KING'S COLLEGE LONDON

UKRI Gateway to Research · FY 2024 · 2024-07

Researchers discovered more than 60 years ago that cells infected with viruses produce a substance that protects neighbouring cells from viral infection. This secreted substance was termed Interferon, as it 'interferes' with infection. Since then, many different interferons have been discovered, and their functions in anti-viral immunity have been extensively studied. Interferons has even been used as a therapy against viral infections. However, it remains unclear whether interferons have similar roles during bacterial infections. Bacterial infections pose a significant threat to human health and there are increasing numbers of bacteria that are resistant to almost all clinically available antibiotics. It is therefore essential that we discover alternative treatments for bacterial infections. An attractive area of research are drugs that activate the immune system to naturally combat infection. Interferons are one such candidate anti-bacterial therapy, but we first need a greater understanding of their roles in bacterial infection, in part to see if they could have harmful effects. This proposal will focus on the major human pathogen Salmonella enterica, a bacterium which affects over 100 million people each year, causing different diseases including gastroenteritis and typhoid fever. Salmonella invades human cells where they multiply and hide from the immune system. Worryingly, resistant strains of Salmonella are emerging across the globe, rendering this pathogen a major threat to human health. In this proposal, we will study whether different interferon families play beneficial or harmful roles in Salmonella infection. We will investigate how interferons affect the ability of Salmonella to multiply within host cells and control immune responses. We will also study the functions of different interferons in mice infected with Salmonella. This project will also identify if virulence proteins that Salmonella uses to cause disease can alter the ability of cells to produce or respond to interferon. Overall, this research will give us a better understanding of the functions of interferons in Salmonella infection, and how we can use this knowledge to develop new treatments for Salmonella infections.

UKRI Gateway to Research · FY 2024 · 2024-07

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 · 2024-07

Novel and innovative tools and techniques are required to ensure that whilst mining is carried out in order to achieve some of the United Nations Sustainable Development Goals, it is not at the detriment of others. Yet, whilst extensive work and research is carried out to address a number of concerns for the mining industry, the tools developed are rarely implemented - even where the science is excellent. There are a number of reasons for this, but we believe one of the most important is due to the complex relationships present within the raw materials sector. The mining industry itself is very complex, with a broad and diverse range of stakeholders. Innovation is often enabled by ACADEMICS, but not always in collaboration with MINING COMPANIES, hence the tools developed may not service them well. Where the two do work together, barriers may include FINANCE, as INVESTORS may not fully understand the advantages of the innovation. Perhaps the best way to integrate novel approaches may be through POLICY and REGULATORS, yet they may not have the subject specific knowledge to enforce this. Both the PROMT and PAMANA project are developing new scientific methods to improve aspects of mining in the Philippines. A Knowledge Exchange (KE) programme, carried out by Fellows who understand these nuances, will address the barriers outlined above. KE will improve understanding of stakeholder perceptions, challenges, and benefits. Then, tools and techniques can be embedded into stakeholder organisations. We propose a KE Fellowship to capitalise on diverse skills, and experience of building relationships across communities, private sector, and public sector; grounded in technical expertise in ecosystem science and economic geology. Our ambition is to build lasting networks that allow PROMT and PAMANA partners a vehicle to embed their research into stakeholder relationships and facilitate partnerships for further collaboration and project follow-on.

UKRI Gateway to Research · FY 2024 · 2024-07

The standard practice for evaluating the generalisation of supervised machine learning models in NLP tasks is to use previously unseen (i.e. held-out) data and report the performance on it using various metrics such as accuracy. Whilst metrics reported on held-out data summarise a model's performance, ultimately these results represent aggregate statistics on benchmarks and do not reflect the nuances in model behaviour and robustness when applied in real-world systems. We propose a robustness evaluation framework for NLP models concerned with arguments and facts, which encompasses explanations for robustness failures to support systematic and efficient evaluation. We will develop novel methods for simulating real-world texts stemming from existing datasets, to help evaluate the stability and consistency of models when deployed in the wild. The simulation methods will be used to challenge NLP models through text-based transformations and distribution shifts on datasets as well as on data sub-sets that capture linguistic patterns, to provide a systematic coverage of real-world linguistic phenomena. Furthermore, our framework will shed insights into a model's robustness by generating explanations for robustness failures along the lexical, morphological, and syntactic dimensions, extracted from the various dataset simulations and data sub-sets, thus departing from current approaches that solely provide a metric to quantify robustness. We will focus on two NLP research areas, argument mining and fact verification, however, several simulation methods and the robustness explanations are also scalable to other NLP tasks.

UKRI Gateway to Research · FY 2024 · 2024-06

So far, treatment of heart diseases has relied primarily on the administration of pharmacological drugs that only alleviate symptoms of the disorder. In the case of various cardiomyopathies with genetic aetiology, these shortcomings can be overcome by using gene therapy methods, yet simple vector-based gene replacement might be impossible to implement. This approach is limited by the size of several of the affected genes, as well as dominant mode of inheritance. Therefore, repair of the target gene using editing methods based on homology directed repair (HDR) appears to be the most viable strategy. This approach requires the delivery of the appropriate repair template, together with CRISPR/Cas9 suite to target cells using adeno-associated viral vectors (AAV). To date, extremally low efficiency of HDR process in cardiomyocytes have precluded the widespread therapeutic application of this strategy. Through functional high-throughput screening, the host laboratory has identified factors that significantly expand the HDR capacity in cardiomyocytes, both in vitro and in vivo. However, the mechanism underlying this effect remains largely unexplored. Therefore, the aim of this project is to unravel the molecular mechanisms behind AAV-mediated HR in cardiomyocytes following CRISPR/Cas9 DNA break induction. This study will specifically focus on comprehensive analysis of the interactome of the proteins engaged in HDR and their interplay with DNA damage response in cardiomyocytes. Furthermore, it will be combined with functional assessment of the impact of best performing targets in vitro and in vivo. Obtained results will provide a better understanding of the molecular mechanisms underlying AAV-mediated HR in post-mitotic cells and enable identification of potential strategies to improve the efficiency of this process contributing to the development of safe and cost-effective biotherapeutics in the future.

UKRI Gateway to Research · FY 2024 · 2024-06

1 in 4 women in the UK are reported to experience mental illness in the perinatal period, constituting a costly public health issue linked to reduced family wellbeing, obstetric complications, and adverse child outcomes. The significant health burden is greater for those facing barriers to accessing mental health support. For example, young women and women with minoritised ethnicities or lower socio-economic status are less likely to seek and receive treatment in British mental health services. Further, women face fears and stigma regarding offspring exposure to their mental illness during pregnancy, despite a lack of robust causal evidence in this area. My previous work shows that uncertainties remain regarding the causal impact of mothers' mental illness in pregnancy on child outcomes. I propose an 18-month fellowship to address these challenges, identifying families who could benefit from further support, directly addressing parents' own concerns. I will use linked administrative data from the 'Education and Child Health Insights from Linked Data' (ECHILD) database, holding English administrative health and education records for 20 million individuals born in England since 1984. I will curate a linked longitudinal national dataset to explore mothers' perinatal mental health and links with offspring developmental outcomes. My work will be guided and enhanced by a parent advisory group and the charity Centre for Mental Health. First, I will explore inequities in women's contact with secondary mental healthcare services during pregnancy, focusing on demographic groups at risk of marginalization (i.e., exploring women's age, ethnicity, number of children, and neighborhood deprivation). I will focus on maternity episodes for women in ECHILD between April 2010 - March 2022. I will describe trends in women's contact with secondary mental health services across this period, while documenting nuances in data quality and availability from Hospital Episode Statistics and the Mental Health Services Datasets. I will interpret trends in the context of temporal administrative database and policy changes, for example following government investment in specialist perinatal mental health services from 2016. I will explore the extent to which inequities in service provision appear maintained over time, informing further policy action. Second, I will connect mothers' pregnancy data with birth and offspring outcome data, linking child records from Hospital Episode Statistics and the National Pupil Database. I will rigorously test and improve the quality of data linkages, to ensure accuracy of mother-child and child sibling pairs in the cohort. I will describe the final sample characteristics, including the number of offspring and data availability. Thus, I will produce a valuable resource for timely new intergenerational research, helping move the UK administrative data infrastructure towards alignment with flagship Scandinavian population-level data resources, linking records across family members at scale. Third, I will quantify associations between mothers' mental illness in pregnancy and offspring outcomes (birthweight, gestational age, foetal and neonatal death, chronic health conditions, and primary school attainment). My results will contribute knowledge on the origins of offspring early health and development. I will interpret correlations in the context of the data quality, informed by my earlier learning. Several quasi-experimental methods, including 'sibling-comparison designs', can then be applied to test causal pathways between mother and child variables, spanning beyond my fellowship end. Thus, this work paves the way to provide families, clinicians, and policymakers with robust, evidence-based information on the possible intergenerational effects of perinatal mental illness.

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

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

Colorectal cancer (CRC) represents a significant proportion of malignant diseases. Interventions are often carried out during the latter stages of development, leading to low patient survival rates and poor quality of life. In 2022 a European Commission report stated that "colonoscopy-based screening has higher sensitivity than testing for blood in stool, but it is less acceptable to participants". At the same time, effective methods to treat polyps in the colon are limited. Current approaches are often associated with unsafe oncological margins and high complication rates, requiring life-changing surgery. EndoTheranostics will usher in a new era for screening colonoscopy, advancing the frontiers of medical imaging and robotics. A tipgrowing or eversion robot with a sleeve-like structure will be created to extend deep into hollow spaces while perceiving the environment through multimodal imaging and sensing. It will also act as a conduit to transfer miniaturised instruments to the remote site within the colon for diagnosis and therapy (theranostics). With these capabilities, the system will be able to offer: 1. painless colon cleansing in preparation for endoscopy; 2. real-time polyp detection and tissue characterisation through AI-assisted multimodal imaging; 3. effective removal of polyps by conveying a "miniature mobile operating chamber" equipped with microsurgical tools to the target through the lumen of the eversion robot. The unique technical and clinical challenges will be tackled by the PIs, each bringing complementary skills, backed by their institutions with wide expertise and exceptional facilities. The synergy and added value evident in this team will lead to breakthroughs not possible through independent research. The outcomes of EndoTheranostics will revolutionise the theranostics of CRC, impacting the quality of life of millions of individuals. Ultimately it will launch a new era for endoluminal intervention with applications beyond medicine.

UKRI Gateway to Research · FY 2024 · 2024-06

Transmigration of T-cells into tissues occurs in specialised regions of post-capillary venules, termed high endothelial venules (HEVs). HEVs are lined by a distinct population of high endothelial cells that are characterised by their unique morphology and expression of PNAd, a potent L-selectin ligand. Homeostatic HEVs are restricted to lymphoid tissues with lymph node (LN)HEV identity imprinted by constantly migrating peripheral dendritic cells (DCs). Ligation of the afferent lymph, or depletion of DCs, have both been shown to result in loss of LNHEV identity. Peripheral HEVs arise during chronic inflammation, with tumour (t)HEVs correlated with improved survival and therapy response in multiple human cancers. Despite activated DCs accumulating near the tumour vasculature, whether interactions between DCs and endothelial cells (ECs) have a role during tHEV generation has yet to be proven. Using multiplexed imaging and spatial transcriptomics this project will characterise DC and EC interactions and confirm or refute the hypothesis that DCs are involved in tHEV identity. By describing the tHEV niche and understanding how these specialised regions are regulated, this project can have considerable impact in the treatment of cancer patients, as well as informing future lines of therapeutic interventions.

UKRI Gateway to Research · FY 2024 · 2024-06

Quantum physical systems consisting a large number of particles are difficult to study: this is well known in the context of statistical physics, whose "holy grail" is to understand the emergent behaviour of such systems starting from the microscopic models. When many-body systems are probed at distances and time scales 'large enough' (at mesoscopic scales), their emergent and rather complex behaviour is well described by hydrodynamics. The latter can be described as the observation that the motion of many interacting particles is constrained by local conservation laws: the hydrodynamic equations, in fact, are basically continuity equations relating density and current density associated with the conserved quantities themselves. While for generic systems with a few conserved quantities (tipically energy, momentum and number of particles), this is known since a long time, a similar hydrodynamic framework was only recently unveiled for systems possessing infinitely many of such conservation laws, i.e., integrable models (known for escaping standard thermalization to the Gibbs ensemble). This theory is known as Generalized Hydrodynamics (GHD). But, how 'quantum' are the current hydrodynamic descriptions of quantum systems? In fact, the local relaxation assumption implies quantum decoherence among different fluid cells and, therefore, notably, the loss of equal-time long-range quantum correlations among the fluid cells (including zero entanglement). From there, the necessity to re-quantize such theories, and in particular, of relevance for us, GHD. This is what we achieved in 2020, by establishing the theory of Quantum Generalized Hydrodynamics (QGHD). This framework already proved able to give, in an elegant and simple fashion, non-trivial analytic predictions for quantities which were, before, thought inaccessible, especially in the case of fully interacting models. Still, it is relatively new, and therefore there are many open questions calling for an answer. This challenge is the starting point of this proposal, aiming at exploring different directions, ranging from theory to applications and experimental validation of the theory itself.

UKRI Gateway to Research · FY 2024 · 2024-06

Depression is a leading cause of disability, mainly because most people with depression are either not benefitting from standard treatments or feel that standard treatments are not suitable for them. Important reasons are many people's mixed feelings about relying on medication, medication side effects, or difficulties in actively engaging in complex talking therapies which require homework and actively changing one's behaviour and routines, such as cognitive behavioural therapy (CBT). The latter is very difficult to do particularly when feeling more marked levels of depression. The aim of the project proposed here is to develop a novel psychological treatment for the large number of people who either do not engage with or disengage from currently available mental health services due to the limitations of standard treatments. Using simple self-guided strategies which can be easily implemented on a day-to-day basis is promising to meet the needs of people who are sensitive to medication side effects and who do not want to depend on others, as well as those whose symptoms prevent them from engaging in active behaviour change as required even by online versions of standard psychotherapies. Our project proposal builds on evidence that distorted personal memories play an important role in explaining two key symptoms of depression: a diminished ability to look forward to positive experiences and feelings of self-worthlessness. The proposed novel treatment combines two previous treatments, which empower people with depression to tackle their memory distortions by 1) training memory flexibility for positive experiences, and 2) tackling self-blame-related memories. Both approaches have shown promising results in our previous pilot trials, but their delivery using online sessions and an app which can be accessed on people's mobile phones, as well as their combination into one course of treatment over 8 weeks has not been investigated. The current proposal develops this novel psychological treatment and subsequently tests its feasibility in a clinical trial comparing the novel treatment with a standard computerised CBT as currently available in the UK National Health Service. Our recently completed pilot trials in people with major depression used simple self-guided memory re-interpretation and memory flexibility strategies under supervision of a non-trained psychologist. Here, we will investigate whether it is feasible to deliver these treatments in a combined and fully remote way and to enhance their day-to-day implementation with an extended web-based mental health platform, which our collaborators have developed to stem the pandemic-related increase in demand for depression treatments in Brazil. After developing an online version of our combined psychological treatment, we propose to recruit 86 people with current major depression and no bipolar disorder. They will be randomly allocated to either of two types of online treatment: 1) 8 weekly standard internet-based CBT sessions, or 2) 5 weeks of memory flexibility training, followed by 3 weeks of self-blame memory re-interpretation, both integrated into our web-based app. This project will allow us to determine whether our proposed treatment and mental health app has the potential to be useful in the future. This would enable us to apply for funding for a large trial to provide clear evidence for our novel treatment. This is an indispensable step towards our long-term goal of delivering novel affordable and widely available alternative treatments for those who we cannot help with standard treatments.

UKRI Gateway to Research · FY 2024 · 2024-06

Climate extremes can cause devastation. The most severe events have killed millions and, through complex cascades, resulted in profound additional impacts, for example the collapse of East Pakistan following the 0.5 million deaths from the 1970 Bhola Cyclone. As the climate warms to a level not experienced in human history, the potential for unprecedented extremes is also growing, either from familiar hazards like heatwaves reaching unfamiliar intensities, or the arrival of events that are new in character -- for example the first time a powerful tropical cyclone ravages the highly-developed shorelines of the Persian Gulf. Such novel threats are 'unseen': they sit outside all human experience, and their potential impacts are, therefore, highly uncertain. Upward extrapolation of the consequences from the most similar events in history may provide a very conservative estimate of what to expect, as the element of surprise could cause even greater impacts on a society that is unprepared. The potential for novel climate extremes to manifest as Global Catastrophic Risks (GCRs) -- with world-wide impacts, killing at least 10 million people or causing at least $10 trillion of damages -- therefore deserves urgent attention. The most concerning unseen extreme on the horizon is the emergence of heatwaves so severe that, for the first time in human history, the atmosphere becomes a heat source rather than a sink over large, well-populated regions. Such conditions mean that regardless of fitness, levels of hydration, or access to fans, prolonged exposure (in the order of hours) would be deadly. We do know that these events will occur given sufficient global warming, and that they may become widespread as early as this century; but precisely where is at risk and how soon the threat may emerge is not well understood. The potential societal impacts of such an event are almost completely unknown. For example, is unprecedented mortality inevitable if the atmosphere becomes a heat sink? If so, might it trigger mass migration due to place abandonment? Or could the most at-risk communities become resilient to such extreme heat? The Fellowship will address these critical research gaps in our understanding of unseen heatwaves. Through an ambitious program of physical science it will provide new insight into how much warming is required for regions to experience heat beyond human tolerance. Focussing on one of the hottest cities in the world (Jacobabad, Pakistan), it will grapple with the complexity of how heat at regional scales manifests within people's homes, finally joining up future climate model projections with the conditions that people are likely to experience within their community. Through an equally ambitious program of social science research, the Fellowship will also tackle the question of how resilient communities may be to these future heatwaves, and the extent to which that could be strengthened through adaptation. At the same time, the interdisciplinary Fellowship team will also zoom out to explore what other unseen climate extremes most threaten our future, and which -- perhaps with GCR potential -- should be prioritised for urgent risk reduction efforts. This challenge of identifying novel threats is particularly difficult because it requires that we overcome the cognitive bias of history to identify the much wider set of extreme events that could have occurred, whilst also accounting for a changing climate. It will be overcome by the Fellowship using 'top-down' (hazard-centred) techniques, whereby historical events and climate model simulations are used together to map out the domain of physically-plausible threats. Bottom-up (vulnerability-centred) approaches will in turn inspire and narrow the search of this very large phase space. These perspectives, once refined, will constitute a new framework to systematically identify, and reduce risk, from the most dangerous unseen climate extremes.

UKRI Gateway to Research · FY 2024 · 2024-06

Wider research context: Ischemic heart disease is the most common cause of death world-wide with ventricular tachycardia (VT) as direct consequence of it. Catheter ablation for VT is an important therapeutic option. Despite advances in ablation tools, procedure times remain high with a relevant risk of complications, whilst success rates are punitively low. The procedure is frequently guided by the identification of exit sites of scar-related slow-conducting isthmuses which provide the reentrant substrate. "Pace mapping" identifies exit sites by matching the surface ECG QRS of catheter-stimulated beats from different myocardial locations with the QRS of the clinical VT. Objectives: We propose the development and clinical validation of virtual mapping as a pre-procedural planning tool to identify critical isthmuses. Our solution aims to reduce catheter ablation procedure times, increase safety, and significantly improve the accuracy of target selection, improving patient care and long-term outcomes. Methods: Advanced CMR protocols will be developed to facilitate the acquisition of scar data at a resolution adequate to create detailed patient-specific models, upon which virtual pace maps will be constructed. This will enable us to perform uncertainty analysis, developing an imperative quantitative understanding of the sensitivity of our virtual predictions to the inputted data and parameters. The developed methodology will later be applied to clinical data collected from 25 VT ablation patients, providing a carefully controlled series of specific tests of our virtual approach. Level of Originality: The suggested studies on how virtual pace-mapping can identify critical isthmuses using clinical data of patients undergoing VT ablation are entirely novel. The suggested study on how virtual pace-mapping can identify critical isthmuses using clinical data of patients undergoing VT ablation have not been entertained previously.

UKRI Gateway to Research · FY 2024 · 2024-06

Climate change will mean more people on the move as extreme weather threatens lives, destroys property and ruins livelihoods. Most people will move from the countryside to the city. However, some will change their local mobility patterns, or take up seasonal migration to find work elsewhere. Others may choose to stay and adapt to the changing conditions. Climate mobilities is a term used to describe these diverse migration responses to climate impacts. This project works to support city and municipal councils in preparing for diverse climate mobilities. City mayors are considering how to invest in infrastructure and city planning for climate-related migration. However, unless the actions they take are driven by the priorities of the most affected, they may end up making things worse for people. Therefore, this project focuses on what a desirable future home and neighbourhood would look like from the perspective of those on the move and the communities that host them. Traditionally, such information has been difficult for planners and policymakers to include in their existing decision making structures. Therefore a key part of the project is to understand how to weave the information we gain from the precariously housed into the metrics and indicators that governments would be more familiar with. In this way, the project provides entry points for policymakers to carry out more transformational projects that address underlying poverty and inequality. The research takes place in four locations, investigating different climate mobilities: 1) Highly climate change-exposed Inuit communities who do not want to leave; 2) Rural climate-related migrants moving to the Kathmandu in Nepal; 3) People displaced by flooding in Durban, South Africa; and 4) International migrants in London, UK who fall through the cracks in the city's adaptation actions. The project uses community-led and arts-based research methods that value and elevate the knowledge of people on the ground. The project also engages local municipalities and regional and national governments to ensure that such knowledge is incorporated into future adaptation planning.

Fonds de recherche du Québec – Santé · FY 2023-2024 · 2023-04

Volet: Formation postdoctorale - Citoyens canadiens et résidents permanents; Domaine: Santé des populations; Objet: Interactions gènes et environnement; Objet: Santé mentale et psychopathologie des enfants et des adolescents; Application: Santé; Application: Santé publique; Mots-clés: CORRELATION GENE-ENVIRONMMENT, INTERACTION GENE-ENVIRONNEMENT, QUARTIER DE RESIDENCE, INTERVENTION EN MILIEU SCOLAIRE, VICTIMIZATION, REUSSITE SCOLAIRE