KING'S COLLEGE LONDON

UKRI Gateway to Research · FY 2025 · 2025-01

Numerical relativity refers to the solution of Einstein’s equations on a computer, and ranges from simple laptop calculations in spherical symmetry, to large-scale simulations that require several million core hours each; the latter includes simulations of the last orbits and merger of black holes and/or neutron stars, which have played a central role in the breakthrough results in gravitational-wave astronomy over the last decade (and leading to the Physics Nobel Prize in 2017), the dynamics of exotic objects and spacetimes (cosmological perturbations, critical collapse, boson stars, cosmic strings and more), and new areas of exploration in fundamental physics beyond general relativity. The UK is a leader in all of these areas, with a strong track record that dates back to the first major efforts to tackle the “binary black hole problem” in the 1990s, through providing current flagship models for LIGO-Virgo-KAGRA analyses, and pioneering applications of numerical relativity to cosmology, modified gravity and string theory. With the rapid growth in gravitational-wave astronomy over the next two decades, in which the UK already invests heavily, and the huge potential for numerical relativity applications across many other major research topics, the UKNR community needs to identify the key challenges in numerical methods and code infrastructure, and develop a strategy to allow us to position ourselves to play a leading role in the many breakthroughs that are possible in the near future. Fortunately, most NR applications require a similar set of tools: the ability to integrate forward in time a set of hyperbolic nonlinear coupled partial differential equations (the Einstein equations, or variants thereof) on large grids distributed over many processors, with high resolution focussed on relatively simple geometries. This makes it possible in principle to develop a great deal of infrastructure that can be shared across the entire community. Our vision is to bring together all the NR groups within the UK to form a collaborative UKNR community with a shared vision and that speaks with one voice. This community will be both inward looking and outward looking. For the former, we will foster collaboration in code development/exploitation with code sharing and jointly training, and identify our future digital infrastructure needs as a community. For the latter, we will survey the current and future global digital infrastructure landscape in order to formulate a UK-wide strategic plan for NR code development as we move into the exascale era. In parallel to the international meetings, UK community meetings, town hall exercises, and a range of other networking activities,  we will undertake an extensive benchmarking of NR codes to make a technical assessment of the ways in which current code infrastructures can be streamlined or combined, to provide technical input on the direction of future code development, with the ultimate goal of this work informing a future CCP in numerical relativity.

UKRI Gateway to Research · FY 2025 · 2025-01

Cancer is the one of the major causes of deaths worldwide and despite our increased understanding and the development of more improved treatments, many advanced cancers are still incurable. The majority of these deaths are due to metastasis whereby through cascading events, cancer cells escape the primary tumour, acquiring cellular characteristics which enable them to colonise other parts of the body. Several underlying mechanisms of this process are not understood and require the development of new biological models which can mimic cellular interactions within these complex tumour ecosystems. Until recently most of our understanding of the basic molecular principles of cancer have come from experimentation with single layer 2D cell culture models. Whilst inexpensive and easy to image, they are not representative of the way cells actually interact in an in vivo environment. 3D cell cultures (i.e. spheroids, organoids), have gained great significance in recent years as they can provide a much more realistic environment to simulate biological interactions. Unfortunately as the relative size, heterogeneity and hence complexity of these 3D cell cultures increases, it imposes severe limitations when imaging with any optically based technique. Local variations in refractive index induce optical aberrations and scattering, and coupled with absorption, lead to severe a degradation in optical resolution, as well as a loss in signal and contrast. The key objective of this fellowship is to develop novel optical imaging strategies which will enable for the first time, the complete interrogation of tumour derived spheroid models, to understand how cancer cells to dissociate from the primary tumour, evade immune surveillance and invade surrounding tissues. The original application aimed to enhance light sheet fluorescence microscopy (LSFM) with fluorescence lifetime imaging (FLIM) capabilities. LSFM enables high-speed volumetric imaging essential for observing the dynamic behaviour of cancer cells. Incorporating FLIM allows extraction functional data from these images, providing insights into the molecular interactions within spheroids. In the fellowship renewal, I plan to take these capabilities further by focusing on more complex tissue models that resemble aggressive cancer types like triple-negative breast cancer. Using advanced light-sheet FLIM microscopy, I aim to achieve a more detailed understanding of cancer cell behaviours and interactions within these models. A key advancement in our research is the integration of three-photon excitation into our advanced FLIM microscopy platform. This technique will enable deeper penetration into 3D cell cultures, allowing exploration of spheroids and organoids beyond the limitations of current imaging methods. The ability to visualize deeper structures within these models opens new avenues for understanding the mechanisms of cancer cell behaviour. Moreover, the scope of this research extends to other areas of biology, including developmental biology, neuroscience, and cardiovascular research. The imaging technologies have broad applications and the potential to provide novel insights into various biological processes, enhancing our understanding of disease mechanisms and potential therapeutic approaches. Overall, this project represents a significant advancement in optical imaging, with the potential to impact not just cancer research, but also a wide range of biological and medical fields. By pushing the limits of our imaging capabilities, Iaim to deepen our understanding of complex biological systems and contribute to the development of new treatments and strategies in healthcare.

UKRI Gateway to Research · FY 2025 · 2025-01

Progress in gene therapy has been remarkable over the last decade. While most of the in vivo applications are based on the adenoassociated virus (AAV), broader use of these vectors is limited by their tropism for post mitotic cells and their relatively low efficiency. Very high doses are thus required, with consequent toxicity. Analogous efficiency considerations also apply to CRISPR/Cas9 gene editing. In the heart, this technology would offer the ultimate solution for many hereditary conditions. However, most gene editing applications to date focus on ex vivo cell treatment and to the introduction of mutations that inactivate a genomic element, rather than pursuing true mutation repair in vivo. How can we improve AAV gene therapy and precise gene editing? While many laboratories focus on vectors and editors, HELP-GT pursues the innovative idea to act on the target cells. We aim develop reagents that render cardiomyocytes more permissive to transduction, or to homology direct repair or prime editing. This concept is analogous to that of adjuvants in immunology. Our adjuvants are small non coding RNAs (microRNAs, siRNAs, anti-microRNA), which we identify through systematic screenings and then formulate using lipid nanoparticles together with AAV. For screening and testing, we have available platforms based on primary rodent cardiomyocytes, human cardiomyocytes from iPS cells and human myocardial slices from explanted hearts. For gene therapy, we will test our small RNA adjuvants in both mice and pigs, also to identify a most effective administration route. Precise gene editing will be developed for two mouse models carrying human mutations in the genes for MYBPC and RBM20, which are frequent causes of hypertrophic and dilated cardiomyopathy respectively. Besides its translational value, HELP-GT will offer an unprecedented possibility to understand the mechanisms that regulate AAV gene transfer and gene editing, and thus advance the field beyond state-of-the-art.

UKRI Gateway to Research · FY 2025 · 2025-01

Let p be a prime. Serre's Conjecture states that certain 2-dimensional mod p manifestations of number-theoretic symmetries arise from complex analytic functions called modular forms. The refined part of Serre's Conjecture further predicts the minimal invariants (weight and level) of such a modular form. Serre's Conjecture can be interpreted as a prototypical example of "mod p Langlands reciprocity,'' with the refinement as a form of "local-global compatibility.'' Serre's Conjecture is now a theorem of Khare and Wintenberger. The equivalence between the conjecture and its refinement was already known, and is integral to their proof. The weight part had been proved by Edixhoven, who further provided an alternative formulation that uses a geometric definition of mod p modular forms and includes modular forms of weight one. In the same spirit as the seminal works of Wiles and Taylor-Wiles, the proof of Serre's Conjecture is inextricably intertwined with that of modularity theorems (i.e., cases of "classical Langlands reciprocity''). Furthermore, local-global compatibility is not only an essential part of the thread weaving together the proofs of classical and mod p modularity results; it is also fundamental to arithmetic applications of modularity, such as to Fermat's Last Theorem and the Birch--Swinnerton-Dyer Conjecture. The refined Serre Conjecture and its generalizations have been inspirational in the development of the p-adic Langlands Programme, which aims to place the powerful interplay above in a much broader framework. These generalizations, however, have largely had an algebraic flavor, absent the geometric perspective inherent in Edixhoven's variant. This perspective was reintroduced in the co-I's work with Sasaki, enriching the scope of Serre's Conjecture and building its connection with the mod p geometry of Shimura varieties (a class of varieties generalizing classical modular curves). The connection has in turn produced novel insights into this geometry, as in the PI's recent work with the co-I. The overarching vision of this proposal is to develop that interface. Its primary strands aim to i) establish a new framework for mod p Langlands reciprocity, ii) produce fundamental advances in our understanding of Shimura varieties in characteristic p, and iii) expand aspects of the interface to the p-adic context. To place the proposed research in the current landscape, we remark that the p-adic Langlands Programme is only beginning to take shape; the proposed research introduces novel approaches and perspectives that will help build its foundations and broaden its applicability. Meanwhile, our work on Shimura varieties will lead to new insight and results in arithmetic geometry and develop symbiotic links with several other fertile ongoing lines of research, such as the emerging theory of automorphic forms on G-Zips. Furthermore, the proposed research will enhance the UK's standing as a leading centre for research in number theory, and especially the Langlands Programme.

UKRI Gateway to Research · FY 2025 · 2025-01

Neurodevelopmental conditions such as autism and Attention deficit hyperactivity disorder (ADHD) affect up to 10% of children and are associated with other mental health difficulties. Both conditions are associated with reduced educational attainment, occupational success and quality of life, making effective identification and intervention imperative. Although autism and ADHD are not typically recognised until school age or older, underpinning genetic and environment factors are present prenatally and behavioural and brain changes can be detected from early infancy. Thus, the causal mechanisms that underpin behavioural symptoms of autism and ADHD are clearest in early development, before the full symptom profile emerges. Within Phenocades, we will test our new theory that behavioural symptoms result from early-emerging changes in sensory processing and activity regulation that affect a child's behaviour, thus disrupting the experience-dependent specialisation of neural systems underpinning social engagement and executive attention. To do this, we will recruit a new cohort of infants with a family history of autism and/or ADHD who will complete in a multimodal protocol at 10, 14 and 24 months. For the first time, we will measure the dynamics of brain function during exploration and interaction using hyperscanning and wearable neuroimaging; collect home-based data to capture a child's interaction with their natural environment; and use behavioural shiftability experiments to yield causal insights into how early differences in behaviour shape later brain function. To examine longer-term outcomes and examine the genetic architecture of infant neurodevelopmental traits, we will conduct new analysis of existing multimodal longitudinal data from n=600 infants with a family history of autism/ADHD with outcome at 3 to 7 years. Taken together, this work will generate transformative new insights into developmental pathways to neurodevelopmental conditions.

UKRI Gateway to Research · FY 2025 · 2025-01

Chiral molecules of opposite handedness are indistinguishable when they interact with a mirror-symmetric object, but have dramatically different responses when they interact with another chiral object. Chiral sensing methods are of paramount importance in fundamental science, from chemistry to biology and physics, as well as in industrial sectors such as the pharmaceutical industry. Amongst these methods, all-optical ones like optical rotation are well established and easy to use, but are limited by very low signals and are also affected by experimental noise. In this project, I aim to develop the theory for new all-optical chiral sensing methods that are highly efficient, highly sensitive and robust against noise. To achieve efficiency and sensitivity, I will use synthetic chiral light (SCL), a new type of light that produces unprecedently strong enantiosensitive signals by encoding its handedness in the temporal evolution of the electric-field vector of the light. To provide noise robustness, I will extend the concept of SCL and create chiral topological light (CTL), that is, SCL with a spatial distribution of handedness with non-trivial topological properties. By transferring the CTL topology onto the molecular response, I will enable the observation of novel chiral observables that are robust against noise owing to their topological nature. Additionally, I will use SCL to modulate the coupling toward the environment of an ensemble of chiral molecules, inducing exceptional points (EPs) and harnessing EP-related effects such as topological population transfer in an enantiosensitive way. Finally, I will devise a sensor for chiral detection based on optical fibres that will be tuned to an EP and interact with a surrounding medium via SCL, paving the way for a new generation of chiral sensors.

UKRI Gateway to Research · FY 2025 · 2025-01

Hydrodynamics is a powerful framework for studying the emergent, large-scale behaviours in many-body interacting systems. It is now understood that some of the general principles underlying hydrodynamics can in fact be applied much beyond conventional systems. This includes systems in one dimension of space which possess the property of integrability. These are, by many measures, non-chaotic, and therefore were believed until recently to lie beyond the realm of hydrodynamics. In the last few years I have co-pioneered and developed their hydrodynamic theory, dubbed generalised hydrodynamics. It is one of the most successful non-conventional hydrodynamic theory, and finds many applications, from soliton gas to models of statistical mechanics, quantum chains and cold atomic quantum gases, with stunning experimental verifications. The development of GHD required us to focus on the general structures of hydrodynamics, leading us to propose new general methods to understand physical quantities at the largest scales of space and time, including fluctuations, correlations, and ``structured behaviours" such as many-body oscillations. This calls for a re-think of what the universal principles of hydrodynamics are. Can we describe non-equilibrium motion, fluctuations, correlations and structured behaviours in many-body systems from hydrodynamic principles? Can these be derived from microscopic models? Do they form a basis for the emergent laws of many-body physics, from large to small scales? GHD gives partial answers and a clear way forward, but much is still open. This project will attempt to answer these questions, using GHD and integrability as powerful tools for physically relevant systems and exact calculations. This will require varied skills and expertises. My track record of directing successful research teams, combined with my world-leading expertise on generalised hydrodynamics and emergent behaviours, places me perfectly to lead this groundbreaking project.

UKRI Gateway to Research · FY 2025 · 2025-01

JENNIFER3 aims to continue, further develop and finalize the research and communication activities started in 2015 within the JENNIFER project and currently being carried on by the JENNIFER2 MSCA-RISE project, which will conclude in may 2025. The community forming the JENNIFER3 consortium is putting together three research programs at experimental facilities located in Japan where very rare processes can be observed: accelerator produced neutrinos (T2K and HyperK collaborations), cosmic neutrinos detection (HyperK collaboration) and a high luminosity electron-positron collider (Belle II experiment at SUPERKEKB). Such programs use different approaches, are sensitive to different “messengers” of the new physics world and are essential to complement the so called “energy frontier” investigation which is carried on at the LHC. Sinergy and knowledge sharing among them is the drive force of the JENNIFER3 project, which on one hand fosters the collaboration of European scientists with the Japanese research community, while on the other hand promotes close collaboration among different European research groups around key technologies, such as cloud computing and data network developments, machine learning applications for data filtering and reconstruction, photon detection, solid state detectors, particle beam monitors. Collaboration with private sector technology providers is also essential to reach the scientific objectives of the project. All project members are also committed to disseminate and communicate their work to the scientific community and to the European society through various initiatives aiming to different targets. Cross fertilization between different research communities and approaches is the real added value to boost the project impact, both in terms of scientific results and of researchers’ careers.

UKRI Gateway to Research · FY 2025 · 2025-01

The aims of the fellowship are to examine how emerging technologies can fundamentally re-envision the conceptual models and mechanisms-of-delivery for existing prevention interventions in the context of child mental health. Such an innovative approach is needed to address the unprecedented mental health treatment gap faced across the UK and worldwide: more than 1 in 10 children and young people have a clinically diagnosable mental health disorder, yet only 30% have had access to appropriate intervention, and less than half of these improve from the treatment. Mental health promotion interventions are seen as one of the principled ways of addressing these issues: by developing key protective factors (such as emotion regulation or parenting techniques) for both at-risk and general populations, such interventions can improve wellbeing and reduce the incidence of mental disorders. However, even the most effective programmes are still dependent on in-person delivery techniques and intervention mechanisms available since the 60s, thus lacking scalable mechanisms to support children in the everyday settings where protective competencies are needed, and being developed. The core vision proposed by the fellowship research agenda is that digital technologies can lead to an entirely new model of mental health interventions that are fully incorporated into the lives of target populations, thus addressing the need for situated learning support. However, beyond PI's pilot work, HCI and Prevention Science fields lack even a basic understanding of the fundamental research questions necessary to deliver such situated interventions: it is not at all clear, for example, how to design technologies that provide useful contextualised support for children and their adults around protective competencies (technical RQs), how to do so in a psychologically effective way (psychological RQs), and how to design interventions that are engaging for users and are addressing their immediate needs (socio-technical RQs). The fellowship takes up these challenges and lays out an ambitious programme of work designed to start unpacking these broader issues at the intersection of technology, psychological theory, and human- centred design. Our work to date has provided a proof-of-concept for such situated interventions in the context of emotion regulation: moving from an innovative design to qualitative deployments and randomised control trials, and now to pilots within a NHS trust all ... in the first 3 years. The continuation of the fellowship will focus on developing a similar proof-of-concept for parenting interventions; and to support world-leading implementation science centres (at Oxford, UW, and Harvard) in applying situated interventions models in large scale deployments. Working together with a strong interdisciplinary mentorship network across KCL, Oxford, Stanford, Harvard, UW, Northwestern University, and University of Michigan, among others, the ambition is to not only create effective interventions that can be deployed at scale, but also influence the wider research communities, and contribute to the UK and EU policy calls to deliver new approaches for mental health promotion. PI's personal and career growth will continue to be substantially boosted by the fellowship. Beyond enabling a full cycle of truly interdisciplinary work, which would traditionally span a range of UKRI panels and epistemological commitments, the fellowship structure will facilitate a network of academic and clinical partnerships across a range of leading research centres worldwide, developing the basis for PI's interdisciplinary thought leadership for years to come. These will include, among others, long-term residency at Oxford; as well as close collaboration and repeated visits to US-centres at Harvard and University of Washington.

UKRI Gateway to Research · FY 2025 · 2025-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases for which there are currently no cures. Although the mechanisms remain unclear, these diseases ultimately result in the complete degeneration of axons, the long wire-like extensions that neurons use to carry signals to distal synapses and transmit information to other cells. As a result, neurons become unable to communicate with other neurons or muscle cells. However, although this represents a key feature of the disease, recent work suggests that before any structural degeneration, axons show abnormal function that manifests at multiple sites along the long wire-like structure. In other words, axons cease to work properly before they are lost. This proposal aims to systematically investigate and address this axonal dysfunction at an early stage to develop novel therapeutic strategies aimed at recovering proper function, rather than axon loss. The primary objective of this research is to identify the molecular basis of axonal dysfunction in human ALS/FTD neurons and design therapeutic strategies to counteract and recover this dysfunction in the hope of halting disease progression and preventing axon loss. To achieve these goals, we will develop human neurons from induced pluripotent stem cells that carry mutations found in patients with ALS and FTD. By generating motor neurons and growing them with muscle cells, we will create a neuromuscular system to study ALS and, in parallel, by growing excitatory and inhibitory neurons at ratios that resemble those found in the brain, we will establish a neuronal network to study FTD. Armed with these state-of-the-art in vitro systems, we will use a combination of imaging and electrophysiological techniques to characterise altered axon function in ALS/FTD neurons. We will complement the analyses of our ALS and FTD in-a-dish systems described above with in-depth molecular investigations to identify genes that are dysregulated in ALS/FTD and establish how they affect the function of axons. The goal is to pinpoint the culprits underlying axonal dysfunction. Having isolated key target genes, we will establish whether axon dysfunction is responsible for disease progression and, if so, which aspects of this dysfunction are the most relevant. Our overall approach will be to either recover specific aspects of axon function in ALS/FTD neurons or induce dysfunction artificially in neurons without the disease. Finally, with this comprehensive knowledge at hand, we will renormalise the expression of target genes found to be important for key axon functions to prevent the progression of ALS/FTD. These findings will allow us to develop new strategies to recover axon function in ALS/FTD neurons during the early periods of the disease, which may also prevent axon loss and neuronal degeneration. We believe this pre-clinical work could make a significant impact in the development of new therapies for ALS/FTD as well as other neurodegenerative diseases.

UKRI Gateway to Research · FY 2025 · 2025-01

Cardiovascular disease remains the number one cause of death worldwide, of which coronary artery disease leading to heart attack and ultimately heart failure is the biggest contributor. There is no known cure for heart failure, other than organ transplantation which is compounded by limited donor hearts and a requirement for lifelong toxic drugs to prevent organ rejection. All current drug-based treatments only serve to assist the survived heart muscle and blood vessels after heart attack but do not reverse disease progression. Thus, there is an urgent unmet need for novel therapeutic approaches to regenerate the injured heart and to reverse established heart failure. Here we propose to establish a new MRC-BHF Centre (called RECREATE) to develop advanced therapies for heart attack and heart failure. We will bring together world leading scientists and clinicians from King's College London and the Universities of Oxford and Edinburgh, combined with other academic partners as well as biotech and pharmaceutical industry representatives to develop new medicines and to deliver them to the injured or failing heart. We will define patients for treatment based on current clinical guidelines. We will develop improved diagnostic measures to refine treatment groups across what is known to be a mixed population of heart attack and heart failure patients. The drugs will be made up of nucleic acids, such as modified RNA, as was used in COVID-19 vaccines. Together with delivery vehicles, we will ensure that they specifically target the heart in both models of disease and in patients, thereby maximising the impact of our therapies. Our approach will restore lost heart muscle, increase numbers of functioning blood vessels, reduce inflammation, and reduce tissue scarring to maintain or enhance heart function. By leveraging additional support, we will progress therapies to patient clinical trials within the lifetime of the Centre. We will develop delivery methods that are non-invasive, combined with cost-effective treatments to ensure that our therapies can be utilised in all primary health care systems, including those within developing countries. The Centre will widely disseminate its progress and key findings to the public and patients alike and is firmly committed to training, career development and the promotion of early career researchers. We will establish a fully inclusive and diverse research culture, all working towards the common goal of developing novel advanced therapies to treat heart attack and heart failure patients.

UKRI Gateway to Research · FY 2024 · 2024-12

The heart works as a muscular pump, which needs a healthy amount of shortening and lengthening of heart muscle in each region of the heart to maintain good overall pump function. Diseases such as heart attacks, heart failure and heart rhythm disorders, as well as heart damage caused by cancer therapy drugs, are diagnosed and monitored by measuring pump function, including changes in regional heart contraction and motion. Strain is an engineering quantity which measures contraction and relaxation as a relative change in length. Accurate measurement of strain in all regions of the heart is vital to understand mechanisms of disease. Medical imaging methods such as echocardiography and cardiac magnetic resonance imaging are being used to measure regional strain, to help diagnose disease and monitor treatment, and to develop and evaluate computational analyses of heart function. However, current quantification methods are inaccurate and imprecise, since strain is highly sensitive to image artefacts, noise, and low resolution. Worse, strain estimates vary systematically between different imaging modalities and even between different commercial software products. Vendors use "black box" closed source solutions which hamper reproducibility. This leads to different standards and measures being used by different doctors. Subsequently, it is not known which of the many measures available is best for diagnosing heart disease and predicting outcomes. Clearly, a new way of solving this problem is required. This project will develop novel technologies for measuring motion and strain in the heart which are standardized between imaging modalities. We will use "artificial intelligence" neural network methods to automatically process different types of medical imaging examinations to obtain more accurate and precise strain measurements. These networks will be trained to learn how to predict the underlying motion and strain from thousands of image simulations, as well as thousands of patient scans, using a statistical atlas of heart motions. By simulating realistic images with exact high resolution heart motions derived from the statistical atlas, the networks will learn how to handle image artefacts, noise and low resolution in real images. More fundamentally, we will examine how statistical atlasing methods can help us discover which strain measures are best for diagnosing and predicting heart disease. We will then deploy these methods in high-throughput heart imaging clinics at St Thomas' Hospital, Royal Brompton Hospital, and other NHS hospitals. By making open-source tools widely available for doctors, we will test how standardised measurements and reports will work in practice. This will also reduce the costs of patient evaluation, by getting the information we need from commonly-performed scans and avoiding the need for specialized equipment. More accurate and precise evaluation of patients with heart disease will improve patient care, by identifying high risk patients and optimizing treatment dose. In particular, many cancer patients suffer from heart muscle damage caused by their cancer drug therapy. Our tools will enable better identification of which patients are at most risk and may require a change of treatment.

UKRI Gateway to Research · FY 2024 · 2024-12

MRI is a key methodology in modern neuroimaging, but conventional MRI relies on visual interpretation of intensity differences in the images, which is heavily dependent on scanner settings. Quantitative MRI (qMRI) is an attractive alternative MRI method that allows quantitative measurement of physical tissue parameters, enabling objective comparison between patients and across time. Moreover, qMRI facilitates early detection of pathological changes in the brain resulting from neurological disorders such as multiple sclerosis. Unfortunately, and despite the demonstrated potential in research settings, the implementation of aMRI in routine clinical practice remains limited due to long scan and post-processing times. Even though artificial intelligence has recently led to breakthroughs in the medical imaging field, reduced transparency about the underlying processes and limited information about the accuracy of the results has limited its use for clinical qMRI applications so far. In IQ-BRAIN, we propose a unique research and training programme that tackles this urgent need for improved and accelerated q MRI methodology for neuroimaging applications. By integrating both physics-based models and trustworthy artificial intelligence methods along the qMRI pipeline, our innovative approach combines the best of both worlds. IQ-BRAIN will prepare the next generation of qMRI specialists trained in the different aspects of the qMRl-neuroimaging pipeline, that can bridge the gap between qMRI method development and clinical need. Through a training programme of network-wide events, international secondments, and strong interaction between partners from academia, industry and hospitals, IQ-BRAIN offers early-stage researchers a rich combination of knowledge, expertise and essential transferable skills that prepares them for a thriving career as R&D professionals in the qMRI field.

UKRI Gateway to Research · FY 2024 · 2024-12

Micro-apartments and studios are now widespread in English cities, often advertised as offering convenient city centre living for young professionals and post-students. They have also been heralded in some quarters as an energy-efficient solution to the problem of increasing housing demand, maximising the number of units on a given site. However, some of these smaller homes are below the government's (2015) Nationally Described Space Standard of 37m2 for a single occupancy, one-bedroom dwelling. While the existence of these standards suggests these homes should theoretically not exist, they have been developed through Permitted Development Rights which allow developers to sidestep formal planning permission, as well as being permitted in situations where planning authorities feel they respond appropriately to local housing need. Yet the number and location of these small homes is not well understood; nor is there understanding of the impact of living in a 'sub-standard' sized home. While well-designed small homes may fulfil some residents' housing needs, there remain concerns that very small homes may be inadequate, negatively impacting on relationships and preventing the accumulation of personal possessions important to 'home-making'. This given, we have completed preliminary 'proof-of-concept' work in London using Energy Performance Certificate (EPC) data, matching this to other data (e.g. Price Paid Data, Local Planning Databases), showing that sub-NDSS homes account for more than one-in-ten of London's new homes, and that their number has actually increased over the last decade. This project will extend the breadth of our pilot research, exploring the wider geographies of very small homes in English cities whilst increasing depth of understanding by assessing whether small homes ever constitute adequate homes. It will do this through linked Work Packages on the production, regulation and consumption of small homes, combining the expertise of researchers from geography, computer science and legal studies who have an established track-record of publication in housing studies. WP1 will construct a national database of c.25m properties in England using EPCs as a source of floorspace data, combining this with Price Paid Data, Zoopla, local planning, and housing data. Subsequent spatial analysis of this data in three LPAs will identify the location of sub-37m2 homes at neighbourhood level, gauging their relative affordability, and assessing overall residential amenity. WP2 will explore how the homes identified in WP1 have been permitted by the planning system. Exploring questions of legality, and the often-indistinct boundaries between planning law, norms and standards, interviews with key stakeholders, combined with documentary analysis and Planning Appeal documents, will examine how ideas of housing adequacy are invoked in given circumstances, facilitating the emergence of very small homes in particular neighbourhoods. WP3 will recruit residents in small homes in three LPAs to explore how these properties are lived in, and adapted, considering residents' housing trajectories and broader aspirations. It will address liveability through innovative visual and qualitative methods that will allow us to explore the unspoken dimensions of physical space that are crucial to homemaking. Combined, these WPs will transform understanding of the national housing crisis and housing futures by identifying the causes and consequences of the production of small homes in England, addressing policy-relevant questions concerning the adequacy and acceptability of this form of housing while contributing to international debates on urban policy, gentrification and the financialisation of housing.

UKRI Gateway to Research · FY 2024 · 2024-12

The ever-increasing usage of electronic devices results in demands for energy which will soon outstrip the world’s energy supply. The development of low-energy consuming, high-speed electronics is thus an urgent and extensive area of current research. Exciting recent discoveries in this area are ushering new types of electronic devices, through the use of novel materials and device design. Examples are the use of ferroelectric and multiferroic memory devices, molecular electronics, or whole new device architectures, such as brain-inspired “neuromorphic” ones. While these advancements are promising, their practical application is at present hindered by technological issues which still need to be overcome. In this project we contribute to the effort of producing novel energy efficient memory devices called nonvolatile multistate memories by harnessing the properties of ultrathin ferroelectric materials. We will use atomistic modelling methods to explore the stabilization of multiple state of polarization using "ferroionics", that is, the modification of the magnitude and direction of the ferroelectric polarization through ionic adsorption on, and insertion into, ultrathin films. In ultrathin ferroelectrics, the polarization is quenched below a critical thickness, however, it can be restored through the adsorption of ions which fully compensate the ferroelectrically induced surface charge. The direction of the ferroelectricity will depend on the sign of the adsorbed charge, with positive (negative) adsorbates inducing a down (up) polarization. In this project, we hypothesize that the adsorption of ions which only partially compensate the surface charge might lead to currently unknown polarization states of ultrathin ferroelectric materials, either by stabilizing phases with a value of the polarization corresponding to the adsorbed surface charge, or by creating domain structures whose value of the overall measurable polarization would depend on the ionic coverage. Thus, controlling the boundary conditions of a ferroelectric thin film, would allow us to create a system with multiple polarization states. We will also explore intercalation of the ions within the film, and the creation of surface defects, in order to connect the work done in this proposal to currently achievable experimental systems. Thus, this work will provide the theoretical framework to produce ferroelectric nonvolatile multistate memories.

UKRI Gateway to Research · FY 2024 · 2024-11

The nucleus is the cellular organelle that contains the genetic material. This compartment is surrounded by a double membrane known as the nuclear envelope, that allows the controlled exchange of material with the cytoplasm. The traditional view has been that the nuclear envelope is a passive barrier that mostly protects the genome and allows gene expression. However, we now know that under certain conditions, such as exposure to physical forces, cells can experience mechanical stress that deforms the nucleus. These deformations of the nuclear envelope can initiate signalling pathways that induce changes in gene expression and cellular behaviour. On the contrary, extreme deformations can lead to rupture of the nuclear envelope and genomic instability. We therefore need to know the relationship between nuclear deformations and cellular function. This project will answer this question by combining molecular and cell biology approaches with advanced quantitative microscopy and biophysics. We will build on our recent work identifying factors that regulate the shape of the nuclear envelope, thus allowing the selective perturbation of shape control. Specifically, we will elucidate i) what type of NE deformation constitutes a physiological signal or a pathological perturbation ii) the ultrastructure and dynamics of NE under stress iii) how NE deformations influence physiological functions such as the cellular adaptations to physical confinement and mechanical stress. This fundamental knowledge may inform new mechanisms of disease, from cardiopathies to cancer.

UKRI Gateway to Research · FY 2024 · 2024-11

The genome is the complete set of genetic information of an organism, a 'blueprint' found within DNA. Mutations to this genome can disrupt normal cellular function in an organism. However, there is one crucial biological process where high amounts of mutations in DNA are desirable and in fact indispensable for human health. When an immune system encounters foreign elements (for instance viruses or vaccines), mutation of the antibody-encoding genes is required to adapt and allow the immune system to build immunity. This process is called somatic hypermutation and it occurs in B lymphocytes or B cells located within specialized structures called germinal centers that form in lymphoid tissue, such as the spleen, tonsils and lymph nodes, when B cells encounter foreign antigens. During somatic hypermutation, mutations in the antibody genes create subtle alterations in the "shape" of the antibody which changes its binding strength (also called affinity) for the target antigen on the pathogen or vaccine. Somatic hypermutation is accompanied by a process called affinity selection where B cells expressing mutated antibodies with higher affinity for antigen are identified and preserved. In essence, adaptive immunity is achieved via a Darwinian-style process of accelerated evolution consisting of multiple cycles of mutation and affinity-based selection, the latter being dependent on how strongly the mutated antibodies bind the target antigen. This germinal center reaction eventually produces B cells expressing antibodies with the highest affinity for the antigen and is, therefore, the nerve center for the generation of adaptive immunity. There remain many open questions regarding the mechanism by which somatic hypermutation operates and how the unique architecture of germinal centers, which supports these reactions, is formed and maintained. The goal of this proposal is to improve our understanding of somatic hypermutation and germinal center biology by delineating the function of a specific gene that we have recently identified to be important for both somatic hypermutation and germinal center architecture.

UKRI Gateway to Research · FY 2024 · 2024-11

Neuronal cells in the brain are connected to each other by trillions of synapses, but the rules that govern how these connections are formed in the mammalian cortex are not well understood. A controversial topic is the role of neuronal activity, which has been largely viewed as only being involved in later maintenance or pruning of excessive connections. However, we have found a very early window in development where a specific type of activity - the spontaneous release of neurotransmitter - can drive excitatory synapse formation in the mouse hippocampus, or 'archicortex' - an evolutionarily older part of the cortex that is important for learning and memory. We showed this was the case in both cultured tissue slices (in vitro) and in the living organism - 'in vivo'. In this proposal we aim to test whether this is also true in human hippocampal slices, and then explore whether similar or different activity dependent rules apply in the formation of local excitatory synapses in the neocortex, which make up the majority of synapses in the cortex and are involved in all aspects of computation carried out by the neocortex. We will focus specifically on the connections between layer 5 pyramidal neurons, which start forming very early in development. We will compare data from both human and mouse cultured slices, to see if these rules are common between species or diverge, and will then validate our in vitro findings by testing them in the mouse in vivo. Overall, we will learn what role different types of neuronal activity play in driving synapse formation, comparing two different regions of cortex: the evolutionarily older hippocampus and the 'newer' neocortex to see whether these rules apply across diverse regions, and also comparing mouse with human, to identify to what extent these rules are conserved between these two species. Furthermore, our in vivo experiments will tell us whether findings in vitro in neocortex can be replicated in vivo. In the longer term, the results of this project will have important implications for translation of both fundamental findings as well as therapeutic approaches in neurological and neurodevelopmental disorders from the most widely studied model organism, the mouse, to human. This sits within the BBSRC research priority 'understanding the rules of life', part of 'Advancing the frontiers of bioscience discovery'.

UKRI Gateway to Research · FY 2024 · 2024-11

In the absence of sleep memories remain unstable. Sleep provides an ideal environment for the formation and stabilisation of memories through a process called memory consolidation. This process is what enables new information acquired during wakefulness to be stored into representations that can later be accessed to guide behaviour and influence our actions. Memory consolidation requires coordinated interactions between neuronal activity in cortical regions in the brain's surface and the hippocampus, a structure that lies deeper in the brain. Until now, our ability to investigate the dialogue between the cortex and the hippocampus has been limited because the only tools available to influence neuronal activity in the human hippocampus required the invasive placement of intracranial electrodes. However, in a recent study we demonstrated that, using a technique called Temporal Interference Stimulation (TIS), we can now selectively influence brain activity in the human hippocampus without surgery. TIS is a form of non-invasive electrical brain stimulation that uses an ingenious combination of high frequency (kHz) oscillating currents at slightly different frequencies that by themselves are too fast to influence the activity of neurons but can travel and meet at a target location deep in the brain. Where they meet, they generate an interference pattern that changes the activity of neurons at this location. Using TIS, we can now influence activity in the hippocampus and thereby investigate how the hippocampus influences the cortex during sleep and how it contributes to the interactions required to the formation of stable memories. In this project, we will combine TIS with electroencephalography (EEG) to measure brain activity while we sleep. EEG uses electrodes placed on the scalp to record the activity of neurons, and like TIS, is non-invasive. Using EEG, we can detect brain wave patterns associated with memory consolidation. These patterns have been associated with a stage of sleep called non-rapid eye movement (NREM) sleep. We will use these NREM sleep patterns and measures of memory performance to assess the effects of TIS on memory consolidation. Our project is comprised of a series of studies, each investigating one question pertinent to understanding the cortical-hippocampal dialogue during sleep. We will begin by investigating whether influencing hippocampal activity before or after playing sound cues during sleep to artificially enhance which memories are consolidated affects the brain wave patterns related to memory consolidation and memory performance. We will then use TIS protocols designed to synchronise activity between the cortex and the hippocampus to enhance the naturally occurring brain-wave patterns associated with memory consolidation during NREM sleep and improve memory performance. Finally, we will direct our attention to our other sleep stage, rapid eye movement (REM) sleep. REM has fascinated scientists for almost a century because of its possible association with dreams, but we know less about its role in memory consolidation. By influencing the activity of the hippocampus during REM sleep, we hope to understand more about the role of REM sleep in human memory consolidation. By the end of the project, we will know more about how the cortex and hippocampus can be influenced non-invasively to shape how memories are consolidated during sleep. This knowledge can then be applied to boost sleep's memory functions in those suffering from memory disorders.

UKRI Gateway to Research · FY 2024 · 2024-10

In England and Wales, it is currently estimated that one in four individuals convicted of a serious violent offence will reoffend within two-years. In the Criminal Justice System (CJS), risk assessment tools are used identify who is at high risk for reoffending and this informs sentencing, supervision, and rehabilitation approaches. Currently the performance of these resource-intensive tools is less than optimal. As reoffending patterns change it is important to keep updating these tools and testing new risk factors. Emerging evidence suggests that some educational factors like school type or early academic attainment are associated with violent offending and so might help improve the predictability of violence risk assessment tools. The Oxford risk of Recidivism tool (OxRec) is a 14-item evidence-based, open access online risk assessment tool. It was developed using Swedish population register information to estimate the risk of violent recidivism in individuals released from prison and has been tested on probationers in the Netherlands where the tool is used. As the tool shows good predictive ability, is free to use and takes only 10 minutes to complete using routinely available information there is potential for it to be considered as a cross-agency violence recidivism risk assessment tool in England and Wales. To date, it has been tested on a small number of individuals using Thames Valley police records, but validation in a larger and nationally representative sample of released prisoners in England and Wales is required. Using a large cohort of released prisoners in England and Wales this proposed project aims to (1) examine the early educational factors are associated with violent recidivism (2) externally validate a prediction model for violent reoffending (OxRec) and (3) examine the extent to which the identified educational risk factors further improve the performance of the OxRec tool in predicting violent recidivism. Our study cohort will be established from the prison discharge dataset and consist of individuals born on or after 31st August 1985 up to and including 31st August 2000 who were subsequently released from prison between January 2008 and December 2019. Information on these individuals' prior offending and violent recidivism following release from prison will be established from the Police National Computer database and confirmed using the prison reception and population datasets. By using these prison release dates, each prisoner can be followed up from date of release until the first violent recidivism event occurs or the study ends (December 2021). The education history of these prisoners will be examined using the National Pupil database, which has already been linked to crime records. Criminogenic and non-criminogenic factors related to recidivism will be described using information taken from the Offender Assessment System (OASys) risk assessment. Using a type of time-to-event analysis, we will examine whether educational factors are associated with 1-year and 2-year violent recidivism (aim 1), we will then test whether the OxRec tool is generalisable to the England and Wales prisoner population (aim 2) and whether adding educational factors to the OxRec has the potential to improve its predictability (aim 3). Establishing whether early education variables are associated with violent recidivism among released prisoners has the potential to improve violence risk assessment tools' predictive performance; to support critically informed professional judgement and decision making in the CJS; and to promote the importance of early childhood interventions at a public health level.

UKRI Gateway to Research · FY 2024 · 2024-10

In MND the connection between different nerve cells, synapses, are lost very early on, even before any clearly visible disease symptoms. The aim of this project is to establish whether RBM3, a cold-shock protein that was shown to be neuroprotective in Alzheimer's and prion disease by preserving synapses could be harnessed also as therapeutic approach for ALS/FTD. For this, we plan to exploit a novel system we developed that allows recreating complex but controlled networks of neurons in a dish to assess whether synapse health in diseased neurons improves upon delivery of therapeutic antisense RNAs that increase RBM3 levels. We will establish here whether increasing RBM3 levels can preserve synapses in MND and therefore whether it can be harnessed as a therapeutic approach.

UKRI Gateway to Research · FY 2024 · 2024-10

The project context: The World Meteorological Organisation is an understudied specialised agency of the United Nations which exists to foster international cooperation at a global scale. It facilitates exchange and interaction between the meteorological and hydrological institutions of members, like the Caribbean Meteorological Organisation, to support forecasting, monitoring, early warning, assistance, capacity development and resilience building. International meteorological cooperation is essential to managing the destructive impacts of climate change, but faces emerging risks today that are poorly understood. Norms and patterns of state behaviour are transforming, international power relations are shifting, and historical inequities that underwrite unequal vulnerabilities to climate change are being recognised. Climate change is entangled with systemic changes in international relations, alongside producing climate-based risks to security and resilience. The WMO is a principal location in which the interaction between international relations and climate change may be studied. The challenges the project addresses: Tropical storms and hurricanes in the Caribbean are expected to become more destructive as a consequence of climate change, causing significant harms to human life, infrastructure, industry and property in the small island developing states of the Caribbean Community. Caribbean States depend on international cooperation to prepare for and manage the impacts of tropical storms and hurricanes, to share resources and expertise across borders, and coordinate relief efforts. In studying the international relations of tropical storms in the Caribbean, this research project advances understanding of the challenges facing international meteorological cooperation in a changing world order, improves policy and practices of international collaboration around tropical storms and hurricanes, and supports the resilience and security of Caribbean states. The aims and objectives of the project: 1) To study the history of how states and societies interact and co-develop in relationship to tropical storms and hurricanes in the Caribbean, so as to develop understanding of how they shaped and continue to shape international orders. 2) To map the field of international expert actors that assemble around tropical storms and hurricanes in the Caribbean, for the purpose of prediction, mitigation and response, so as to better understand how international cooperation works today. 3) To interrogate the relationship between the Caribbean Meteorological Organisation and the World Meteorological Organisation so as to better understand the risks to international cooperation in responding to climate change. 4) To document the barriers to international cooperation in prediction, mitigation and response to tropical storms and hurricanes in the Caribbean so as to produce recommendations towards improving international collaboration in a changing international order.

UKRI Gateway to Research · FY 2024 · 2024-09

In the summer of 2015, the president of the Spokane Washington NAACP chapter, Rachel Dolezal, was "outed" as white during an interview with a local news station; publicly and privately, she identified herself as a Black woman. Though ostensibly a local interest story about a disgraced community figure, the story quickly caught national then international media interest, spreading further and faster through discussion on social media. Much of this discourse began attaching an unfamiliar term to Dolezal: "transracial". This term is used to indicate that, though Rachel Dolezal acknowledges she was born to Caucasian parents, she claims her identification with Blackness is genuine; Dolezal believes she is Black, that Blackness is "a state of mind" she inhabits. In the days and weeks that followed, journalists from major publications in the UK and the USA wrote articles adding details to the story and opinion pieces offering their judgements on Dolezal's racial escapades; as time went on, academics began publishing papers and then books discussing Dolezal, transracialism, and the socio-cultural construction of racial identities. Much of this work sets out to argue that Rachel Dolezal either is or is not Black and, in this way, this discourse about "transracialism" has become a debate about our popular and scholarly definitions of Blackness. This is the point my project, Ambiguities in Black, takes up: what does this discourse that emerged in the wake of the Rachel Dolezal transracialism scandal do to ways of talking and thinking about Blackness? Because I suggest Rachel Dolezal - or the social figure she has come to represent - has implications that reach beyond herself; she (or it) re-emerges in stories of others accused of similar racial transgressions, be it the changeable racial character of American academic Jessica Krug or European social media influencers accused of "blackfishing". It has become difficult to have conversations about racial transgression that are not haunted by Dolezal's figure, which is another way of saying Rachel Dolezal has become a cultural archetype of a certain kind of bad racial actor. And, as I argue in the project, the discussion of her case - by journalists, social media users, and academics - has become a public forum that mediates on "authentic Black identities". This question of what Blackness is and how we might know whether someone is Black is long contested and of vital importance to critical race theorists and scholars of Blackness, as well as anti-racist political actors. By analysing the post-Dolezalian transracialism discourse, my project produces answers as to the assumptions and logics about racialisation and Black identities circulating and structuring this popular media and academic discussion, and the ways in which the discourse can be seen to complicate, alleviate, or exaggerate rising tensions in our cultural, political, and theoretical dialogue on racial identity. Applying a Black feminist analytical lens, I ultimately argue the discourse produces a conceptualisation of Blackness that remains captive to hegemonic, anti-Black racial logics. Ambiguities in Black contributes original knowledge in the study of transracialism, definitions of Blackness, and discursive formations of race. The ESRC postdoctoral fellowship will facilitate the preparation of a book manuscript and series of journal articles to disseminate my findings in the scholarly community. It will further allow me to pursue engagement with a non-academic audience, sharing insights on the cultural production of racial identities.

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

Atrial fibrillation (AF) is a common heart rhythm problem affecting over 1.5 million people in the United Kingdom and is associated with an increased risk of stroke, heart disease and death. The condition is defined according to the duration of AF episodes with paroxysmal episodes lasting <7 days and persistent episodes lasting >7 days. AF can be treated using a procedure called ablation where parts of the heart which may cause AF are cauterised. This creates scar tissue, which doesn't conduct electricity, and aims to interrupt abnormal electrical circuits that may cause AF. The procedure may reduce symptoms and improve quality-of-life. Unfortunately, the procedure is only successful in 40-85% of patients and is less successful in patients with persistent AF. A repeat ablation can be performed when the initial procedure has been unsuccessful. However, repeat ablations themselves are unsuccessful in around 25-45% of patients. The reasons why the procedure works in some patients but not others are unknown but may be due to differences in the way in which AF develops and progresses amongst individuals. During ablation procedures, large amounts of data known as electroanatomic mapping data are acquired. These data, which are related to individual patients' heart shape and function, may allow us to understand the range of different disease states that exist amongst patients with AF. This may help us understand why some patients respond to ablation procedures whereas others do not. Aims and objectives The aim of the study will be to use electroanatomic mapping data to understand the range of different disease states that exist amongst patients who have been uniformly classified as persistent AF. This information, which is acquired during the first ablation procedure, will be used to determine how patients may respond to a repeat procedure. Below three main objectives are described: Define subgroups of persistent AF patients based on atrial properties. Understand the mechanisms which initiate and maintain persistent AF in individual patients. Use data from the first ablation procedure to predict response to a repeat procedure. Potential applications and benefits We aim to create practical tools that can predict how well a second ablation will work based on the results of the first one. This will help patients by making sure that those who undergo a second procedure are more likely to benefit from it. The tools will also help clinicians in determining which patients would benefit from repeat procedures. A reduction in potentially unnecessary ablation procedures, which cost >£7000 per procedure, will also have a positive impact on catheter laboratory waiting list times and costs. Previous research developments using electroanatomic mapping data have been limited by the fact that the data are manufacturer-specific and difficult to retrieve. To address this issue, our group has developed OpenEP, a freely available tool capable of enabling the storage and analysis of electroanatomic mapping data in a standardised format, making it efficient in terms of computer storage. Within this study, we will use OpenEP to conduct an analysis of clinical and electroanatomic mapping data from patients with persistent AF. The use of OpenEP as a platform will facilitate further large-scale analyses of electroanatomic mapping data enabling these data to be used to improve the care of patients with heart rhythm problems.