IMPERIAL COLLEGE LONDON

UKRI Gateway to Research · FY 2024 · 2024-08

Dilated cardiomyopathy is a disease of the heart muscle, where it becomes stretched and weak. It is one of the most common causes of heart failure and heart transplant. Heart failure is a late feature of dilated cardiomyopathy and happens when the heart is unable to pump enough blood around the body. Our current treatment of dilated cardiomyopathy focuses on the management of heart failure. Yet, we diagnose many individuals before this point. Little is known about how to prevent the development of heart failure. We hope to better understand the early stages of dilated cardiomyopathy and discover therapies to prevent heart failure. We know that in late disease, the heart cells produce less energy and scar builds up in the tissue. This contributes to weakening of the pump. We will investigate whether these problems happen in early disease using specialised blood tests and a heart scan, known as an MRI (magnetic resonance imaging). We will study individuals with early dilated cardiomyopathy and those who carry genetic changes that makes them susceptible to developing the condition. This will allow us to understand the causes of early disease in different patients and select the best treatment for different forms of the condition.

UKRI Gateway to Research · FY 2024 · 2024-08

Why the research is needed?: Chronic obstructive pulmonary disease (COPD) is a lung disease primarily caused by smoking-related damage to the airways. Patients with COPD experience frequent disease flare ups ('exacerbations'). Most commonly, exacerbations are caused by a virus called rhinovirus (RV), also known for causing the common cold. Exacerbations can have a significant impact on quality of life with requirement for hospital admission. From previous studies, we know that the COPD lungs produce lower quantities of specialised mediators called 'interferons' that counteract viruses and may predispose to infection. However, we do not understand the reasons why this defect occurs in COPD. Gaining this knowledge will help us to design new preventative or therapeutic strategies. What questions do we want to answer?: The immune system plays an essential role in fighting viral infections through recruitment of 'white blood cells' to the lungs. These cells are essential for fighting infection and can produce chemicals called reactive oxygen species (ROS) that help to fight bacteria and viruses. However, there must be a fine balance as too much ROS in the airways causes damage and may adversely impact the immune system. ROS production is known to be inappropriately increased in the airways of patients with COPD and our preliminary studies suggest that this has detrimental effects upon the ability of the lungs to produce interferons. My research will seek to answer the following questions: 1. How exactly do ROS affect the way the immune system responds to viruses? 2. Do patients with COPD have different levels of certain ROS in comparison to healthy people and does this affect their ability to combat viruses? 3. Can we target ROS in COPD to boost immune responses and prevent exacerbations? How will we try to answer them: I will firstly carry out experiments in mice, that are not possible in human subjects, to delete a gene and block production of ROS. I will examine the effect that this has on the immune response to RV. I will measure virus levels to see how well the immune system has managed to control the infection, what types of immune cells have been recruited and how active they are and how much mucus is produced (a sign of increased inflammation in the airways). This will determine which parts of the immune response to viruses are controlled by ROS. Next I will use human airway samples from a previous study where patients with COPD and healthy volunteers have been deliberately infected with RV. I will measure ROS levels in the airways and determine whether they correlate with subsequent susceptibility to and/or severity of viral infection. Finally, I will use a model where mice are treated with an enzyme to cause damage to the lungs mimicking the changes seen in COPD. Using this COPD mouse model, I will administer therapies that target ROS to evaluate whether this can enhance the immune response to RV and prevent exacerbation. What will we do with our findings?: Through these experiments, I will define the key components of the anti-viral immune system in the airways that are affected by ROS. In doing so, I can identify important targets for new treatments that restore the balance in the immune response to viruses and reduce the impact of these infections on patients with COPD

UKRI Gateway to Research · FY 2024 · 2024-07

Since the dawn of humankind people have looked up at the sky, perhaps projected every day images into the dazzling variety of shapes that cumulus clouds produce, and asked "why do clouds form and then disappear?" and "why does it rain?" To this day these questions remain unanswered, although of course our understanding of the physics of clouds has advanced enormously. It has been provocatively asked "can we understand clouds without turbulence?" to which my response is a resounding "no!" Clouds grow by entraining environmental air across the sharply defined visible boundary of the cloud. Similarly they decay through precipitation, and more importantly the detrainment of air back to the environment. Neither of these processes are well understood. In recent years I have jump started the field of entrainment between two adjacent regions of turbulence, or turbulent/turbulent entrainment (TTE) which is precisely the scenario that occurs for a warm cumulus cloud in the turbulent atmospheric boundary layer. Entrainment dilutes a cloud and fundamentally alters its microphysics, yet TTE for a cloud is not understood in part because of its inherent intermittency. Without understanding the TTE of water mass, energy, momentum, buoyancy, and heat into a cloud it is not possible to parameterise it and thereby improve weather/climate forecasts. TITCHY will do this, through a carefully co-articulated campaign of state-of-the-art experiments and simulations specifically devised to assess the importance of my TTE paradigm to cloud microphysics. The second thrust of TITCHY is to examine the physics of water droplets within a cloud; in particular the forces that act on them and how they affect the collision/coalescence process that ultimately yields raindrops. These forces are subject to intermittent turbulent physics hitherto neglected but potentially of critical importance. Based on my transformative new ideas, TITCHY seeks to tackle a centuries-old problem with a modern outlook.

UKRI Gateway to Research · FY 2024 · 2024-07

Enabling identify how fibrotic lung disease will progress in a specific patient will allow clinicians to initiate patients on appropriate treatment at the earliest opportunity and slow disease progression. It remains one of the most urgent challenges for effective management for patients with progressive fibrotic lung disease. In this project, we will deliver 5 innovations: (1) building a large-scale repository of FLD images paired with patients' physiological data and clinical information (10647 cases from collaborators of the host institution); (2) advanced adversarial and diffusion probabilistic synthesis models for FLD images and voxel-level annotations; (3) state-of-the-art organ and tissue segmentation as well as quantification models with self/semi-supervised learning, multimodal contrast learning, fuzzy theory and transformer variants. (4) top-tier multimodal prognosis methods with the prevalent large language models and federated learning trained on self-built repository and publicly large-scale multimodal lung datasets, through all image inputs, diagnostic reports, quantified organ & tissue features, and clinical information. (5) infusing explainability in the AI models for discovering novel biomarkers to predict FLD progression.

UKRI Gateway to Research · FY 2024 · 2024-07

In the UK, over 9000 people are diagnosed with oesophageal cancer each year. Unfortunately, only 15% of these individuals will live beyond 5 years. Whilst chemotherapy and radiotherapy treatments are available for oesophageal cancer, most patients do not respond and are left with a poor prognosis. To improve the quality of life for patients suffering from this cancer of unmet need, new therapeutic strategies are essential. Cancers grow rapidly and often outstrip their own blood supply, leading to a state of low oxygen levels (known as hypoxia). This hypoxia is an important cause of treatment resistance in oesophageal cancer. Although new drugs targeting hypoxic tumours have been developed, numerous studies have shown only certain patients will respond to these medications. We currently have no clinically acceptable method to measure tumour hypoxia. Existing biomarkers for tumour hypoxia have failed to be translated into clinical practice as they are too expensive, impractical or have limited reproducibility. Therefore, we are unable to identify which patients may benefit from hypoxia targeting drugs. This makes designing clinical trials difficult and consequently there are no hypoxia-targeting agents approved in oesophageal cancer. Designing a practical and scalable test for tumour hypoxia would allow researchers to identify patients who may benefit from hypoxia-targeting medications. This could lead to a wave of new personalised therapies in this patient group. Our lab has developed a breath test to identify patients with oesophageal cancer. This breath test uses the altered profile of small volatile molecules found in exhaled breath to help diagnose oesophageal cancer. This breath test is safe, simple to perform, easily repeatable and highly acceptable to both patients and the public. Research has shown that some of the volatile molecules detected in breath are generated by cancer cells and are affected by hypoxia. Therefore, we aim to tailor our established breath test to identify which patients are suffering from hypoxic oesophageal tumours, allowing clinicians to predict their response to hypoxia-targeting drugs. To achieve this, we will build on our preliminary work demonstrating cancer cells exposed to hypoxic conditions produce a distinct volatile organic compound (VOC) signature. First, we will establish the biological pathways underpinning the unique VOC response to hypoxia in oesophageal cancer cells. Then, using our biobank of patient-derived organoids from oesophageal cancer patients, we will verify these cell findings in organoids exposed to hypoxic conditions. Finally, our study in oesophageal cancer patients using the hypoxia-labelling agent Pimonidazole will use human tissue to provide us with a deep understanding of the metabolic and genetic adaptations cancer cells undergo in response to hypoxia. From this information, we will construct a breath test for tumour hypoxia in oesophageal cancer patients using existing patient breath datasets. An effective hypoxia breath test would be the first of its kind. It will provide researchers with the opportunity to design clinical trials using hypoxia-targeting medications for the patients who will benefit most. This personalised therapeutic strategy could provide new treatments for these patients and improve their survival. The repeatable nature of breath testing means the test could even be used for therapeutic monitoring. The innovative prospect of a hypoxic breath test could advance the oncological management of oesophageal cancer and aid the progress of precision medicine.

UKRI Gateway to Research · FY 2024 · 2024-07

Problem: Menstrual disturbance affects one-fifth of women of reproductive age. Functional hypothalamic amenorrhoea (FHA) is one of the commonest causes responsible in one-third of cases. FHA occurs due to a combination of low body-weight, excessive exercise, and stress, on a background of genetic susceptibility. FHA causes subfertility and adverse effects on bone and cardiovascular health. At present, the mechanisms underlying FHA are incompletely understood, and treatment options are limited e.g., gonadotrophin releasing hormone (GnRH) pump therapy is the first-line treatment, but is scarcely available. Other available treatments including clomiphene are less effective in FHA. Therefore, there is an unmet research need to advance our understanding of the pathways underlying FHA and to develop novel therapeutic approaches to improve care for affected women. Context: Kisspeptin is the key regulator of GnRH neurons and the reproductive endocrine axis. Evidence suggests that kisspeptin is the 'GnRH pulse generator'. Leptin is a major signal of energy availability and is reduced in FHA. Leptin is a permissive signal that is requisite for healthy GnRH neuronal function, and leptin treatment can restore GnRH pulses in women with FHA although with undesirable associated weight-loss. However, existing data suggest that leptin does not act directly on kisspeptin neurons, but rather via an intermediary neuron such as agouti-related peptide (AgRP) neurons in the hypothalamus. AgRP neurons abundantly express leptin receptors and physically connect to kisspeptin neurons. Hypothesis: I hypothesise that leptin inhibits AgRP neurons, which in turn regulate kisspeptin neurons to play a causal role in the pathophysiology of FHA. Aims: 1. Validate a novel mouse model of FHA. My pilot data shows increased AgRP expression in two independent mouse models of FHA. Whilst 'caloric-restriction' is an established model of FHA, our lab has recently developed a novel 'caloric-dilution' model of FHA. This model uses a low-calorie feed such that mice can eat without restriction until they feel satiated such that hunger pathways should not be activated. However, they do not eat sufficiently to avoid a calorie deficit, and thus could be a more representative model of women with FHA. I will characterise the reproductive phenotype in this new model of FHA and compare it to the established model. 2. Investigate the causative role of hyperactive AgRP neurons in driving the FHA phenotype. As the models of FHA have increased AgRP activity (see pilot data), I will use inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based technology to reduce AgRP-neuronal activity to evaluate the impact on reproductive hormone levels and phenotype (e.g. uterine / ovarian weight). 3. Determine whether chronic kisspeptin administration can restore a healthy reproductive phenotype in the mouse models of FHA. I will administer a subcutaneous infusion of kisspeptin via a micro-osmotic pump for 2 weeks to the two mouse models of FHA and assess whether reproductive health can be restored. 4. Determine whether chronic kisspeptin administration can restore ovulation in women with FHA. I will conduct a clinical study in women with FHA to assess whether a chronic infusion of kisspeptin for 2 weeks can restore ovulation. Applications and benefits: This research will significantly advance our understanding of the mechanisms underlying FHA and establish whether AgRP neurons regulate kisspeptin neurons to result in FHA. I will evaluate the therapeutic potential of kisspeptin administration both in mouse models of FHA and in women with FHA.

UKRI Gateway to Research · FY 2024 · 2024-07

Mammalian development and subsequent organ maintenance relies on the ability to deliver the right cells to the right place at the right time. This highly coordinated process relies on the proper regulation of cell fate transitions in stem cells. However, at this time, how cell fate transitions are regulated is poorly understood. One aspect to how transitions are regulated is how the instructive genes are positioned and expressed in the nucleus. Indeed, the spatial organisation of the genome, and how it changes in a cell, helps to control when and how genes are activated. Proteins found at the outside of the nucleus, referred to as nuclear envelope proteins, tether specific genes to the periphery of the nucleus and play an important role in regulating those genes. As evidence of their importance, mutations in nuclear envelope proteins often result in developmental disorders. Mutant nuclear envelope proteins have been implicated in a range of human pathologies such as premature ageing (e.g. Hutchinson-Gilford progeria syndrome) and neuromuscular diseases (e.g. Emery-Dreifuss muscular dystrophy). It is therefore important to understand how these proteins influence mammalian development to shed light not only on how these diseases emerge, but also to exploit the therapeutic potential of differentiating stem cells towards specific lineages of choice. Nevertheless, how nuclear envelope proteins influence gene expression in stem cells during development remains unclear. At the same time, the nuclear envelope proteins in question have also been shown to be sensitive to forces, which are ubiquitous during development and organ maintenance. Furthermore, stem cells are highly responsive to these forces, altering gene positioning and expression in response to them. In this proposal, we hypothesize that forces on the nucleus alter the function of nuclear envelope proteins and thus gene positioning and expression. We further hypothesize that this force-mediated genetic regulation is an important aspect of fate transitions. To test our hypotheses, we will focus on two questions. First, how do nuclear envelope proteins regulate gene expression in stem cells? Second, how do forces affect nuclear envelope proteins and subsequent gene expression during stem cell differentiation? In the proposed research, we will investigate these questions to bring greater understanding not only to spatial regulation of gene expression in stem cells, but also to how stem cells respond to, and exploit, forces in their environment. Here, we address how nuclear envelope proteins influence early mammalian development by taking advantage of recent advances in next-generation sequencing that allow us to study how the genome folds at the level of a single cell and 'state-of-the art' microscopes capable of tracking individual proteins and genes in living cells. We will first identify genes that are controlled by nuclear envelope proteins during stem cell differentiation (Aim 1). We will then use high-resolution microscopes to track individual genes 'live', allowing us to determine how nuclear envelope proteins control expression of these genes: is it by positioning or tethering them at the nuclear periphery where they are silenced, or by recruiting specific proteins to these genes that influence their expression (Aim 2)? Finally, to understand which nuclear envelope proteins influence the ability of a cell to sense forces in the cell, we will use a bespoke cell stretcher to apply mechanical stress to cells and use approaches described in Aim 1 and 2 to determine which specific nuclear envelope proteins are required for genes to respond to these external forces (Aim 3). These results will shed light on the role of nuclear envelope proteins in human development and disease, enhance understanding of the role of forces in development, and also improve strategies for differentiating pluripotent stem cells towards specific lineages for regenerative medicine.

UKRI Gateway to Research · FY 2024 · 2024-07

Both genetic and environmental factors affect the ageing process, leading to differences in ageing rates. Therefore, a person's "biological age", or overall physiological state, may differ from what is expected given their actual (chronological) age. Differences in biological aging rates mean some people die earlier and have more health problems in later life. In the first part of my project, I used metabolomics (whole sets of metabolites or small molecules) data from multiple population-based cohort studies in the UK, Europe, and the USA, to develop blood tests of biological age using advanced statistics. We found that the metabolomic-based biological age tests provided improved prediction, over chronological age itself, of age-related ill health and mortality. Furthermore, We found that that biological ageing was slower over two years among people who were supported to follow a healthier lifestyle, compared to those who did not receive this support in the FINGER study. For the next part of my project, I will examine if the metabolomic-based biological age test can predict cognitive and physical aging among two cohort studies of older people (the CHARIOT PRO and TILDA studies). I will further refine the metabolomic-based biological age test, so it is less expensive and easier to measure in clinical laboratories. I will also test the use of proteins, another biologically important class of molecules, to develop biological age models in over 20,000 people in the EPIC and CHARIOT PRO studies. Since we know which organs in the body produce specific proteins, it is possible to test "organ-specific" ageing. This is useful as different biological systems in the body may age at different rates, and I will test organ-specific ageing against many types of disease. Furthermore, I will use genetic data and a technique called Medelian Randomization to test if proteins and metabolites that are correlated with age, may cause unhealthy ageing. I will use this information to further improve the biological age tests. Finally, I will analysis the pathways that connect proteins, metabolites and genetic factors involved in ageing to more deeply understand the biological processes that change with age.

UKRI Gateway to Research · FY 2024 · 2024-07

The goal of this grant is to develop new organic materials for solar cells that can convert light from red to blue. Done with sufficient quantum efficiency, this would enable a photovoltaic device (solar cell) with a power conversion efficiency of nearly 50%. This compares to a traditional single band gap device with a maximum efficiency of 34%. As these upconverting films are entirely optical, they can be made relatively easily, and the design process of the light management and the combined electrical/optical design of the single-bandgap solar cell can be separated. Our approach is to develop methods to model the processes occurring on a computer. This is challenging, as when you excite a material with a photon, the standard Born-Oppenheimer approximation we use in most quantum mechanics stops working, and we have to consider an exponentially exploding set of entangled quantum states. Also, the molecules that are useful for a technical application are very large (hundreds of atoms). This stretches our ability to solve the equations of quantum mechanics even in the Born-Oppenheimer approximation, on the largest computers. We have two main routes to overcome these limitations: First, we will develop methods and new computer codes that make use of the Feynman path integral approach to quantum mechanics. This alternative formulation has not had much application to materials, mainly because the mathematical objects you need to manipulate are quite abstract. One nice thing about this approach to quantum mechanics is that it can deal with infinite degrees of freedom, with a hierarchy of approximations that can be turned on and off for the problem of interest. Second, we take some of the ideas and techniques in machine learning, and apply them to quantum chemistry. We will develop methods to fit empirical quantum mechanical models to the materials are interested in, considerably reducing the computational burden, while retaining accuracy. Both these approaches are enabled by modern scientific programming languages and agile software development practices from industry - small teams can now implement a large quantity of new methods in a short amount of time. However, modelling will only take you so far. We will also do spectroscopic measurements on molecular upconverting devices, combining them with modelling in order to understand the working mechanism; these measurements will also validate the approximations made in our models. A particular technique we will use is called electron paramagnetic resonance. This is directly sensitive to the quantum mechanical spin of the excited states. Our aim is to develop empirical design rules for how to make higher efficiency devices. These will pass on to our synthetic chemistry collaborators, who will make these new molecules, which we will measure. Closing the loop on modelling, experimental validation, and then design and measurement ensures we are kept deeply in touch with reality, and offers the best route to make progress.

UKRI Gateway to Research · FY 2024 · 2024-07

Arsenic (As) contamination continues to be the world's largest silent killer, affecting millions of human lives and countless livestock. Reports suggest that the global distribution of As is massively spreading over the USA, Asian countries, the UK, and European countries due to a combination of both geogenic and anthropogenic factors. According to FAO, an overwhelming number of countries have reported the presence of As in their agricultural soil, contaminating associated crops. This As-uptake is primarily dependent on the redox speciation of As in soil, which in turn depends on the soil physico-chemical parameters. In the paddy field soil, the oxic/anoxic cycle continues, and this also influences the microbial community in that soil. Most microbes produce different extracellular polymeric substances (EPS) that form biofilm and are responsible for beneficial processes associated with, for example, key geochemical cycles. Given that reactive nitrogen is the second most limiting elemental nutrient for organisms, including in biofilms, the nitrogen-fixing and nitrogen-self-sufficient biofilms we propose to explore will reveal fundamental new features of these complex bacterial communities. Nitrogen fixation in biofilms-here occurring in the air-is also likely to be important in sustaining these communities, specifically in environments that are limited in reactive nitrogen, such as most soils. Diazotrophs can fix atmospheric nitrogen into plant-available forms under specialised culturing conditions. Ambient oxygen has hitherto been considered a main barrier to developing nitrogen bio-fertilisers. Biofilm formation on roots has been reported, but their capacity to fix nitrogen has not. We propose to study the unexplored biology of nitrogen-fixing biofilms on plants to provide the molecular knowledge base to ultimately develop nitrogen bio-fertilisation for agriculture. To do so, we will explore the genetic and molecular underpinnings of nitrogen fixation in biofilms in the air, how the nitrogen-fixing biofilms form on plant roots, and quantify and improve the nitrogen benefits they render to plants. Each of the objectives is expected to be productive on its own terms and have an individual impact on the socio-environmental benefits. The distribution of As in soil depends on its physico-chemical properties and associated microbial communities. From our previous research, it is expected that the soil As mobility and bioavailability will be less in aerobic soil with frequent water application for crop cultivation. The results will be supported by the metatranscriptomics data of biofilm/EPS-responsive genes and proteins under differential soil-plant setups. This will confirm the optimum soil profile for supporting bacterial biofilm formation and stability. Soil microbial diazotrophs will be screened for EPS-responsive genes to understand the degree of biofilm formation in natural conditions and after EPS-gene over-expression. The As adsorption on the biofilm surface with simultaneous N-fixation will be traced. While implementing the diazotrophs at plant roots, there will be a higher uptake of available nitrogen. Higher N-uptake and minimized As translocation will certainly promote plant growth. Biofilm N-fixation and subsequent release to the plant rhizosphere will make it readily available for plant root uptake. The present era is fighting with mainly three aspects of environmental issues: (i) soil health quality and its biotic management which is indicative of SDG 15 (Life on land), (ii) food crises and crop productivity minimizing global hunger status, the indicator of SDG 2 (Zero hunger) and (iii) human health issues and their management which is connected to SDG 3 (good health and well-being). The ideology of this project revolves around three pillars- soil arsenic mitigation, nitrogen fixation for plant uptake and crop quality enhancements with less As loading. These three aspects are directly linked to the mentioned SDGs.

UKRI Gateway to Research · FY 2024 · 2024-07

Atmospheric Carbon Emissions Sampler - this project develops a product that collects atmospheric carbon for radiocarbon analysis, which can determine the amount of carbon that has been added by fossil fuel emissions. The potential users of the product include researchers, industrial sites with mixed fuel combustion, nuclear power plants, city and state governments and private companies.

UKRI Gateway to Research · FY 2024 · 2024-06

Cardiovascular Diseases (CVDs) are the leading causes of death in the world. Congenital heart malformations account for as many as 30% of embryos or foetuses lost before birth. To properly develop, the heart needs to generate mechanical forces during the growth of the whole structure. This, in combination with genetic information, is required for assembling a functional heart. Currently, most studies focus on how genetic programmes control cell identities and their subsequent roles in cardiac development. In contrast, the mechanical forces that are integral to the growth and assembly of the heart are much less explored. This is surprising as abnormal mechanical forces can deregulate gene expression and lead to diseases such as congenital heart disease and cardiomyopathies. Understanding how biomechanics regulates cardiac morphogenesis is thus of utmost importance. This project will explore the interplay between genetic control and self-organization emerging from cell mechanics during cardiogenesis. Our hypothesis is that mechanotransduction is at the centre of this interplay. We will study the role of mechanotransduction in the emergence of multicellular flow and the mechanism of a newly characterized cell shape change associated with cardiac chamber morphogenesis.

UKRI Gateway to Research · FY 2024 · 2024-06

Few problems in fundamental physics are as clearly motivated or as important as discovering the nature of the elusive dark matter that accounts for most of the mass of the universe. Direct detection experiments located deep underground are searching for the rare interactions of these well-motivated, relic particles in very sensitive detectors. Liquid xenon (LXe) technology has led these searches for over a decade. Recently, the top international collaborations in the field have come together in the XLZD consortium to build the definitive experiment: one able to discover or rule out electroweak-scale particle dark matter in the accessible parameter space remaining above the very challenging neutrino background. Exciting opportunities exist also in neutrino physics, including establishing the existence of neutrinoless double-beta decay; this is another paradigm-shifting discovery which may be accessible to such an experiment, which could explain the matter-antimatter asymmetry in the universe. This proposed 'rare event observatory' will deploy a LXe detector with up to 80 tonnes of 'active' mass in an ultra-low-background experiment to address these and other questions, at least two of which could entail Nobel-Prize worthy discoveries. This Pre-Construction project prepares the UK contribution to the XLZD experiment and builds the case to bring this ambitious international experiment to the UK. STFC is developing a major new underground laboratory at the Boulby mine, and XLZD would be the centrepiece of the new state-of-the-art facility. A future construction project must be carefully prepared, and this development work is delivered through this Pre-Construction project. The proposed UK contribution to XLZD includes major experimental hardware systems, especially those most naturally suited to the host nation; these will be designed and prepared in this phase. In addition, we will deliver with key industrial partners bold programmes for clean manufacture underground, for engineering and skills development, and for environmental sustainability. These programmes relate to challenges that must be addressed, but which we deliberately develop into opportunities: to provide return to UK industry and wider economic impact, to develop capabilities that support future STFC and UKRI projects, and to be a pathfinder in how Big Science moves towards Net Zero.

UKRI Gateway to Research · FY 2024 · 2024-06

Cells must sense, measure, and respond to mechanical forces in their environment to carry out their functions. These forces govern biological processes ranging from cardiac activity to respiration and the immune response. Dysregulation of mechanical forces is implicated in diseases such as cancer, fibrosis, and neurodegeneration. Over the past two decades, the field of mechanobiology has seen significant growth, thanks to the development of new experimental techniques. However, existing methods are confined to relatively few laboratories due to their reliance on specialised equipment and interdisciplinary expertise. Additionally, available tools can only analyse tens to hundreds of cells per experiment, which further restricts their use. In this project, our goal is to create an accessible toolkit for cell biologists to quantify forces mediated by receptors within cells. Our toolkit will consist of pre-packaged system components that empower cell biologists to measure mechanical forces transmitted by any receptor-ligand pairing in any cell type, using equipment that is readily available in biological laboratories. We will also streamline protocols for its application, making our toolkit a straightforward "off-the-shelf" force-measurement solution. Our technology, named FORCE-DNA (Fluorescence Optical Readout of Cellular Forces using DNA Amplification), is founded on a category of molecular force sensors known as DNA tension gauge tethers (DNA-TGTs). DNA-TGTs are double-stranded DNA molecules that irreversibly rupture when subjected to a critical force. These tools have been successfully employed to quantify the tension required to activate mechanosensitive receptors in cells. In our approach, we will leverage DNA-TGT rupture to trigger a cascade of DNA self-assembly events through a process called hybridisation chain reaction (HCR). This process generates an amplified fluorescence signal that can be detected in a multi-well format using either a microplate reader for high-throughput applications like screening and diagnostics, or through a fluorescence microscope for detailed information about force distribution at the molecular scale. We will also develop calibration protocols to accurately correlate fluorescence intensities with absolute forces acting on receptor-ligand bonds. The specificity of DNA base-pairing will enable the simultaneous detection of forces generated by up to five receptor-ligand pairs within the same cell during a single experiment. Importantly, FORCE-DNA can be applied to investigate any receptor-ligand pairing in any cell type, using equipment that is commonly found in biology laboratories, all at a cost of <£100 per multi-well plate. We envision that FORCE-DNA will become the go-to method for measuring receptor-mediated forces across all areas of cell biology research.

UKRI Gateway to Research · FY 2024 · 2024-06

Many bacteria need to swim to cause diseases ranging from food poisoning to cholera. Understanding how they swim is essential for the development of therapeutics to block these diseases. Most bacteria swim using helical propellers called flagella that are rotated by molecular motors embedded in the cell surface. Although understanding flagellar motility has focused on the flagella of Escherichia coil and Salmonella enterica, whose flagella are dotted over their cell surface, many bacteria polarly-localize their flagella. These polarly-localised flagella and their molecular motors are considerably more complex than those of E. coli and Salmonella. This proposal seeks to understand the functional implications of the differences between polar and non-polar flagella. Our core techniques are bacterial genetics (which we can use to alter various characteristics of flagella) and electron cryo-microscopy (which we can use to directly visualise molecular structures so we can understand the underlying mechanisms of swimming changes from our genetic changes), which we will augment with other techniques through a stable of long-term established collaborations. We will focus on our model for polar flagellation, Campylobacter jejuni, because we can easily make genetic alterations to change key flagellar characterstics, and it is well-suited for the techniques we will use.

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

Treating bone fractures affecting millions of people worldwide is a major challenge for orthopaedic surgeons. Bone fractures can have a major impact on health and quality of life, but also impose a significant economic burden on the healthcare system. Severe non-union and highly communicated fractures with continuous bleeding can become life-threatening. The increasing demand for bone grafts reflects in growing market size annually. Traditional bone fixation methods metals, screws and pins for bone fixation suffer from challenges of foreign body reactions and require additional surgeries for removal. Clinically used calcium phosphate cements and cyanoacrylates lack osteogenic potential, and stability in wet environments, do not support cell adhesion, and produce toxic monomers on degradation. There is an unmet need for bone adhesive to repair fractures, as currently there are no clinically approved biomaterials. The proposed bio-adhesive bone glue (FIX-Heal) of bone-mimetic components fixes bone to bone, scaffolds to the bone, supports cell growth and provides antimicrobial, healing properties attributed to released calcium ions for bone regeneration. This bio-resorbable and biocompatible green glue of polymers and bioactive glass makes a strong bond with the bone and is free from any chemical crosslinkers and toxic products after degradation. The project of bio-inspired green glue incorporates green principles into biomaterial science, helping create a more sustainable and environmentally friendly future in line with the European mission Horizon 2020 of the European Green Deal and the UN decade of healthy ageing. The project will be executed by a team including a host, researcher and collaborators with expertise in bioactive glass, adhesion and antimicrobial testing for bone fixing and regeneration. The researcher will gain skills that can enhance employability. The project will have societal, technological and commercial potential as a novel bone bioadhesive.

UKRI Gateway to Research · FY 2024 · 2024-06

NWTF is a distributed facility with the hub at Imperial College and facilities spread across UK universities (nodes) at: Bristol, Birmingham, City, Cranfield, Cambridge, Glasgow, Imperial, Manchester, Loughborough, Oxford, Southampton and Surrey. A novel facility from a new member at the University of Liverpool is included in these proposals. NWTF membership depends on the institutional commitment to support its facilities, its research priorities and co-location of an active research group with the facility. It is not fixed, and membership can reflect any changes to node activity such as low usage or personnel change over a period of some years. Each NWTF+ of the seven proposals describes the motivation for new facilities to be built - one proposal for each cost centre. This proposal contains justifications for the MSBS (at Oxford and Imperial), the NWTF hub (Imperial) plus those for transformational equipment at the other six NWTF institutions. MSBS offer an unrivalled opportunity for making sting-free measurements of time-dependent forces acting on aerodynamic models. Except for the usual challenges associated with Reynolds-number dependence, an MSBS offers the best way of estimating forces on engineering bodies as in 'flight', such as submarines, UAVs and re-entry space capsules. Often such bodies operate in a mixed ballistic / aerodynamically assisted regime. The understanding of the fluid forces is important when the flight is ballistic, and essential when, for example, recovery of a UAV or space capsule depends on an accurate measurement of the operating forces, lift and drag. Measurement of dynamic properties (mass, and inertia of the vehicle) and aerodynamic properties (of the vehicle and its control surfaces) are key to precise control. MSBS offer the opportunity to identify unsteady aerodynamic phenomena that are of paramount importance for control of highly manoeuvrable vehicles operating at high (post-stall) angles of attack or indeed novel vehicle configurations and flapping flight. Hardware-in-the-loop simulations would enable free-flight testing of such vehicles in the wind tunnel. The NWTF hub provides a single point of contact for access to university wind tunnels and researchers enabling connectivity and collaboration by matching researchers from both the UK and abroad to facilities. A general principle is that, even if the converse is possible, movement of the researcher to the facility is more efficient than transport of facility/equipment to different sites. This involves the recognition that a particular site offers more - expertise, training, data storage - than just the facility itself. This proposal extends the role of NWTF by developing interactions with both industry and public-sector institutions such as EPSRC/UKRI and government departments (DBT, DSIT). It has strong links with the Aerospace Technology Institute. These developments require a new outward-facing role, a Director of Operations and Business Development. This is a key organisational role which enables NWTF to be defined as an organisation (possibly as a legal entity) in its own right. The importance of fluid mechanics across all sectors of the UK economy has been established, with NWTF demonstrating a new viable model for the running of, and enabling access to, state-of-the-art facilities. While NWTF has recently made significant contributions to R&D (often involving industry partners), the scope thus far has excluded industry facilities of higher TRL. While university support includes that for training and skills development at both undergraduate and postgraduate levels, the benefits of the NWTF model have yet to be fully exploited in all relevant sectors of the economy, most notably industry. Through its Director of Operations, NWTF has initiated meetings to discuss the construction of new and the development of existing facilities that meet perceived gaps in the TRL5+ landscape.

UKRI Gateway to Research · FY 2024 · 2024-06

The purpose of the extension phase of my UKRI FLF is to understand the implementation of human milk bank services in the UK. Prior to the start of my FLF, milk bank services in the UK were generally small under-resourced services, with debate amongst neonatologists about whether they were necessary at all. Since then, the work published during my FLF and from others globally have highlighted the breadth of public health impacts that access to donor human milk can have on both the individual level, in terms of support for maternal mental health and ameliorating adverse infant outcomes of supplemental feeding, and at the societal level with regards to support for breastfeeding and broader perceptions of human milk. This year, the WHO has launched a Guideline Development Group aiming to establish minimum standards globally for the operation of human milk banks, and there is an increasing clinical awareness that donor milk should be available as a supplement for infants where maternal milk is unavailable, including term as well as preterm infants. Greater focus on the sector has also arisen as a consequence of the 2022 formula shortages where vulnerable infants were left without safe feeding options. Human milk banks in the USA had to quadruple output to meet the needs of hospital services. There is currently no emergency planning for such circumstances in the UK context, but a high likelihood of similar supply shortages developing in the near future. The main aim of my FLF was to create evidence that could inform the creation of a National Milk Bank Service, with equitable opportunity to donate and receive donor milk. The need for such a service has largely been established, but there are a number of risks of inappropriate service implementation. These include safety risks, lack of equity, commercialisation, disruption to service provision, and failure to support maternal breastfeeding where possible. Phase 2 of my FLF will therefore build on the foundations laid in the first phase of my UKRI FLF, complementing the work achieved so far, and establishing a cohesive programme of broad implementation research. The proposed programme will build on the network of diverse stakeholders and academic expertise brought together within the first phase of my UKRI FLF to address these gaps before milk banking services are further scaled in the UK, working across four workstreams: 1) the research team will make an assessment of donor milk acceptability using paradigms established recently on complex public health interventions by Sekhon et al., using a variety of methods that include surveys, semi-structured interviews and workshops with key stakeholders, and focus groups; 2) working with health economist, Dr Hema Mistry, a robust assessment of cost-effectiveness and costings will be conduct to facilitate future service planning; 3) the integration of a novel donor portal, facilitating the recruitment, communication and support of milk donors, developed during the first phase of my fellowship will be integrated into the Li-Lac milk bank tracking system and evaluated for efficacy in improving donor experience and volume donated against audited data from 2020-2022; 4) building on preliminary workshops that bring together emergency planners with milk banking and paediatrics experts, work will continue to co-design emergency response and service continuity plans, entrench risk management throughout UK milk banking, and establish the utility of freeze-dried milk as a method of building resilience in the sector. This work will have broad ranging impacts on the intractable area of increasing breastfeeding rates, both in the UK and globally. After a recent presentation WHO European Region webinar on human milk banking, the Chair concluded that, "the case for milk banking had been made - now the focus should be on implementation." My team are in a unique position to meet this challenge.

UKRI Gateway to Research · FY 2024 · 2024-06

Cardiovascular disease is responsible for 26% of all deaths in the UK and estimated to cost the UK economy £19 billion each year. Poor diet is one of the key contributors to cardiovascular disease. In order to help people develop healthy diets and prevent cardiovascular disease we need to know more about how patterns of diet develop over time, how they are influenced by lifestyle changes, and how these influences differ between different population groups. Early adulthood (ages 16-24) is a time when many lifestyle changes are seen, as individuals move from school and family environments, to higher education and/or employment and begin to live independently. This is an important time to support individuals to develop healthy habits which will then persist into adulthood. In this research I will address the question of how the changes that take place in early adulthood contribute to the differences seen in diet and cardiovascular health between different groups of the population in adulthood. In my research I will study: 1. How are patterns of changes in education and employment participation over early adulthood related to adult diet and cardiovascular health? 2. How are the education/employment transitions of early adulthood associated with changes in diet and eating behaviours? 3. What are factors that influence changes in diet and eating behaviours across early adulthood education/employment transitions? I will make use of the best existing datasets available to study these questions in the UK (The 1970 British Cohort Study and the Avon Longitudinal Study of Parents and Children) and internationally (Western Australian Pregnancy Cohort (Raine) Study and the ProjectEAT cohort (US)), and will also collect my own data to examine changes in diet as individuals leave school in the UK. The study builds on my previous work in this area, including literature review, analysis of changes in diet across life transitions in a Norwegian dataset, and cross-sectional analysis of diet quality and cardiovascular health in the UK National Diet and Nutrition Survey. The research will be carried out at the Centre for Diet and Activity Research (CEDAR), within the MRC Epidemiology Unit in Cambridge, which conducts research specifically focusing on the factors that influence dietary and physical activity related behaviours. I will collaborate with experts working in my host institute as well as external collaborators with expertise in cardiovascular health, nutrition, eating behaviours and specialist knowledge of data collection and analysis methods. This research will lead to a better understanding of the factors that are linked to changes in diet and eating behaviours during early adulthood, and how these changes differ between different groups of the population. The findings from this research will help academics and policymakers to understand the most effective way to help people to improve their diet over this age range and reduce cardiovascular disease.

UKRI Gateway to Research · FY 2024 · 2024-06

Central to the UK's ambition to achieve Net Zero is the increasing transition to renewable wind energy. To achieve this goal, the UK has set out a Ten Point Plan for a Green Industrial Revolution which places offshore wind at Point One in its energy strategy. Already a global leader, the UK aims to generate 50% of its electricity using wind power by 2030, nearly doubling its current output. However, the UK is facing a compelling challenge of dealing with massive amount of waste blades while benefitting from wind power. The lifetime of wind blades is 25 years. It is estimated that around 5,200 blades of ~34,400 tons will be decommissioned in the next 5 years in the UK and this number will increase by 10 times by 2050. By then, Europe will have 325,000 waste blades. It is estimated that 43 million tons of waste blades will be decommissioned globally by 2050, making it a pressing national and international issue. The wind turbine blades are predominantly made of fibre glass composites comprising glass fibres embedded in a polymer resin (e.g. epoxy). These composites are engineered to be very tough, making them extremely difficult to decompose in the natural environment. Unfortunately, the current recycling methods are either energy intensive or too expensive, leaving the waste blades to be landfilled or incinerated creating serious environmental problems. Some European countries have banned landfilling waste blades through legislation and the UK is expected to follow this trend. Construction industry is also facing a critical environmental issue because the production of cement (as the key constituent of concrete) is an energy intensive process with huge CO2 emissions. Generally, producing one ton of cement releases about one ton of CO2 in the air, making cement production account for 8% of global greenhouse gas emissions. The UK construction industry consumed 15,218,000 tons of cement in 2020, and it is in an urgent need of technologies for reducing cement consumption to achieve the Net Zero goal by 2050. My fellowship aims to develop a completely new and feasible technology to recycle waste wind turbine blades for making low-carbon concrete (WINDCRETE). This is underpinned by my pioneering research which shows that the silica-rich recycled powder from grinding the waste blades is chemically reactive in alkaline solution (pozzolanic reactivity), so that it can replace cement for making concrete. I will develop WINDCRETE into a new construction material through a series of fundamental research in (a) glass and polymer separation, (b) hydration and molecular modelling, (b) pozzolanic reactivity maximisation, (c) strength/durability optimisation and (d) life cycle analysis (LCA). I have engaged with 9 industrial partners across broad sectors including wind blade manufacturer, cement and concrete producer, construction and designer, waste management, composites trade association and innovator. In close collaboration with industries, I will bring WINDCRETE from the lab to the real world through a startup which is underpinned by two patents developed from this research and successful demonstrations on the partners' construction sites. WINDCRETE brings an exciting opportunity to address two global issues in both wind energy and construction industries, establishing a new paradigm in recycling waste blades while decarbonising concrete. More importantly, I will generalise WINDCRETE to extend its impact to wider industries like aviation, automobile, marine and electronics, which are using massive fibre glass composites but facing the same challenge of recycling the waste.

UKRI Gateway to Research · FY 2024 · 2024-06

The changing conditions in near-Earth space cause space weather. This poses a risk to our everyday lives through the technology we rely upon. Space weather impacts on crucial power, communications, navigation, and transport systems. Monitoring and forecasting it is thus vital. The processes that drive space weather globally are not well understood. The interplay between Earth's magnetic field and charged particles blowing from the Sun forms a protective shield in space, known as the magnetosphere. Space weather occurs because this shield is neither perfect nor static. Energy penetrates our magnetosphere and gets distributed to different regions inside it. But the global response is greater than the sum of its parts. Local processes alone cannot explain the overall response. Instead, space weather phenomena appear to emerge from the complex system itself. To better understand what causes space weather requires a global approach. Large groups of satellites working together, known as constellations, are required. Achieving this through traditional space missions is too expensive. Satellite operators are now launching commercial mega-constellations for communications services. These consist of hundreds to thousands of satellites in low Earth orbit. This orbit is at the interface between the top of our atmosphere and the magnetosphere. How space weather is mediated between these regions is still an open question. So mega-constellations are perfectly placed for space weather monitoring. The satellites use measurements of Earth's magnetic field to orient themselves. But these instruments can detect the signatures of space weather also. This fellowship will thus harness mega-constellations as a tool for monitoring space weather. Mega-constellations provide an unprecedented number of globally distributed observation points in space. I will develop new processing tools to use this data. These will extract and resolve the ever-changing electrical currents mediating space weather. Computer simulations will test the limits of what is achievable. These results will inform requirements on future mega-constellation designs for space weather monitoring. Machine learning will also combat the challenges of analysing "big data" in space. I will adapt methods developed from other fields for use in space weather science. These will reduce the amount of data to analyse and identify patterns present. They will have broad applications across current and upcoming missions, facilities, and simulations. I have partnered with a mega-constellation operator to put these methods into practice. This will establish the current space weather capabilities of mega-constellations. I will derive a new global activity index from this data. This will eliminate the errors and biases in those currently used. A pipeline producing this index in real-time will yield new space weather warnings. Dedicated campaigns will also further scientific research into what drives space weather. These coincide with the upcoming increase in solar activity. The campaigns will focus on waves that emerge during intense space weather events. Like a musical instrument, these waves are processed and guided by their environment. This forms a complex orchestra that encompasses our planet. But we do not know the global nature of this symphony and its importance in space weather. The mega-constellation will at last reveal the structure of the different waves. I will thus determine their effects on space radiation, atmospheric heating, and currents in the ground. This will advance our understanding of how these waves contribute to space weather. This fellowship will revolutionise space weather monitoring by harnessing mega-constellations. It will yield a step-change in capability. Global data will unveil how space weather works, improving our ability to predict it. The fellowship will thus boost our ability to mitigate this threat to society.

UKRI Gateway to Research · FY 2024 · 2024-06

Phages are viruses that specifically infect and kill bacteria. Phages are ubiquitous because they are the most abundant entities in the biosphere and are found in all habitats where bacteria proliferate. The ways by which phages takeover the bacterial cell for making phage progeny have long served as rich sources of information, inspiration, and tools for modern biotechnology, biology, and medicine. This includes, for example, our ability to make drought and disease-resistant crops or vaccines against infectious diseases like COVID. Inside the bacterial cell, proteins carry out all biological functions. The information for making proteins is carried on a molecule called RNA. Therefore, all biological functions in bacteria depend on how RNA is managed and bacteria use sophisticated processes to manage cellular RNA. To what extent phages depend on or change bacterial RNA management processes to benefit production of phage progeny is not known. In this project, we will study the details of how and why phages depend on and/or change bacterial RNA management processes. Results will advance fundamental knowledge by providing new biological insights into the interaction between phages and bacteria and, looking ahead, could provide new resources and knowledge for beneficial applications in biology, biotechnology, and medicine.

UKRI Gateway to Research · FY 2024 · 2024-06

In the past two decades numerous viruses have emerged from animals to cause outbreaks in the human population. These include Swine Flu, Ebola viruses, Zika virus, and three coronaviruses, including SARS-CoV-2, the cause of the ongoing COVID-19 pandemic. The frequency of virus emergence is accelerating likely due to our increased travel as well as global environmental and climate changes that bring humans and animals in ever closer contact. To identify which viruses pose the most risk for future pandemics, it's important to understand what it is about pandemic viruses that enables them to spread so efficiently between humans. One of our most important front-line defences against infection is our innate immune system. This system is present in all cells, and is made up of a network of sensors that can detect invading viruses, activate antiviral defences and initiate a warning system that places neighbouring cells in a state of readiness to stop infection. To infect us and transmit, all viruses must overcome this front-line defence, by escaping detection or by disabling the response or usually a complex combination of both. Viruses that jump between species, such as coronaviruses, must overcome this defence system in each new host. I previously found that, despite having only recently emerged in humans, isolates of SARS-CoV-2 collected at the start of the pandemic could effectively suppress activation of the human innate immune system to allow viral spread. This suggests the virus was pre-armed with countermeasures to overcome human defences. The emergence of more transmissible variants throughout the pandemic, called variants of concern (VOCs), suggests that SARS-CoV-2 is adapting to spread better in its new human host. I discovered that the VOCs were able to suppress activation of the innate immune system even more potently than the early isolates, which may increase their chance of establishing infection to transmit. Virus manipulation can change the course of the innate immune response and drive disease, resulting from inappropriate immune activation that damages tissues, as occurs in severe COVID-19. All together our new understanding helps explain how the innate immune system is a key determinant in pandemic virus emergence, transmission, and disease. The goal of my research programme is to understand how emerging viruses overcome the innate immune system to become pandemic. Studying SARS-CoV-2, and its adaptation to humans in real time, provides an unparalleled opportunity to understand the molecular mechanisms underlying human infection. I will firstly identify the countermeasures the original SARS-CoV-2 virus used to overcome human innate immune defences. This will lead me to discover key innate immune barriers to emerging viruses and understand how they work. Secondly, I will investigate how SARS-CoV-2 variants have adapted to get better at overcoming the human innate immune system to transmit more effectively. This will reveal what aspects of the innate immune system are unique to humans. Thirdly, I will discover how SARS-CoV-2 manipulation of the innate immune system drives inappropriate responses that cause disease. The virus is a master manipulator of the cell environment to make it conducive for viral replication. Because of this, we can use it as an excellent tool to learn how the innate immune response works, which is relevant to understanding other diseases where the innate immune system is defective. Through this fellowship, I will maximise what we can learn from SARS-CoV-2 to lay the groundwork for understanding future emerging viruses, which all encounter the same defences, and discover exciting new biology about how the innate immune system works in health and disease.

UKRI Gateway to Research · FY 2024 · 2024-06

My research focusses on mitochondria, important components of our cells. Mitochondria have two membranes, separating them from the rest of the cell; an inner, folded membrane and an outer membrane. The way these two membranes interact has critical roles in human health and disease, and dysregulation of these processes has been linked to neurodegenerative disorders, cardiomyopathy and neurological disease. My group are building 3D, dynamic models of mitochondria by using computational simulations alongside experimental approaches including cryo-electron tomography. This programme represents a comprehensive, multidisciplinary molecular level study of both membranes of the mitochondria and how they behave in concert and will give us new understanding of how we might control these pathways. The new understanding generated by my research programme will be applied to study other related pathways and, long-term, will be expected to lead to potential new drug targets in mitochondrial quality control pathways. Advancements in understanding membrane protein-lipid interactions in general will also have implications for the advancement of drug discovery programmes.