures. Using another bioinformatic webtool we developed (Manchester Proteome Susceptibility Calculator), we will link age-modified protein sequences to enzyme (matrix metalloproteinase) cleavage sites and to oxidation-sensitive areas to indicate regions of structural damage. We will identify and compare protein fragments from these damaged regions between aged and young samples (western blotting). Some fragments (known as matrikines), released by damaged basement membrane proteins, are known to have cell signalling properties. However, the identity of age-inducible matrikines, and their impact in tissue degeneration, remains almost entirely unknown. Our preliminary work identified a specific protein region in basement membrane collagen IV that is structurally changed in aged kidney and lung. This region is known to be cleaved by matrix metalloproteinase enzymes to release canstatin: a matrikine capable of controlling cell behaviour. This work also aims to identify age-dependent changes in the matrix metalloproteinases that cleave basement membranes, determine the impact of inhibiting these enzymes on basement membrane degeneration, and investigate the cell signalling potential of collagen IV matrikines. Western blotting and zymography will assess whether the concentrations and activities of matrix metalloproteinases change in ageing skin, kidney and lung. Importantly, we will pursue mechanistic studies in an ageing animal model (C. elegans) to determine whether inhibition (RNA interference) of matrix metalloproteinase enzymes affects the integrity of basement membrane collagen IV tracked throughout the animal's lifespan. In parallel, we will expose human skin, kidney and lung cells to collagen IV matrikines in culture, and determine their effects on cell behaviour by transcriptomic and proteomic analysis. The outcomes of this work have implications for the understanding of organ ageing and the identification of potential biomarkers towards new therapeutic interventions. This project aligns with three BBSRC priority areas: healthy ageing across the lifecourse, bioscience for an integrated understanding of health, and data-driven biology.

UKRI Gateway to Research · FY 2024 · 2024-12

The discovery of topological materials has sparked a revolution in our understanding of matter. Distinguished from their conventional counterparts by topological invariants rather than order parameters, topological insulators and metals have not only reinvigorated materials science but also inspired pursuits in for example cold-atom systems and photonic devices, and still affect a broad range of cutting edge theoretical and experimental research. Within this programme, we aim to establish a new chapter in this success story by investigating novel multi-gap topological phases that cannot be addressed by conventional approaches. Encapsulating a paradigm shift beyond single-gap topology, the first manifestations of this physics have recently been surfacing in a variety of contexts ranging from twisted layered graphene systems to magnetic materials and quench dynamics. A central element of our approach relies on utilising a geometrical methodology that cannot only parametrise and characterise uncharted kinds of multi-gap dependent topological phases but is also part of a deeper framework that promises relations between new kinds of observable quantities and novel notions of quantum state distance. Profiting from this unique starting point, MultiTop proposes to use these contemporary handles to explore new topological phases in the contexts of out-of-equilibrium systems, crystalline materials and superconducting structures. This will in turn allow us to uncover new physical observables in these settings upon focussing on boundary effects, defect signatures and electromagnetically induced responses. Finally, we will underpin the impact of the pioneering theoretical nature of the project by designing viable pathways to experiment using ab-initio evaluations and metamaterial modelling. Given the variety of proposed subjects, yet centred around a single new perspective, we anticipate that our programme has a strong potential to uncover fundamentally novel understanding.

UKRI Gateway to Research · FY 2024 · 2024-12

A mutation is the most fundamental process in biology. Mutations can frequently encode an antimicrobial resistance (AMR), a major health problem claiming millions of lives every year. I discovered a density-associated mutation rate plasticity (DAMP), a phenomenon where bacteria at high densities have up to 20-fold lower mutation rates. FLF led me to discover that the collective ability of bacteria to better control hydrogen peroxide reduces mutation rates at high density. The reduction in mutation rate in denser populations is restored in peroxide degradation-deficient cells by the presence of wild-type cells in a mixed population. Which cell density associates with mutation rates in a mixed community? Can cells growing in multispecies bacterial communities affect each other's mutation rate via generation and detoxification of a peroxide? Does community composition affect mutations and evolution of AMR? Renewal will test the hypothesis that mutation rates and mutational spectra in bacterial species, coexisting in the mixed community, are shaped by the collective generation and detoxification of hydrogen peroxide. I aim to quantify mutation rates and mutational spectra in mixed communities and skin microbiome composed of aerobic and anaerobic bacterial species. I will quantify mutations with high-throughput fluctuation tests and cutting edge mutation imaging technique that I developed in FLF. I will quantify mutation rates in constructed mixed communities of aerobic opportunistic pathogens Escherichia coli, Enterococcus faecalis and Pseudomonas aeruginosa grown as batch cultures and within a microfluidic chamber. I will quantify mutations and mutational spectra in an oxygen-tolerant anaerobe Lactobacillus johnsonii and obligate anaerobe Bacteroides thetaiotaomicron in in a pure culture or when cocultured with E. coli. I will specifically test how coaggregation between L. johnsonii and E. coli modify the rate and spectra of mutations in both species. Finally, I will quantify mutation rates in bacterial species isolated from a skin microbiome, growing in a uniquely designed microfluidic device or on human skin keratinocytes. I will test how stressors such as ultraviolet radiation, antibiotics, human stress hormones and antioxidants affect mutation rates of a skin microbiome. Renewal is ground-breaking, because it is the first experimental quantification of mutation rates in various mixed communities composed of aerobes, anaerobes and their co-aggregates. And, I will quantify mutations in a skin microbiome growing in its natural environment, on human skin keratinocytes. I will greatly advance the fundamental understanding of how functional interactions between cells in a mixed community affect mutations and AMR and I shall pioneer studying mutation rates in mixed communities. This fundamental study will identify new mechanisms that promote and perhaps those that hamper the evolution of mutation-based resistance providing a basis from which to develop new strategies to combat AMR.

UKRI Gateway to Research · FY 2024 · 2024-11

CONTEXT: Numerous alternatives to antibodies have been developed that circumvent some of the inherent problems of these large disulphide-linked proteins, with the nanobodies produced by camelids perhaps being at the forefront. Libraries of nanobodies can be raised in vivo from Camelids or in vitro, and are subsequently "panned" with recombinant techniques for the specificity of choice. The resulting nanobodies can then be easily produced recombinantly in bacteria or yeast. CHALLENGE: Frequently, reasonably well-behaved nanobodies can be selected from naïve libraries, with dissociation constants in the range of 0.1-1µM. However, many applications require higher affinity than this, for binding to survive stringent wash conditions, for example, and affinity maturation of the hit nanobody is required. Re-panning of the library will invariably not lead to different nanobodies being produced meaning that re-immunisation of llama or a targeted alteration of the binding site is the best option for increasing binding affinity. Targeted evolution usually requires knowledge of the binding site through crystallographic techniques followed by site-directed mutagenesis. For the majority of protein-protein interactions this is not feasible so we propose to use an NMR-directed strategy for the directed evolution of high affinity nanobodies. AIMS & OBJECTIVE: To use NMR-directed evolution to reliably produce orders-of-magnitude improvements of binding affinity of nanobodies, for the same cost and time as an additional immunisation or a crystallography-based targeted evolution approach. This strategy is to be applied (initially) to a variety of small/oligomeric Target molecules namely: [T1] Heparin oligomers of known sulphation pattern [T2] phosphopeptides of known phosphorylation state [T3] Fragments of bacterial lipopolysaccharides In addition a small protein target (T4), lysozyme will be tested to ascertain applicability of method to small protein targets. IMPACT: The utility of antibodies as tool compounds for medical and biochemical research and diagnosis is well understood. The ability to produce alternatives quickly and without the requirement for repeated inoculations of animals will vastly reduce the cost of these tool compounds, and allow the direction of techniques that use them to new targets, for example toxic bacterial polysaccharides.

UKRI Gateway to Research · FY 2024 · 2024-11

ontext: The ability to functionalise advanced materials on the nanoscale, including enabling localised isotopic enrichment and purification, has been transformed through the development of a bespoke focused ion beam facility (P-NAME) at the University of Manchester (UoM). Open to UK (and international) users in academia and industry as part of the Henry Royce Institute, the demand for this internationally leading capability far exceeds our ability to deliver with a currently approved access requests subject to a ~4 to 6 month waiting time. This is continuing to grow as more research projects are requesting P-NAME time in research proposal submissions. Significant time (~45%) on P-NAME is dedicated to materials enrichment as a critical capability we have developed. Challenges Addressed: The enrichment of Si using isotopic 28Si doping for quantum technology (QT) applications has drawn exceptional international attention. The proof-of-concept demonstration of this has been delivered by the applicants using the P-NAME tool, placing the UK as the international lead. P-NAME is not designed for this work however, preventing its scale-up, and incurring substantial delays to other users as the process is exceptionally slow using the existing capability. This places the UK at risk of losing our lead as others develop dedicated systems for scaling this work. The Advanced Materials Enrichment and Synthesis (AMES) tool requested here will enable accelerated isotopic enrichment and localised synthesis of materials via high-dose focused ion beam implantation alongside ion doping of active species into these materials. In doing so AMES directly enables the scaling of the enrichment process and qubit doping, and releases highly contested time to users of P-NAME for other purposes.

UKRI Gateway to Research · FY 2024 · 2024-11

Biocatalysis is a sustainable technology that harnesses the power of Nature's catalysts, known as enzymes, to perform chemical reactions. Enzymes are inexpensive, biodegradable, produced from renewable feedstocks, operate under environmentally benign reaction conditions and speed up chemical processes with remarkable efficiency and selectivity. For these reasons, the chemical and pharmaceutical industries routinely use certain classes of enzymes in commercial manufacturing processes to replace chemical transformations that are inefficient and/or have a high environmental burden. For example, engineered enzymes are now used to produce pharmaceuticals and agrochemicals, recycle plastics and capture carbon dioxide from the atmosphere, thus contributing to a more efficient and sustainable chemical industry. However, enzymes found in Nature are usually not suitable for use in industrial applications and must first be optimized to improve properties such as catalytic efficiency, selectivity, and stability. Directed evolution is a powerful and versatile technology for adapting enzymes to make them suitable for use in commercial processes, but it is a costly and time-consuming process that requires specialist instrumentation only available in a handful of labs. Moreover, many chemical processes use non-natural reactions for which there are no known enzymes that can serve as starting templates for optimization. In this application, we will establish The International Centre for Enzyme Design (ICED), bringing together world leaders in computational protein design, enzyme engineering and industrial biocatalysis, to change the way that industrial biocatalysts are developed in the future. ICED will establish a fully integrated computational and experimental program, integrating the latest deep learning protein design tools with advanced experimental methods for enzyme engineering, to allow the reliable and predictable design of new and improved enzymes with a wide range of useful activities. In this way, ICED will deliver a step-change needed in the field to allow the rapid design of customized biocatalysts in response to diverse societal needs.

UKRI Gateway to Research · FY 2024 · 2024-11

This grand supports the IRIS Federation to deliver compute to its science activities by placing hardware at GridPP sites.

UKRI Gateway to Research · FY 2024 · 2024-11

Digital research infrastructures connect researchers, policymakers and innovators with the computers, data, tools techniques and skills to undertake ambitious and creative research. Social science data services worldwide play a key role in the digital research infrastructure by curating and managing access to many forms of social and economic data as well as promoting increased data literacy among the community. The UK Data Service (UKDS) is the principal repository for economic, population, and social research data in the UK, where it pioneers data curation and manages long-term access to high quality data. Beyond the provision of data access, the UKDS also acts as a beacon for the social science research community in the creation of knowledge and the promotion of data literacy. New technologies, resources, data and methods are constantly changing (example smart data, web-scraping and AI) and they have already made a huge impact on how researchers’ access, manage, prepare and use data. The social sciences are no different, with many new forms of social data or methods of analysis that are more computationally intensive than most social scientists may be used to. As the data environment continues to evolve, with new forms of data, methods, and greater computing power, the demand for effective computational social science skills within the data services community is increasing. However, conventional training of many data service staff, both new and experienced, in traditional data and statistical methods does not always meet this need and may not allow for the acquisition of new (and increasingly essential) computational skills. Recognising the growing importance of computational skills for data services staff in the social sciences, this project led by academics affiliated with the UKDS will address the critical need for training. The aim of this project is to build capacity within the international data services community, by providing upskilling opportunities for UKDS staff and developing foundational level data skills modules in computational social science for the wider global community. It will also establish a community of practice to provide enhanced support to users through the lifetime of the project and beyond. Direct beneficiaries of this project will include UKDS staff who will be given the opportunity to upskill in computational skills, as well as global data service staff who will be given access to a foundational-level online structured course(s) on computational social sciences. Through both upskilling mechanisms, this project will enhance data services capacity both in the UK and globally, enhance the careers of data service professionals, and through the establishment of a Community of Practice will contribute to a culture of lifelong learning.

UKRI Gateway to Research · FY 2024 · 2024-11

The earth's climate is warming, and scientific evidence shows that this is due to greenhouse gases like carbon dioxide being emitted during the combustion of fossil fuels such as coal, oil, and natural gas. The more greenhouse gases that are added, the hotter the earth will become, and so reducing their emissions is something we should all care about. We can reduce emissions by using renewable sources of energy which do not involve the burning of fossil fuels. Generation of electricity using wind or solar has been successful in the UK, although the use of fossil fuels for heat is still widespread as most houses and offices have a gas or oil boiler to provide heating and hot water. One possible low-carbon alternative is to use heat from geothermal energy. This involves harnessing the natural heat present within the earth. The term geothermal energy refers to any heat derived from the ground, from depths of a few metres to multiple kilometres beneath the Earth's surface. The deeper you travel into the earth the hotter it becomes. In the first 10 meters, layers are warmed by the sun, below this the deeper layers of rock are heated by radiation from the earth's core. The rate of temperature increase with depth is known as the geothermal gradient. Below Manchester the geothermal gradient is around 28 degrees Celsius (degC) per kilometre. For example, if the surface temperature is 10degC then at 1km below Manchester the temperature of will be 38degC (10+28). To extract this heat, you need water. Heat from the surrounding rock is transferred into water stored within these rocks at depth. If the geology is right this can then be then pumped to surface and used to warm buildings, greenhouses, or swimming pools. If water can flow naturally from the rock, it is described as a permeable aquifer. This permeability may be due to interconnected space (known as porosity) between the grains in the rock, you can think of it as being like a bath sponge. Not all rocks have this space between the grains, they have low or no porosity. Water may still be able to flow through these rocks, however, if they are broken or fractured. Think of hitting a pane of glass placed on the ground. Water would still not flow through the individual pieces but could find its way through the cracks. In the same way, fractured rocks can still be a permeable aquifer. A special group of aquifers occurs in the coal mines below Manchester. These aquifers are not natural, but the permeability is created by the tunnels dug out, by thousands of men, women and children undergoing great hardship to mine coal. What a fantastic legacy if we could then use all their hard work to heat our homes, not with coal, but with warm water extracted from these underground voids. The main aim of this project is to make maps of these underground aquifers and mines so we can find the best places to drill and extract this geothermal energy. To do this we need to "look" into the earth using methods such as seismic reflection surveying. We send sound waves into the earth and measure the time taken for them to come back, a little like a bat does when hunting for food. This gives us a "picture" of different layers and their position in the earth. We then trace these in three dimensions to show how their depth varies under the whole of Manchester. If we know the depth, we can predict the temperature of the water using the geothermal gradient. In Greater Manchester many holes (called wells) have been drilled to explore for natural resources such as coal, water and natural gas. They give us a direct view of what types of rocks are below our feet, and whether they are able to produce heated water for geothermal energy. By mapping the depth and temperature of these aquifers we can design wells to extract the heat and move forwards in our decarbonisation of Greater Manchester.

UKRI Gateway to Research · FY 2024 · 2024-11

The original research design for the FLF Decent Work and the City was ambitious in both scope and complexity but has proven to be both timely and relevant in a post-Covid 19 landscape of economic and political transformation. The fieldwork has generated 150 interviews so far and we estimate that there will be at least 200 by the close of phase one in October 2024. We have published six articles in leading international journals looking at employment relations in the foundational economy, labour market transformations, the role of the local state, and bottom-up worker and community organising. We have developed important partnerships and networks across cities that bring into dialogue academic and policy experts from across disciplines to promote mutual learning and maximise research impact. The renewal of the fellowship will allow us to add two cities to the existing sample for the purposes of targeted comparisons and provide the space in which to systematically code and analyse the dataset. This in turn will provide the basis for contextualisation and corroboration of the research findings with local city experts, and a thorough mixed-methods comparative analysis of data across cities. These key areas of activity will build on our existing body of interdisciplinary research around decent work and the urban foundational economy and will yield important theoretical and policy insights at international, national and local scales. In terms of research excellence and innovation, two key themes have emerged from the data collection so far i) the theoretical and practical relevance of 'cities' as a unit of analysis within comparative industrial relations research, and ii) the specific challenges surrounding decent work in the everyday foundational economy that makes up a large share of the workforce in each of our six cities a topic we explored in an international webinar and accompanying blog: https://decentworkcity.manchester.ac.uk/dwc-blog2/the-battle-to-be-seen-and-heard-essential-workers-during-and-after-covid-19/ The FLF was designed with a strong impact and engagement focus aimed at generating useful and usable data for policy makers and practitioners across each of our six cities. Throughout phase one we have worked collaboratively with a range of partners including academic institutions, policy makers, trade unions, NGOs and workers to produce relevant research findings, to generate policy recommendations, and to contribute to wider debates on work and employment at international, national and local level. We have been invited contributors and authors for several ILO reports and events and we are working closely with the regional offices of the ILO in Chile and Argentina. We have also hosted several international roundtable and policy focused events related to the emerging research findings (both in person and online) and have successfully hosted a visiting Professor (Ian Greer) from the ILR school at Cornell University in New York. This will form the basis for a return visit to Cornell/New York in 2024. Both the PI and RA have been invited speakers at various internal and external events and our research findings have been featured in a number of publicly accessible outputs such as blogs, industry publications, university and external research reports. Our ongoing research findings have fed into several local policy reviews and programmes of work around low pay, gender equality and improving the quality of work in care services. This includes the Greater Manchester living wage city region programme, the Good Employment Charter implementation programme, the GM School Readiness programme, and the GM4Women 2028 policy programme. During the renewal phase, these organisations and networks will continue to provide expertise in labour rights, regulation, and community engagement, contributing to a more comprehensive understanding of labour market transformations.

UKRI Gateway to Research · FY 2024 · 2024-11

Antibiotics are used to kill dangerous strains of bacteria that cause harmful infections, but are often inappropriately prescribed for diseases in which inflammation rather than a bacterial infection is the main cause. This includes asthma which is believed to be caused by a certain type of inflammation, driven by the immune system, called type 2 inflammation. Work in animal models shows that the harmless bacteria which normally live in tissues such as the gut and the lung are beneficial for a healthy immune system and can protect against harmful type 2 inflammation in the lung. Many of these harmless bacteria are also killed by antibiotics and there is increasing experimental evidence in animal models showing that antibiotics can in fact predispose to type 2 inflammation in the lung, contributing to conditions such as asthma. To date, there have been no studies in humans directly investigating the effects of antibiotics on immune responses in the lung. However individuals who have taken multiple courses of antibiotics earlier in life are more likely to develop asthma. Our pilot data indicate that antibiotic use in animal models alters immune responses in the lung, specifically by activating the immune cells involved in type 2 inflammation. The aim of the current project is to study whether oral antibiotic use has similar effects in humans. We will first investigate whether antibiotics causes healthy individuals to have abnormal immune responses in the lung. We will characterise different types of immune cells from the lungs themselves, and by looking at immune cells in the bloodstream, we will be able to see how the rest of the body may be affected. We will determine whether any changes to the immune system correspond to antibiotic induced changes in populations of harmless bacteria in the gut and the lung. Next, we will investigate whether antibiotics alter immune responses in asthmatic individuals who already have type 2 inflammation in the lung. We will focus on discovering cells, molecules and pathways that are involved in antibiotic-driven alterations of immune responses. This work aims to reveal new strategies that could be used to counteract the harmful side effects of antibiotics. These new pathways also have the potential to shape more targeted treatment in type 2 inflammatory diseases such as asthma, as well as increasing our general understanding of how harmless "friendly" bacteria help control immune responses in the lung.

UKRI Gateway to Research · FY 2024 · 2024-11

Neurodevelopmental disorders, such as schizophrenia, present a significant burden for the individual and society, and are caused by multiple genetic and environmental risk factors. A main risk factor predisposing individuals to develop such conditions is fetal exposure to maternal inflammation during a critical period of gestation. Yet, not all individuals exposed to maternal infection in utero will develop symptoms of neurodevelopmental disorders later in life. Our proposal seeks to take a significant step in answering why some individuals are resilient and others are susceptible, and what the differences are in biological mechanisms that underpin the fetal response to maternal inflammation. We predict that the answer is linked to individual differences in their response to specific proteins, referred to as cytokines, produced by mothers during an infection. The first step to an answer is to establish what distinguishes resilient and susceptible individuals in the mechanisms of their brain development. Our overall hypothesis is that cytokines produced in the fetal brain of offspring born to infected mothers during gestation modifies the regulation of gene expression in the fetal brain. This, then, leads to altered brain development and ultimately dysfunctional behaviour in susceptible individuals. To test our hypothesis we use a multidisciplinary approach of genomic, behavioural and cell-based technologies in a rat model that allows us to distinguish resilient and susceptible individuals, and to identify changes in the molecular mechanisms that regulate expression of genes (that is, epigenetic mechanisms) for brain development when exposed to maternal cytokines before birth. We are then able to establish which changes in these epigenetic mechanisms lead to symptoms of neurodevelopmental disorders during adolescence. We are particularly interested in being able to identify resilient and susceptible individuals before they develop behavioural symptoms. To achieve this, we will measure a set of biomarkers of inflammation in the blood throughout development and link this to behaviour measured later in life. Finally, we need to demonstrate that the differences between resilient and susceptible individuals are caused by exposure to elevated cytokines and lead to altered epigenetic profiles that ultimately change neuro- and brain development. Here, we will use neuroprogenitor cells and investigate how their development into specific brain cells responds to different cytokines. Our results will enable a step change in our understanding of why some individuals are at greater risk than others of developing neurodevelopmental dysfunction, and a better identification of those individuals before symptoms become apparent. Our results will open up both new broad and specific questions about the molecular mechanisms that underpin resilience and susceptibility, and why they lead to behavioural differences much later in life. laying the foundation for new avenues of future research. In addition, by using blood and behavioural markers that can also be obtained from humans or other model systems our proposal promises also offers significant translational benefits to the clinic and other model systems

UKRI Gateway to Research · FY 2024 · 2024-10

Cystic fibrosis is a genetic disease that leads to the accumulation of mucus in the lungs. Various microbes - including bacteria, fungi, and viruses; called the microbiome - inhabit this mucus, causing polymicrobial infections. Periodically, individuals with cystic fibrosis undergo pulmonary exacerbations: severe respiratory events which can include the feeling of breathlessness, the increase in sputum/mucus production, increased fever, cough etc. It is these events that individuals with cystic fibrosis frequently indicate that they wish to better understand, and that cause the majority of the morbidity and mortality in this patient population. We understand that most of these events are caused by a small number of pathogens which live within the lung microbiome. However, often individuals can be colonised with these same pathogens for years and not be affected by a single respiratory event. In this research programme, I aim to understand how this can be the case. I hypothesise that this is possible due to the interactions - or lack there of - of the pathogen with the microbes that it lives with as part of the lung microbiome. The overall aim of this work is to identify new small molecules which could be used as potential new therapeutics to better treat individuals with cystic fibrosis to prevent and/or lessen the effects of pulmonary exacerbations. To test this hypothesis, my work is split into 3 work packages (WPs): WP1: Use a large collection of cystic fibrosis lung microbiome samples to search for pairs of microbes and pathogens which are uniquely present in severe cystic fibrosis disease. I hypothesise that particular microbes found in some individuals with cystic fibrosis drive pathogens to be more able to drive disease and thus to cause more pulmonary distress. To test this hypothesis, I will look for microbes that are present in individuals who have worse disease (and more pulmonary events) when compared to those who have a milder disease phenotype. WP2: Test the effect of these microbes on cystic fibrosis pathogens in a high-throughput model of infection. I will use a fly infection model because they are small, easy to work with and more amendable to working with in high-throughput. Flies will be infected with the pathogen alone, and the time it takes to kill the fly will be logged and compared to a co-infection with the microbe and pathogen pair. If the fly dies more quickly when the microbe is added, it will signify that the presence of the microbe somehow makes the pathogen more harmful (we will confirm this by infection with the microbe alone which we predict will not cause infection and death in the fly). WP3: Next, I will find new small molecules (i.e., potential new drugs) that can inhibit these interactions. With these important interactions identified, I will next try to block them from occurring so that the pathogen is not able to trigger pulmonary events. Using the same fly model, I will test a set of structurally diverse molecules to see their effect on the time of fly death when flies are infected with microbe-pathogen pairs. These data will then be fed into a machine learning algorithm which will predict new molecules which should inhibit the microbe pathogen interaction the best. I will then make and test these molecules to ensure this is the case. By the end of this programme, I will have a better understanding of how microbes interact with each other in the cystic fibrosis lung, how these interactions drive lung disease and what types of small molecules are able to inhibit these microbe-pathogen interactions.

UKRI Gateway to Research · FY 2024 · 2024-10

Three million people in the UK have a rare disease, a topic the NHS is now urgently addressing, with personalised medicines such as gene therapy envisaged as eventual gold standards. Our own long-term vision is for effective, safe, and long-lasting transformative medical treatments for people with rare early onset lower urinary tract (REOLUT) diseases. These have devastating life-long effects on the health of affected people, not only causing urinary incontinence but also leading to severe urine infections and even life-threatening kidney failure. To reach our goals we must understand the, sometimes genetic, aetiology of these disorders and the detailed biology of how the LUT phenotype arises. In this project we will illuminate the autonomic neural and bladder pathobiology underlying the devastating early onset REOLUT disease called the urofacial, or Ochoa, syndrome (UFS). The key feature of this autosomal recessive disorder is the inability to fully empty the bladder, a functional voiding defect that occurs in the absence of anatomical bladder outflow obstruction (BOO). In parallel, we will study the efficacy and safety of gene therapy treatments to correct aberrant bladder physiology in mutant mouse models of the human genetic disease. As in the human disease, our mouse models carry biallelic variants of either HPSE2, coding for heparanase-2, or LRIG2, coding for leucine rich repeats and immunoglobulin like domains-2. A key biological and therapeutic focus in UFS is the pelvic ganglion (PG), the autonomic relay station that innervates the bladder. Our published studies strongly suggest that bladder dysfunction in UFS is caused by abnormal maturation and subsequent dysfunction of bladder nerves emanating from the PG. Coincidentally, the PG has recently been the focus of exciting studies that demonstrate it has a unique molecular signature compared with either cranial parasympathetic or typical thoracolumbar sympathetic ganglia. Our therapy experiments in this project will build on our recent experimental breakthrough demonstrating the feasibility of neonatal adenovirus vector (AAV)-mediated human HPSE2 gene transfer into, and expression within, the PG. This strategy ameliorated neurogenic bladder defects in juvenile Hpse2 mutant mice as assessed by ex-vivo myography studies. Here we will use the same approach and determine whether bladder nerve pattering is rescued, as assessed by whole-mount immunostaining, and critically whether functionality is restored in the living organism, as assessed by in-vivo cystography. In parallel, we will use single cell RNA sequencing to test the hypothesis that the Hpse2 mutant PG has lost its unique molecular identity, and that this can be restored by neonatal gene therapy. In the second part of the project, we will undertake gene replacement therapy in Lrig2 mutant mice, and we will compare gene expression in Lrig2 and Hpse2 mutant ganglia to define shared molecular pathways in UFS. To provide further translational steps toward human therapy, we will modify our neonatal therapy protocol to give gene therapy later after birth to determine whether correction is possible in mice with more established disease. We will also undertake analyses of a wide range of organs to clarify the safety of our therapeutic approach. Our study will be a paradigm for understanding and treating the expanding list of REOLUT diseases that have defined monogenic causes.

UKRI Gateway to Research · FY 2024 · 2024-09

Energy security and the scale of change needed to meet net-zero targets are top of the global political agenda. Up to 70% of worldwide energy is currently lost as heat and this is expected to improve to just 50% by 2030, representing vast quantities of wasted energy and unnecessary greenhouse gas emissions. This creates an urgent need for technologies to improve energy efficiency, which would make low-carbon energy go further and provide "breathing space" to develop and scale-up other net-zero technologies such as electric vehicles, grid storage and carbon capture. Thermoelectric generators (TEGs) harness the Seebeck effect in a thermoelectric material to recover waste heat as electricity, and are a front-running technology for improving the efficiency of energy-intensive processes. TEGs are flexible and can, with the right materials, be used at scales from powering wearable devices to recovering waste heat from industrial furnaces. However, despite established applications in the aerospace industry and an estimated $1.2bn global market by 2027, large-scale thermoelectric power is currently not feasible due to limited efficiency and the scarcity and toxicity of the materials used. High-performance thermoelectric materials must balance a large Seebeck coefficient and electrical conductivity with a low thermal conductivity. This makes optimising the thermoelectric figure of merit, ZT, a complex interdisciplinary materials-design challenge. Furthermore, a high-performance thermoelectric not only requires high efficiency (large ZT), but must also meet cost and sustainability requirements for the intended application. With this in mind, progress in thermoelectrics has historically been limited by a poor understanding of thermal conductivity and how to engineer it, which has led to unsustainable materials made from rare and/or toxic elements such as the current industry standards Bi2Te3 and PbTe. The initial part of the Future Leaders Fellowship has made use of state-of-the-art computational materials modelling to address two key questions: What are the key microscopic processes that suppress or enhance heat transport in materials, and how can we use materials design and engineering to control them? In doing so, the Fellow and team have established a cutting-edge research programme on thermal conductivity and thermoelectrics, which has provided new fundamental insight into the heat transport in thermoelectrics together with modelling tools to make accurate predictions of the thermal conductivity, electrical properties and ZT of a wide range of thermoelectric materials. Over the three years of the FLF Renewal period, we will exploit these developments to design efficient, cost-effective and sustainable materials for thermoelectric power and related renewable-energy applications including photovoltaics (solar cells). By working with experimental collaborators and industrial partners, we will further seek to progress these materials from predictions to prototype devices. In parallel, we will also consolidate the developments from across the FLF to make them as widely accessible as possible to the project beneficiaries, and thus maximise the impact of the research programme. The continuation of the research programme will deliver thermoelectric materials suitable for widespread commercialisation and enable the UK to reap the economic benefits of the $560bn global market for energy efficiency while contributing to the UN Sustainable Development Goals of affordable and clean energy, climate action, and reducing poverty. The improved ability to control heat transport enabled by this programme will also benefit other technologies, for example more efficient solar cells, better thermal management in batteries and improved power electronics and silicon chips, providing considerable scope to maintain and grow our research beyond the Fellowship.

UKRI Gateway to Research · FY 2024 · 2024-09

Our Solar System has different populations of planetary bodies - the innermost part closest to the Sun is dominated by the large rocky terrestrial worlds Mercury, Venus, Earth-Moon, and Mars. Beyond the orbit of Mars, the asteroid belt hosts small rocky and metal-rich bodies, then there is the giant planet zone (Jupiter, Saturn, Uranus, Neptune), and beyond that the outer Solar System which is dominated by ice-rich bodies. This structure has not always been fixed - in the earliest part of Solar System history some bodies migrated inwards towards the Sun and others migrated outwards towards the far icy limits. This dynamic environment often resulted in hypervelocity high-energy collisions between bodies. Where collisions occurred, impact craters were formed: these craters are seen on every solid surface and occur at all spatial scales. The number, size, shape, and products of these craters provide us with knowledge about ages of planetary surfaces, the structure and stability of planetary crusts, and the nature of the impactors that caused them. We can use the rates at which impact craters were formed to inform us about past Solar System dynamical processes. This helps us understand how other exo-planetary systems around other stars evolve. We can also use this knowledge to understand the risk from impacts on Earth in the more recent past, and ultimately at the present day. Our project will use samples from the Moon to probe Solar System scale impact processes. The Moon is an ideal place to test these questions as it has a very ancient surface compared to planets like the Earth, Venus and Mars which have been recently geologically active. Thus, as the Moon is located so close to the Earth, it is a great laboratory to understand how our own planet must have been affected by impacts in the past. The Moon is also a relatively accessible field locality - we have already collected many samples from its surface through human and robotic missions, and have some samples that are naturally delivered to us here on Earth as meteorites. In our project, we will measure the chemistry and age of these different types of lunar samples to understand when different size lunar impact craters formed and what types of impactors were colliding with the Moon. In particular, we will investigate the timing of very large impact basin formation (craters bigger than 150 km in diameter) before 3.9 billion years ago, to test if they were formed over a gradual period of time, or if they formed in a very short window known as a 'cataclysm'. We will also investigate crater formation over more recent periods of the Moon's history, during the last 2 billion years, in the window when life on Earth was starting to proliferate. For all these different time periods we will also ask what types of impactors collided with the Moon - did they originate from early planets that broke apart, from material in the asteroid belt, or from further out from the icy parts of the outer Solar System? This will help us understand how material has moved around the Solar System at different times in the past, shedding light on dynamical processes in the Solar System throughout the past 4.5 billion years.

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

A central tenet of biology is that information found in the DNA of genes is converted into a messenger RNA molecule (mRNA), which is then translated into a chain of amino acids called a 'protein'. Proteins carry out most biological functions, catalyzing metabolic reactions as well as serving structural and regulatory roles. The complement of mature proteins present in a cell dictate its identity, function and health. Therefore, it is critical to all life that cells have the capacity to control which proteins are produced, when they are produced, their level when produced and their site of production within the cell. Some of the most abundant proteins in the cell such as proteins involved in the production of energy and in the production of proteins themself are often 1000s of times more abundant than other more regulatory proteins. One key stage where these controls are evident is when the machine for producing proteins, termed the ribosome, is recruited to the RNA. Scientists over the last 50 years have gradually pieced together a pathway involving a series of protein factors that are important in the translation of mRNA. More recently they have added the precise structures of the individual molecules within many of these proteins. Overall, this has led to a canonical textbook model for the process of ribosome recruitment to an mRNA that is conserved from yeast to human cells and is called the translation initiation pathway. In our recent work, we have used the relatively simple yeast model system to ask- how well do the 1000s of different mRNA molecules present even in a simpler cell interact with these different translation factors? This work has led to a surprising observation. Many of the mRNAs producing the most abundant proteins in the cell - proteins critical for fundamental pathways of life - interact poorly with these translation factors. This then begs a question- how do these mRNAs that are fundamental to all living systems effectively compete for ribosomes in a sea of other mRNAs? Hence, we started to look at where mRNAs are translated within cells. Again, we were surprised to find that many of the fundamental mRNAs described above are translated at specific sites that have been termed 'translation factories'. It makes sense to produce these proteins in a special place within the cell, as it means the process can be fine-tuned and co-ordinated without interfering with more general production of proteins. However, the rules that decide which mRNAs are translated in a local factory and the protein factors involved in the translation process in these sites are very poorly understood. Therefore, in this proposal, we will determine the molecular rules that enable translation of fundamental heavily translated mRNAs. This will include the RNA sequences and protein factors involved in translation factories, the role of canonical translation factors at these sites, and the importance of these mechanisms for a cell's life. A greater understanding of how cells prioritise the mRNAs that are translated into protein will have immediate applications in the production of medical and commercial proteins - enabling high level expression of valuable proteins, and will also impact upon studies of disease- from diseases where proteins aggregate in cells such as Parkinson's to nutritional diseases associated with deficiencies in particular proteins involved in metabolism.

UKRI Gateway to Research · FY 2024 · 2024-09

This project investigates the relationship between early school absenteeism and subsequent patterns of antisocial behaviour and criminal activity throughout the individual's life course. Focused particularly on the influence of demographic and community factors, this project is guided by two pivotal questions: Firstly, what are the consequences of school absenteeism on antisocial behaviour and criminal activity across the life course? Secondly, how are the effects of absenteeism on crime moderated by socio-demographic and community conditions such as ethnicity, sex, and economic background? Previous research has indicated that school absenteeism is associated with future crime involvement, but little is known about the extent to which demographic, family and community conditions moderate the links between school non-attendance and crime. The significance of this gap in evidence cannot be overstated. It is essential to determine whether school absenteeism is indeed an early predictor of future crime across population groups, or whether wider societal disparities exacerbate the persistently negative effects of school absenteeism. Importantly, such a link may only exist in communities affected by structural inequalities and segregation, or it may simply reflect wider social disparities that manifest in individuals' dysfunctional engagement with various institutions at different stages of life. This project will bridge critical gaps in research, providing evidence on the direct and mediated effects of school absenteeism on crime trajectories and contributing to evidence-driven practices to enhance education outcomes and crime prevention. The Fellowship project will use the extensive 'Ministry of Justice & Department for Education linked dataset', a rich resource that, to our knowledge, has not been previously used in academic research to investigate the effects of school absenteeism on crime. This dataset offers unique information about a vast array of variables for a sample larger than any other similar study to date. School absence measures are obtained from the National Pupil Database, while life-course indicators of individual involvement in antisocial behaviour and crime are sourced from the Police National Computer. The methodological approach followed in this project will incorporate a range of quantitative research techniques designed for longitudinal data analysis, including multivariate regression as well as survival analysis and mediated growth models. This will allow us to investigate the dynamics between school absenteeism and its impacts on antisocial behaviour and crime over time, while also considering the moderating role of socio-demographic and contextual variables. The project connects with several areas of research interest identified by government bodies such as the Ministry of Justice and the Department for Education. The team will engage with government agencies and practitioners throughout the project. This will include early consultation meetings, ongoing discussions, and an end-of-project roundtable. These interactions will ensure that the project's aims and analytical strategies align with policy objectives and have a meaningful impact on policy and practice. Research findings from this project will be crucial for developing explanations of crime over the life course. Importantly, they will also help derive practices to mitigate the persistent negative effects of school absenteeism across traditionally marginalised and segregated population groups. We will identify not only whether and how absenteeism predicts future crime involvement, but also for whom this is an early predictor. This information is crucial for enabling context-specific interventions to prevent societal harms associated with crime and to reduce the early involvement of boys and girls with the criminal justice system.

UKRI Gateway to Research · FY 2024 · 2024-09

Nuclear Physics aims to understand the structure and dynamics of nuclear systems. It is the key to understanding the Universe from the first microseconds of its inception when the quark-gluon plasma prevailed, through its history of star and galaxy formation where nuclear reactions play an essential role both in the generation of energy and the creation of elements. The field also has applications that benefit society in diverse areas, from medicine and security to power production, and a strong impact on other fields of science. The Manchester group is part of the UK nuclear community which has devised a mode of operation that enables it to make leading edge contributions at an international level. Experimental work is performed at specific overseas facilities with focussed investment in the necessary instrumentation to carry out this work. Theoretical projects are undertaken using models incorporating forces inspired by the underlying quantum chromodynamics. Atomic nuclei are a unique quantal laboratory in which microscopic as well as mesoscopic features, driven by effective two- body and three-body forces, can be studied. They are complex many-body systems, but often display unexpected regularities and simple excitation patterns that arise from underlying shell structure, pairing and collective modes of excitation. Such properties are also exhibited by simpler mesoscopic systems (for example, metallic clusters, quantum dots, and atomic condensates) the understanding of which draws heavily on techniques developed and honed in nuclear physics. A fundamental challenge is to understand nuclear properties ab-initio from the interplay of the strong, weak, and electromagnetic forces between individual nucleons. In recent years, enormous progress has been made with such programmes for light nuclei. For heavier nuclei, shell, cluster and other beyond mean field many-body techniques, based on effective interactions, provide essential frameworks for correlating experimental data, yet still lack the refinement to reliably predict nuclear properties as one moves more than a few nucleons from well-studied stable nuclei. Experimental measurements are made to test modern theories using the techniques of transfer reactions, gamma-ray spectroscopy and measurements of hyperfine atomic effects using lasers. We also aim to make connections between the interactions of nucleons and the underlying theory that describes the strong force, Quantum Chromodynamics. Key quantities are the polarisabilities that describe how the structures of nucleons respond to external electric and magnetic fields. We are developing theoretical tools to determine these from experiments on the scattering of photons from hydrogen and other light nuclei. The latter are needed to learn about the the properties of the neutron since it is an unstable particle, and are also interesting for the testing of nuclear forces in few-body systems and for the calculation of muonic atom Lamb shifts.

UKRI Gateway to Research · FY 2024 · 2024-09

To achieve the UK zero carbon emission target by 2050, alternative energy generation with zero CO2 emission, such as wind, solar, and nuclear energy, is now the target of urgent development to completely replace the use of fossil fuels such as coal, oil, and natural gas. However, the widely used nuclear fission reactors have many issues, for example, the difficulty of nuclear waste treatment and storage and the risk of uncontrolled chain reactions. On the other hand, nuclear fusion energy has many potential advantages, for example, four times higher energy than fission, abundant hydrogen and its isotopes as the fuel, and the short lifespan of the radioactive waste products. However, the development of fusion reactors puts a high demand on materials, as these must withstand high energy levels, high transmutation rates, high temperatures, and high thermomechanical stresses. This brings major material design challenges and requires the design and development of superior materials, along with innovative, facile, manufacturing routes, especially for the first wall structures and breeder blanket of fusion reactors. The structure is not only irradiated by the plasma but also undergoes neutron bombardment from the plasma, as well as high loadings of helium and hydrogen, which causes serious damage to the structural materials. Currently, one of the potential materials designed for the first wall and blanket structures on the fusion reactors is the reduced activation ferritic/martensitic (RAFM) steels, due to the superior thermal conductivity, relatively low thermal expansion, and resistance to radiation-induced swelling and helium embrittlement, as well as the easy commercial process, compared to other materials. However, the properties of these RAFM steels restrict their maximum operating temperature to only 550C, which is much lower than the service temperature of 650C. Moreover, irradiation induces the hardening of these steels at lower service temperatures (250-350C) and embrittlement at high temperatures (450-550C), which also restricted their application. Thus, the 3rd generation oxide dispersion strengthened (ODS) RAFM steels have been developed through nanoparticle and ultra-fine grains, which successfully increase the operating temperature to 650C. However, the limitation of the ODS RAFM steels is the obvious difficulty in powder manufacturing at a sufficient scale to be used in the first wall and blanket structures in fusion reactors. ODS steels also have a problem with a high ductile to the brittle transition temperature. This severely limits their applicability. Thus, there is still an urgent need to develop new RAFM steels for the structure materials on fusion reactors with a service temperature of 650C and easy manufacturing to various scales and structures. In this project, according to ODS RAFM steels, the guiding principles of a fine structure and a high-temperature stable precipitate phase will be used to design new, processable, RAFM steels. For example, the intermetallic precipitates and carbonitrides, which have a lower coarsening rate than carbides at high temperatures, will be the target precipitates; these can be achieved through alloy design with corresponding heat treatment. Moreover, grain refinement can be achieved through the modification of the manufacturing process, for example, by using ausforming, which will produce an extremely high dislocation density. Subsequently, during heat treatment, these dislocations will form nanoscale subgrains through recovery and recrystallization. Thus, the ultimate goal of the research will be to produce new RAFM steels for supply to the spherical tokamak (STEP). This requires advances to allow materials selection between 2023 to 2025 and provision to produce net electricity from fusion in 2040. It will also support the UK to be the world leader in fusion materials design and develop this prominent position through cutting-edge research on groundbreaking material systems

UKRI Gateway to Research · FY 2024 · 2024-09

Access to safe drinking water is centrally linked to public health, well-being and economic prosperity. Although water quality is strongly linked to many of the UN Sustainable Development Goals (SDG 6: Clean Water & Sanitation, 3: Good Health & Well-Being, 5: Gender Equality, and 2: Zero Hunger), there is still a long way to go to achieve equitable access to safe drinking water, particularly in the Global South. To accelerate progress, we need new interdisciplinary approaches to tackle complex water quality challenges, especially with increasing stressors like rapid urbanisation and climate change impacting groundwater resources widely used for drinking. The aim of my FLF is to create a roadmap towards improved groundwater quality management in the context of the Global South by bringing together systematic approaches to improve the understanding of dominant groundwater processes and to support evidence-based decision-making for effective groundwater remediation. We will develop and demonstrate this approach in relation to two selected contrasting locations in South Asia (e.g. Bihar, India) and East Africa (e.g. Uganda) and for selected priority groundwater contaminants relevant to those locations. The roadmap approach developed here could then be applied to different scenarios in the future. We will bring together expertise in groundwater pollution (e.g. chemical, microbial, emerging contaminants, antimicrobial resistance), (bio)geochemical processes, remediation technologies, machine learning, decision science (e.g. agent based modelling, multi-criteria decision analysis) and social science to address local water quality and remediation challenges in these two areas. We will co-design decision tools, iteratively integrating scientific data with modelled predictions, to enable informed, locally-relevant decision-making for effective groundwater remediation. We will address an integrated set of key objectives and hypothesis (see objectives) through a series of Workpackages (WP) implemented as: (i) WP 1: Field-based Investigations comprising of WP 1.1 Multipollutant & Process Investigation and WP 1.2 Community Science; (ii) WP 2: Lab-based Investigations comprising of WP 2.1: Water & Sediment Characterisation and WP 2.2 Remediation Evaluation; (iii) WP 3: Predictive Modelling comprising of WP 3.1 Machine Learning; WP 3.2 Agent Based Modelling; and WP 3.3 Multi-Criteria Decision Analysis; and (iv) WP 4: Synthesis & Communication comprising of WP 4.1 Stakeholder Engagement and WP 4.2 Open Resource Bank Development. Our project team brings together highly complementary expertise and skillsets. I am an environmental engineer with expertise in groundwater pollution and remediation, with substantial experience managing and implementing complex, multi-partner research projects in South/Southeast Asia, Africa and South America. I am joined by Co-Investigators from The University of Manchester, British Geological Survey, University of Birmingham and University of Bath, along with international Project Partners from University of Melbourne (Australia), KTH Royal Institute of Technology (Sweden), Mahavir Cancer Sansthan (India), University of Heidelberg (Germany), Mbarara University of Science and Technology (Uganda) and independent affiliates from India and Malaysia. Collectively we bring together decades of interdisciplinary expertise in water science, remediation, water management, water and health, biotechnology, decision science, social science, participatory science, stakeholder engagement and extensive local knowledge in India and East Africa. The results and tools generated will improve the understanding of the complex natural and anthropogenic processes impacting groundwater quality in the selected locations and will better enable evidence-based decision making for effective groundwater remediation, with the roadmap generated able to be applied to other scenarios in the future.