KING'S COLLEGE LONDON

UKRI Gateway to Research · FY 2025 · 2025-03

The successful translation of research knowledge to societal impact is a topic that has attracted the interest of governments around the world for a number of years. In 2014 the UK government introduced an ‘impact’ element to university assessment in the Research Excellence Framework (REF) to incentivise academics and their institutions to increase their contribution to society. Although there was a lot of push back at the time, in effect the government was saying: ‘demonstrate to us that about 10% of the research activity funded over the past 20 years in your university has made a contribution to society, and if you can we will give you more funding’. After the last two cycles of REF (2014 and 2021), the research team were involved in large-scale analysis of the impact case studies (ICS) commissioned by UKRI and Research England. Text mining approaches were used to identify impact topics based on the common use of keyword phrases in Section 4 (details of the impact) of the ICS. In combination with classification of the research disciplines (fields of research) that underpinned the research, it was possible to show the flow of impact from disciplines, through REF ‘units of assessment’, into impact topics. In both assessments the outcome of such analysis shows a multitude of impact pathways across all academic disciplines, leading to the conclusion that impact is extremely varied and difficult to categorise. This outcome was also observed in another study conducted by the project team on the results of the Hong Kong Research Assessment Exercise 2020. The current project aims to build on these analyses by investigating pathways to impact, based on a combined analysis of REF 2014 and 2021 ICS. The objective is to map common and unique pathways and examine their characteristics. Quantitative text mining will (i) map impact pathways from the underpinning research to impact topics for the combined dataset of 13,158 ICS, (ii) identify and describe common and unique pathways within the dataset, and (iii) identify any differentiating characteristics in the available metadata. Informed by the quantitative analysis, a series of ‘deep dives’ of common pathways will then be undertaken. The qualitative analysis will focus on cataloguing the types of mechanisms that have facilitated knowledge translation, and the beneficiaries of the research. A further text mining stage will apply this learning back to the whole dataset, seeking to automatically detect mechanisms that led to impact, along with beneficiary groups. This will result in a ‘data dictionary’ of impact mechanisms and beneficiaries, that can be applied to future text analysis of ICS. The project will contribute to our understanding of research impact and its beneficiaries, as well as having a number of real-world benefits. It will generate actionable insights for policymakers, universities and funders on effective approaches to support research translation. For example, it is likely that a particular mechanism is more frequent in one discipline than another, indicating the possible effectiveness of more targeted approaches to research support (including through impact acceleration accounts, technology transfer offices, etc). It will also generate guidance and toolkits for researchers on how to maximise the impact of their own research.

UKRI Gateway to Research · FY 2025 · 2025-03

In today's digital landscape, securing communication is paramount. Our proposal project focuses on a class of cryptographic primitives called key exchange, which underpins secure communication protocols used by billions globally. This includes Signal, the cryptographic protocol behind WhatsApp and Facebook Messenger, or Transport Layer Security (TLS), which safeguards communication between servers and users. These protocols rely on the Diffie-Hellman key exchange (DHKE). However, DHKE is vulnerable to attacks by quantum computers, and faces a growing quantum computing threat. One solution to this is post-quantum cryptography, a subset of cryptography that remain secure even against quantum computers. However, while post-quantum cryptography is finally maturing (as evidenced by NIST's post-quantum standardisation), their integration into real-world cryptography has not. This proposal addresses an important gap in the field: while numerous protocols have introduced post-quantum modifications individually, a systematised, universal approach to replacing quantum-vulnerable DHKE primitives with post-quantum cryptography has not been undertaken. Our proposal aims to create a universally-applicable framework that seamlessly transitions quantum-vulnerable DHKE into post-quantum cryptography based on NIST's proposed standards, specifically post-quantum key encapsulation mechanisms (KEMs). A key encapsulation mechanism is a cryptographic primitive in which one user (the sender) can transmit a secret to another user (the receiver) using their public key. The difficulty in this approach lies in the flexibility of DHKE, which post-quantum KEMs do not share. For instance, a DHKE public key can be combined with many different DHKE private keys to generate a shared secret key, allowing for many different variations of DHKE. However, a post-quantum KEM ciphertext can only be correctly decapsulated by a specific public key. This means that post-quantum cryptography used as a DHKE replacement cannot be combined similarly to DHKE, and thus a straightforward transform from DHKE to post-quantum cryptography does not exist. Our project aims to introduce a framework of generic transformations, to replace DHKE with post-quantum KEMs, while achieving (and formally proving) the same security properties. Thus, we aim to introduce a single, standardised approach to the post-quantum transition for secure communication. Our project will begin with surveying and categorising the security properties of all DHKEs, including forward secrecy, authentication, and key-indistinguishability. For each, we propose a generic replacement using KEMs, preserving their security properties, and each transformation will be formally analysed to prove that it maintains the security of the original. After, our project transitions to implementing and benchmarking these new replacements to understand their specific performance characteristics, demonstrating the exact costs and benefits associated with each transformation. We will propose a standard that allows stakeholders, such as designers of secure cryptographic protocols and the wider research community to utilise the proposed framework. Finally, our project applies our generic transformation to real-world cryptographic protocols, implementing and benchmarking these transformed protocols. The impact of the proposed research is significant - users of DHKE-based cryptographic protocols range from the general public, securing the communication of online transactions, to national interests, where DHKE establishes the security of messaging protocols used daily by politicians. Businesses and institutions can all benefit from our work when considering the scope of post-quantum transition. The Project Lead, Benjamin Dowling, is an expert in the formal analysis of cryptographic protocols, and has also been involved in post-quantum transitional efforts, such as the post-quantum Noise framework, a DHKE-based cryptographic protocol that is used by WhatsApp.

UKRI Gateway to Research · FY 2025 · 2025-03

Electronic devices have been transforming healthcare since the invention of the first electrocardiographs and pacemakers. Organic bioelectronic devices are cutting-edge healthcare technologies that translate biological signals generated by ions into electrical current, bridging the gap between biology and electronics. Organic bioelectronic devices have the potential to revolutionise medicine by treating conditions that traditional therapies cannot cure, and without the side effect associated with drugs. They are made of flexible materials which can be tailored to match the properties of different organs/tissues, limiting the body’s inflammatory response; this makes them ideal as implants for nerve regeneration after spinal cord injuries. They are also much more sensitive than silicon-based devices, allowing researchers to resolve signals from individual neurons – thus helping track down the source of seizures in epileptic patients. Other promising applications include sensing and diagnostics, from wearable glucose sensors for diabetes to ingestible devices to replace invasive exams such as gastroscopies or colonoscopies. Despite this tremendous potential, designing new materials for bioelectronics is extremely challenging, and the state of the art is limited to a handful of successfully tested materials. Bioelectronic devices behave like sponges or gels, absorbing and releasing ions and water. Thus, suitable “mixed conducting” materials must be both hydrophobic (to transport electronic charges) and hydrophilic (to accommodate water/ions). We understand how electrons and ions move, separately, in different materials, but designing a single material with the right balance between these two contrasting properties is very difficult.   Even small changes to the chemical structure of mixed conductors can drastically affect the ionic/electronic conductivity. We do not yet have general rules that can help us predict how a certain material will perform. A systematic exploration of the chemical space is vital to address the various requirements for each application. However, bioelectronics currently lacks datasets to enable large-scale materials discovery. This project addresses these challenges using large-scale molecular simulations and computational tools borrowed from other fields, such as drug discovery, that have not yet been applied to bioelectronics. We will design thousands of potential new materials, then use “computational microscope” techniques to predict how they absorb water and ions, and select those with the best ionic/electronic conducting behaviour.          Experimental Project Partners will synthesise the most promising candidate materials, validating our predictions and helping refine our predictive models. By collecting a high volume of data on hundreds of new materials, we will gain a better understanding of the fundamental laws governing mixed transport. Our computational exploration will not only benefit our experimental Partners, but the wider bioelectronic community. We will share our results, tools and data, enabling other researchers to build on our work and accelerating innovation in bioelectronics and related fields (drug delivery, batteries, artificial neural networks). Our project is ambitious, but our team has the right skillset: we combine unique expertise in bioelectronics, computational modelling (predicting the properties of new materials), chemical synthesis (making and testing new mixed conductors), and software development (solving technical problems to advance scientific discovery). In the future, organic bioelectronics may become the new standard for treatments and diagnostics of a wide range of medical conditions. By better understanding the structure and properties of mixed conductors, this project will bridge a fundamental knowledge gap and boost the design of improved bioelectronic devices.  

UKRI Gateway to Research · FY 2025 · 2025-03

The use of simple and renewable starting materials to construct complex and useful organic molecules is an important goal in sustainable chemistry. The selective functionalisation and valourisation of aromatic compounds through CO2 fixation is an immensely important reaction that allows complex organic compounds to be synthesised from renewable and cheaply available CO2.  The organic molecules produced from these reactions can serve as intermediates or active constituents to manufacture pharmaceuticals, agrochemicals, cosmetics,  and specialty and commodity chemicals. However, selective fixation of CO2 to recalcitrant, unactivated aromatic compounds is difficult to achieve, and a green and efficient enzyme-catalysed system to fix CO2 to unactivated organic compounds like benzene is unprecedented. This project therefore aims to identify, engineer, and develop for the first time enzymes capable of catalysing selective fixation of CO2 to these recalcitrant aromatic compounds as a sustainable chemical synthesis method. Efficient methods for CO2 fixation can have profound and potentially transformative applications in the synthesis of a broad range of useful aromatic compounds. Since these aromatic compounds are the most prevalent building blocks of most of the chemicals that our society depends on, e.g. pharmaceuticals, agrochemicals and cosmetics, efficient selective fixation of CO2 to aromatic compounds will have far-reaching impacts across a broad range of industry sectors. On a broader point, these proposed artificial CO2-fixation systems will contribute to sustainable synthesis, reduce overdependence on fossil fuel, and represent an immensely important anthropogenic CO2 recycling strategy to mitigate the climate and health impacts of excess atmospheric CO2. This proposal directly addresses a chemical science and engineering grand challenge - “Utilising carbon dioxide in synthesis and transforming the chemicals industry”.

UKRI Gateway to Research · FY 2025 · 2025-03

Cytotoxic T cells are a critical part of our immune system. They are the white blood cells responsible for detecting and destroying cancer cells. For them to function properly they first need to migrate into the cancer tissue. They then tightly attach to their targets before killing them. Tumour tissues, however, tend to be much stiffer than healthy tissue and it has previously been shown that T cells can struggle to enter stiff tumours. This increase in stiffness is due to several reasons, including the accumulation of fluids and the growth of the cancer cells themselves, which leads to fluid and mechanical stress. Our research focuses on cytotoxic T cells and we plan to determine how fluid and mechanical stress can affect their ability to attach to and destroy cancer cells. We suspect that one critical factor is that they need to be able to rapidly change both their shape and their size. This allows them to migrate through narrow gaps in tissues and to attach to target cells to destroy them. However, if tumours are particularly stiff, such as is the case for breast cancer, we suspect that the external forces acting on T cells may be too big for them to overcome and their ability to navigate through the tumour and kill may be restricted. Of particular interest thereby is a protein called WNK1, which previously has mostly been studied for its role in salt reabsorption in the kidney. New results from our lab, show that WNK1 also has vital roles in T cells and is required for them to change their size and shape. In this project, we will investigate how tumours stiffness affects T cell shape and size regulation and thereby their ability to destroy cancer cells, and how the two major components of tumour stiffness contribute to these processes. As T cells lacking WNK1 are very small and unable to change their shape, they will serve as a model to study what the impact of size and shape regulation is on T cell function. The knowledge gained in this study will create insight into how stiff tumour tissues affect T cell-dependent anti-cancer responses. Furthermore, it may help to develop drugs that can either inhibit or enhance the function of T cells and will therefore impact on developing treatments against cancer.

UKRI Gateway to Research · FY 2025 · 2025-03

Regulatory T cells (Tregs) are a subset of immune cells dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg development or function result in uncontrolled immune responses and tissue destruction, contributing to the pathogenesis of multiple autoimmune and inflammatory disorders. On the other hand, excessive recruitment and activation of Tregs leads to inadequate immunosurveillance, as seen in cancer. Recent discoveries have demonstrated that metabolic processes, redox homeostasis, and mitochondrial function are critical to sustain Treg homeostasis and function and ensure effective immunoregulation. However, these findings are derived from animal models, and the extent to which the same mechanisms apply to humans needs to be elucidated. Such knowledge would allow the design of novel strategies to either disrupt Treg function (e.g. in cancer) or to boost their activity to re-establish tolerance (e.g. in autoimmunity). A particularly pressing indication is hepatocellular carcinoma (HCC), which has emerged globally as one of the most common and deadly malignancies (third most common cause of cancer deaths worldwide). HCC exhibits a suboptimal response to immune check point inhibitors, particularly when the cancer develops in patients with chronic liver disease (CLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD), which is now the leading cause of HCC in the West. Targeting intra-tumoral Tregs in this setting could overcome the limitations of currently available immunotherapies and drastically improve the prognosis of HCC. The challenge the project addresses Tregs accumulate in large numbers within HCC tumours, which negatively correlates with overall patient survival, suggesting that they are key in suppressing immunosurveillance. However, knowledge on the mechanisms underpinning their fitness/adaptation within the HCC microenvironment is limited. My previous work indicates that in CLD patients Tregs are dysfunctional and prone to apoptosis. This is the result of redox, mitochondrial, and metabolic abnormalities, linked to the deficient activation of the nuclear factor E2-related factor 2 (Nrf2) signalling pathway. When HCC develops, typically in the setting of CLD, the tumour microenvironment reverses the Treg metabolic abnormalities caused by CLD. This process is also dependent on Nrf2, which is highly activated in tumour-infiltrating Tregs and promotes their viability. My current fellowship application seeks to elucidate the exact mechanisms by which Nrf2 regulates the metabolic adaptation of Tregs to the HCC microenvironment. Furthermore, I will determine if the genetic/pharmacological inhibition of Nrf2 enhances anti-tumour immunity in pre-clinical in vivo models of HCC.

UKRI Gateway to Research · FY 2025 · 2025-03

Challenge Loneliness is a major societal concern, contributing to poorer physical and mental health, lost productivity, and death. The number of people aged over 50 experiencing loneliness in England is predicted to reach 2 million by 2026: an increase of 49% since 2017. Breathlessness disrupts the daily lives of over a third of older people. It accompanies most chronic conditions (e.g. lung disease, heart disease, cancer, neurological conditions). Breathlessness is multidimensional and causes high levels of suffering, and typically worsens over time. People with breathlessness are more likely to experience depression, loss of mobility, and increasing isolation in their communities. About 1 in 5 people with chronic breathlessness report loneliness, and yet dedicated qualitative exploration of loneliness and rigorous quantitative modelling in this population remains absent. Despite the prevalence and impact of breathlessness being comparable to other multidimensional, distressing symptoms, its contribution to the 'loneliness epidemic' remains unexplored. By ignoring the role of breathlessness in loneliness, we likely miss valuable opportunities to successfully intervene. Vision We aim to develop the first conceptual model of the relationship between breathlessness and loneliness. Our research objectives are to: (1) explore and make visible the lived experiences of loneliness in older people with breathlessness, and (2) determine the relationship between breathlessness and loneliness over time. Approach This mixed methods project includes two main components: -Photovoice study: we will recruit older people reporting breathlessness and loneliness via health clinics, charities and social networks. We will equip them to take photographs across a 2-week period on the theme of social connection, and use a selection of their images as the basis of research interviews about their experiences of loneliness and how this relates to their breathlessness. Participants will be invited to collaborate with our team for the rest of the project, and influence how we share the findings. -Statistical modelling: Using data from an existing nationally representative dataset (English Longitudinal Study of Ageing), we will (a) describe how many older people with breathlessness experience loneliness; (b) undertake structural equation modelling using a cross lagged panel approach to determine the extent to which breathlessness and loneliness are predictive of one another over time; and (c) examine the pathways by which these relationships occur. Mediators (e.g. depression, mobility) will be selected based on previous evidence and preliminary analysis from the photovoice study. Findings will be integrated to form a theoretical model of the relationship between breathlessness and loneliness. The final model will be shared alongside an exhibition from the photovoice study in an interdisciplinary 'sandpit' event, including people with breathlessness and professionals representing diverse disciplines (e.g. psychology, sociology, health, technologies) and sectors (e.g. charities, policymakers, research, care services). Stakeholders will be asked to offer their perspectives and make pledges for action.

UKRI Gateway to Research · FY 2025 · 2025-03

Diabetes affects close to 5 million people in the UK, a number that is likely to increase in the next decade due to an increasing rate of obesity. People with diabetes are unable to regulate their blood sugar levels, which are normally controlled by the hormone insulin. High blood glucose as a result of decreased uptake into cells can result in serious medical complication, including blindness, strokes, and necrosis of limbs. Insulin is produced in the pancreas, and induces cells of the body, primarily muscle cells, to take up glucose and re-balance sugar levels following meals. However, in people developing type-2 diabetes, skeletal muscle no longer responds properly to insulin - a condition known as insulin resistance. While diabetes can be treated with insulin injections, in type-2 diabetes, the most common form of diabetes, insulin resistance renders this therapy ineffective over time. Therefore, a more thorough understanding of the molecular pathways involved in insulin resistance would greatly facilitate the development of new treatments of diabetes. Culturing human cells in a dish provides an ideal platform for finding new drugs, as this avoids issues with species differences, ethical considerations and high costs associated with experimental animals. Cultured skeletal myofibers would be an ideal for studying glucose metabolism, because this tissue is responsible for ca. 80-90% of glucose uptake following meals. However, to date, their use in diabetes modelling has been hampered by the fact that they are contractile, and detach quickly from rigid plastic surfaces in conventional cell culture. In addition, myofibers require innervation by nerve cells called motor neurons to mature into the equivalent of adult human muscle. Researchers have used fat cells to model diabetes instead, but these cells differ in how they control glucose uptake, in particular with regards to cellular trafficking of the glucose transporter GLUT4, a key factor in the regulation of blood sugar by insulin. Here, we propose to fill this technological gap in diabetes research by adapting a 3D-coculture system developed by members of our team for neuromuscular disease studies to investigate insulin responses in muscle. The culture system combines motor neurons and myofibers derived from human induced pluripotent stem cell (hiPSCs) into a multi-well device suitable for high content imaging, a technology commonly used for drug screens. In the devices, muscle fibres are stabilized by a scaffold of aligned elastic nanofibers, which guide uniform growth of myofibers and prevent collapse. We will equip culture wells with nanofiber-based glucose biosensors to directly measure changes in glucose levels. We will incorporate genetic probes to aid the analysis: Motor neurons will be genetically engineered such that their activity can be controlled by light. Myofibers will carry a fusion gene of GLUT4 and red fluorescent protein, which will allow us to track the movement of GLUT4 in live cells in response to insulin and/or exercise. Our proposal combines microdevice manufacturing, hiPSC-derivation of tissue, and analysis of metabolic pathways into a new neuromuscular culture model of diabetes. By the end of the project, we will have established the neuron/myofiber co-culture system, shown that innervated skeletal muscle myofibers take up glucose and mimic insulin responses, and recapitulate the failure of these processes in diabetes. We will have carried out a proof-of-principle screen with potential pharmacological treatments to show the suitability of the system for future drug discovery.

UKRI Gateway to Research · FY 2025 · 2025-03

The prenatal detection of congenital heart disease (CHD) continues to rely on a single imaging modality – 2D ultrasound (2DUS) – for both screening and diagnosis, with a heavy reliance on operator expertise. Advanced 3D ultrasound techniques, which may aid expert diagnosis of complex forms of CHD, are technically limited with poor reliability in clinical practice. This project intends to combine our extensive clinical and biomedical engineering experience to generate a novel acquisition and image-processing pipeline, using deep learning methods to recompile free-hand 2DUS images into isotropic, high spatiotemporal resolution advanced 3D fetal echo (a3DFE) datasets. By leveraging oversampled data acquired in multiple orientations, we will reduce reliance on a single imaging window, improving both reliability and reproducibility. We will then extend our reconstruction network to perform automated segmentation and extraction of functional metrics, coupled with cross-modality validation experiments in preparation for translation into clinical practice. We believe these novel methods will transform expert-level diagnosis of CHD, as well as offering the potential to transform approaches to population-based screening in the future.

UKRI Gateway to Research · FY 2025 · 2025-03

Genetic information is encoded in DNA as an ordered sequence of nucleotide units. Cells can retrieve this information by transcribing DNA into protein-coding messenger and noncoding RNAs. We have previously identified the pyrimidine-rich noncoding transcript PNCTR and showed that it is widely expressed in cancer cells. This RNA originates from an intergenic spacer between repeated genes encoding 47S precursors of ribosomal RNAs in genomic regions called ribosomal DNA (rDNA) arrays. PNCTR can promote cancer cell survival, at least in part, by sequestering multiple copies of the RNA-binding protein PTBP1 in a membraneless perinucleolar compartment (PNC). Cancers cells tend to accumulate mutations, which often make cancers more challenging to treat. Such genetic instability is commonly observed, for example, in breast cancers, the most common cancer type in the UK. Notably, many breast cancers produce the PNC through yet-to-be-understood mechanisms. Our new data suggest that cancer cells may transcribe PNCTR from genetically rearranged rDNA sequences, emerging as a result of error-prone repair of DNA double-strand breaks (DSBs). We also hypothesize that the assembly of the PNC around nascent PNCTR molecules segregates genetically compromised rDNA loci away from the nucleolus. Finally, we propose that PNCTR plays a key part in the breast cancer biology, and that its knockdown may reduce the ability of cancer cells to thrive and metastasize. We will explore these intriguing possibilities by pursuing three distinct but interrelated objectives. 1. Elucidating the role of rDNA rearrangements in PNCTR expression: We will test if PNCTR is commonly produced from genetically rearranged rDNA by sequencing PNCTR-enriched RNA fractions from breast cancer cell lines and patient samples and mining publicly available sequencing datasets. The proposed analyses will also illuminate the role of recurrent rDNA DSBs and different DSB repair pathways in the emergence of PNCTR-encoding loci. 2. Dissecting the mechanisms of PNC assembly: Our new data suggest that the PNC assembles near the PNCTR transcription site. We will test this prediction using proximity DNA labeling and chromatin immunoprecipitation with PTBP1-specific and control antibodies. To examine the PNC assembly dynamics, we will perform live imaging of cancer cells retrofitted with fluorescent markers. By combining these experiments with appropriate knockdown and knockout approaches, we will be able to distinguish between co- and post-transcriptional mechanisms of PNC assembly and find out if this process facilitates the segregation of rearranged rDNA loci to the nucleolar periphery. 3. Understanding PNCTR functions: We will employ appropriate knockdown or/and knockout approaches in both 2D and organoid cultures to investigate the role of PNCTR in sustaining the viability and metastatic properties of breast cancer cells. To understand the underlying mechanisms, we will evaluate the impact of PNCTR/PNC on PTBP1 activity and the integrity of the nucleolus. These studies will yield fundamental insights into the role of genome instability in noncoding RNA production and subnuclear compartmentalization. Furthermore, they are expected to contribute to the development of innovative research tools for the broader biomedical community. We anticipate that this research trajectory will ultimately pave the way for transformative diagnostic approaches and precision therapies for cancer patients.

UKRI Gateway to Research · FY 2025 · 2025-02

Shigella is a major diarrhoeal pathogen, estimated to cause up to 165 million illnesses and 600,000 deaths yearly. There is no vaccine available that protects against shigellosis. Due to widespread antimicrobial resistance (AMR), Shigella is listed by the World Health Organisation as a priority pathogen. Shigella generally induces an acute, self-limiting disease. However, surveillance data and my own work using the zebrafish model have recently demonstrated that Shigella can establish persistent infections. Persistent infections are not cleared completely by the host. They represent a critical public health issue because they can become asymptomatic and are difficult to diagnose and eradicate. Persistently infected carriers also represent a reservoir that promotes further disease spreading. The zebrafish model has helped to uncover important mechanisms underlying Shigella pathogenesis. Using this model, I demonstrated that Shigella can establish persistent infection in vivo. Significantly, Shigella establishing persistent infection also becomes antibiotic tolerant (infection is no longer eradicated by antibiotics), which facilitates the evolution of AMR. My data also indicate an important role for macrophages in establishing persistent Shigella infection. Despite these novel insights, the mechanisms underlying persistent Shigella infection and its precise links to AMR are unknown. Using a combination of models in vitro (THP1 macrophage-like cells and macrophages derived from human induced pluripotent stem cells (hiPSCs) or monocytes) and in vivo (zebrafish larvae), I will investigate persistent Shigella infection and how this facilitates AMR. My specific objectives are: Objective 1. Characterise the niche of persistent Shigella infection. I will apply high-resolution microscopy and cell sorting to follow how persistent infection develops and study its intracellular localisation. I will use sequencing technologies to profile the gene expression changes occurring in macrophages carrying persistent infection. I will also apply gene editing techniques to study further the role of the discovered host factors contributing to persistent infection. This objective will describe the persistent infection niche and identify the host factors underlying persistence.

UKRI Gateway to Research · FY 2025 · 2025-02

Glaucoma is a major health problem and blinds millions of people worldwide. Glaucoma surgery is used to prevent blindness but traditional glaucoma surgery (trabeculectomy) fails primarily due to scarring in 50% of patients after 5 years of follow-up. There has been an unexpected paradigm shift in the types of glaucoma surgeries performed worldwide. New surgical techniques, called minimally invasive glaucoma surgery, have been developed in glaucoma in the last few years, and is replacing trabeculectomy surgery worldwide. Similar to trabeculectomy, the new surgical techniques also fail due to scarring and have an even higher failure rate of 50% after 1 year of follow-up. I will use new powerful technologies to investigate why a large subgroup of patients develops severe scarring and irreversible loss of vision after glaucoma surgery (trabeculectomy and minimally invasive glaucoma surgery). Using this knowledge, I will develop new treatments to prevent this from happening.

UKRI Gateway to Research · FY 2025 · 2025-02

Foldamers are large unnatural molecules which, owing to their inherent functionality, will fold in on themselves to make discrete and predictable higher order structures. The diversity of these structures means that they are one of the most promising areas of synthetic and supramolecular chemistry. Their potential applications span a diverse variety of impactful fields from peptide therapies through to catalysis. The former, which includes the targeting of pathogenic protein-protein interactions, was estimated to be worth £32.1B in 2022 with an estimated growth rate of 6.3% to 2023. Likewise, the catalysis industry was estimated to be worth £22.7B in 2022 with a 4.6% growth over the same period. These are just two examples of the sectors to which the contribution of foldamers could be profound, and that is without mentioning their potential in drug delivery, information transfer, molecular machines, and materials science. The UK has been at the forefront of foldamer research with respect to these fields, but despite the many impressive advances and innovations, further progress has undoubtedly been stymied by a lack of connectivity - not just between research groups developing foldamer structures for these applications, but also between the field itself and allied disciplines. A primary aim of this Network, therefore, is to enable mechanisms whereby new links between different structures and function within and without the field can be easily made and thus open new collaborations and areas of foldamer discovery. This could either be achieved by the cross-purposing of existing systems, or through the rational design of new ones. Whilst networking within the community is important, success will also be critical upon it being open to other communities who may not have considered the application of foldamers to their areas. We will ensure that we connect with them - particularly via established RSC interest groups. A further central aim of creating this network is to provide a strongly supportive environment for ECRs in a variety of ways, including grant-writing mentorship, and financial aid to attend meetings and promote the excellent work within the UK, as well as supporting an annual ECR focus meeting. We are also very committed to supporting EDI within the network and will be working very closely with WISC (Women in Supramolecular Chemistry) who have extensive experience in the support of minorities in the chemical sciences to advise us and to promote EDI issues to the Network.

UKRI Gateway to Research · FY 2025 · 2025-02

The adrenal glands are organs located above the kidneys, that release necessary compounds called hormones into the bloodstream, regulating many essential body processes, including how we respond to stress, our heart rate and blood pressure, and how our metabolism and immune system function. Diseases of the adrenal gland result in these organs not working properly, with life-threatening consequences. Some of these diseases can develop in the womb, when the fetal organs are still developing, and other diseases can affect us at any stage of life. Current treatments are not curative and many patients experience persistent life-long symptoms and poor quality of life. Regenerative therapies are treatments that aim to repair and restore human organs, following damage of disease. For the adrenal glands, regenerative therapies are not advanced enough to treat patients; new adrenal gland cells can be made in a dish in the laboratory, but this process is not very efficient, and the cells don’t function as well as the ones normally found in the body. We think that the failure to efficiently generate adrenal cells in the dish might be because we are not providing necessary biologically active compounds (signals), which cells are normally exposed to when the adrenal glands develop in the embryo. Our research on animal models has uncovered a situation where the right signals are being given, leading to the generation of new adrenal tissue at a time in life when we didn’t think this was possible. These preliminary data demonstrate that if the signals are provided, the generation of functional adrenal cells may be much improved. Our main aim is to pinpoint and study those signals, and reproduce them on human cells in the laboratory, in order to push them to become the fully functioning cells required by regenerative therapies for adrenal diseases. Our approach can benefit regenerative therapies in many ways, from improving current approaches, to instigating entirely new avenues. We expect this knowledge will be helpful for scientists working on tackling regenerative approaches for other organs, and we expect that in the long-term, this study will benefit patients suffering from adrenal disorders.

UKRI Gateway to Research · FY 2025 · 2025-02

Stigma refers to people being 'marked' - in society's eyes - as lesser, unworthy or disgraced. Stigma can lead to discrimination, or unfair treatment. This stigma and discrimination are challenges across society and cause problems in many of the systems that people interact with, such as health care, welfare and policing. We have some understanding of these social and systemic sides of stigma and their complexity, but not enough to understand how to respond and prevent it. This research aims to improve our explanations for the complexity of stigma and so produce new Social Responses to Stigma. The research is especially focused on stigma and discrimination as it relates to homelessness. The stigma that often focuses on people who are homeless and homelessness is a persistent barrier to addressing ill-health and homelessness. It can mean people don't seek care and support, receive poor quality support if they do, or are excluded from resources and realising their rights. A result is worsening health and reduced chances of ending homelessness. Homelessness is just one experience that is the focus for stigma. Overtime we hope the responses generated can have impact across many different experiences and places The project is led by a team from King's College London based in south London. They are working closely with partners from Emmaus, Groundswell, the Lambeth Service Users' Council, Museum of Homelessness and then other services working directly with people who are homeless across south London. A focus for the research is in-depth study in south London to understand the complexity of the stigma that people who are homeless face. The project partners will then develop new responses to stigma by combining the results from the in-depth study with the views and experiences of people across south London, including people currently homeless and those working with them. The new responses to stigma will initially be implemented in south London. We will work to understand their impacts on the systems that provide services and whether there are improvements in peoples' experiences and health. We will then try and ensure lessons from any success are shared with other places and also used to address the stigma attached to other health issues.

UKRI Gateway to Research · FY 2025 · 2025-02

The context The World Values Survey (WVS) covers over 280 questions asked across 120 countries and dates back to 1981, making it one of the longest-standing and most widely used sources of insight into people’s attitudes, values and beliefs and how they are changing. Awareness and use of this unique resource has increased substantially in the UK recently, due to proactive engagement undertaken by the Policy Institute in the last wave. We will build on this momentum, cementing the study as the most accessible, trusted and used source of evidence on the UK’s sense of self and its place in a rapidly changing world. The challenge the project addresses In wave eight of WVS, we would collect a new sample of responses from 1,800 adults living the in UK, supplemented by boosts in Northern Ireland, Scotland and Wales (subject to available funding). Our proposed design addresses two challenges: The first challenge is common to many ESRC Infrastructure projects: how to ensure these vital time series studies remain sustainable, when face-to-face response rates and interviewer capacity are declining, and fieldwork costs rising. Building on learnings from mode experiments conducted by the European Social Survey (ESS) and through partnership with the ESS Headquarters, we propose that for wave 8, we incorporate an innovative ‘bridge wave’ to test the reliability of shifting to self-completion within the UK. In practice, this means that half of respondents will be randomly assigned to completing the survey via a face-to-face interview, and the other half via an online or paper questionnaire. The second challenge is experienced by those who face barriers to using data infrastructures such as the WVS, be it a lack of time or confidence to use a dataset that is inherently complex. Therefore, alongside the data release, we will publish a series of high-profile initial releases summarising key trends and country comparisons, to shine a light on contemporary issues facing the UK and provide a broader community of data users with the evidence to respond to them. Aims and objectives The Policy Institute will build on the solid foundations already laid in the previous wave, ensuring continuity of the study as a high-quality, trusted and resilient resource for a diverse community of data users. Our aims supporting this are threefold: To involve a diverse range of data users from the outset, to ensure the WVS meets the needs of research and policy communities To facilitate high quality international research on life in the UK, that is resilient to an evolving fieldwork market To raise the study’s profile and unlock its impact for a broad community of research and policy communities   Potential applications and benefits We are committed to ensuring the data are widely used, both within academia and beyond. This will be supported by an ambitious engagement strategy (including descriptive releases of initial findings, policy briefings, direct media engagement and a high-profile launch event), which we have demonstrated can build an engaged and influential user base for the WVS in the UK. This study also answers substantive questions about survey methodology approaches, benefiting the wider Data Infrastructure community, and potentially bringing significant cost-savings going forward. It also brings significant societal benefit, allowing a clear read on the issues that matter to the public in the four nations of the UK.

UKRI Gateway to Research · FY 2025 · 2025-02

“No one cares about us – we know our lives are disposable.” This observation was shared with the PI by Fatima, a young woman from Mombasa, following a participatory theatre performance about Covid vaccine rumours. Voicing sentiments with global resonance, Fatima’s commentary highlights the profound dearth of care that underpins her reason for refusing vaccination, and that many Mombasans feel in relation to institutional structures at all levels – a lack of care colours engagements with the state, health institutions and development initiatives. Fatima’s words demonstrate how the giving and receiving of care is racialized, classed and gendered (Mahon & Robinson 2011), and evoke the wide-ranging implications that ‘care deficits’ (Hochschild 2003) can have on health, worth and wellbeing. We live in a world where ‘carelessness reigns’ (Chatzidakis et al. 2020).Care is central to what it means to be human (Heidegger 1967; Tronto1993), and yet is systematically undervalued – neoliberal and patriarchal conceptions of autonomy have failed to account for the mutual interdependencies on which everyone of us depends (Butler 2020). Giving and receiving care is recognized as ambiguous and unpredictable – care is bound up with experiences of dependence, duty and disempowerment as much as connection and interdependence (Cook & Trundle 2020). However, efforts to map and understand care to date have taken insufficient account of the extent to which care intersects with social processes such as surveillance, profit maximization and violent (post)colonial state-building (Charles 2020). These enduring legacies leave many with well-founded suspicions about supposedly benevolent ‘caring technologies’, such as vaccination, as well as towards broader health and social care services provided by state, medical and aid regimes. This project proposes a novel methodology to unpack questions of power, inequality and ambivalence in relation to care in Mombasa. Drawing inspiration from recent interventions on care in applied theatre (Stuart Fisher & Thompson 2020; Mayo 2021) and anthropology (Mol 2008; Cook & Trundle 2020), this project will combine arts-based methods with ethnography to: map understandings and experiences of the presence, absence and ambivalences of care amongst young adults in Mombasa (18–35-year-olds) develop community-led recommendations and practices that support more equitable access to care for all leverage artistic outputs to engage a broad range of actors involved in health and social care provision in Mombasa (including policymakers, community organizers and donors). The project takes forward findings from two previous collaborations between the PI and Jukwaa Arts Productions, a Mombasan creative arts company that specializes in participatory theatre for social change. As Project Partner and Subcontractor, Jukwaa will work with PI to develop an innovative, arts-based methodology for conducting research on care, grounded in a series of workshops with young adults. These workshops will form the basis from which we create two participatory theatre performances, a short film and roundtables in Mombasa, each designed to provoke public debate and policy change around care. An accompanying methodological toolkit will showcase the production and performance process in Mombasa, while outlining arts-based approaches for researching and building more equitable access to care elsewhere.

UKRI Gateway to Research · FY 2025 · 2025-02

Understanding language crucially requires capturing words’ meanings, but these are not directly observable. Words’ meanings change over time and vary by register, genre, style, social and geographic factors. Our knowledge of semantic variation and change in historical languages is largely based on qualitative evidence from dictionaries and small-scale studies. Large quantitative studies are not possible yet because they require high-quality data with rich semantic annotation indicating the meaning of each word’s usage. Since this is time-consuming and complex, we lack large-scale quantitative accounts of semantic variation and change over long time spans. Recent computational methods in historical word sense disambiguation allow us, in principle, to automate semantic annotation. Hence, large-scale quantitative semantic analyses are now within reach. Latin has one of the longest recorded histories, an unprecedented set of tools and digital corpora covering over two thousand years and is a key part of Europe’s cultural heritage. This context places Latin in an excellent position to lead the way in quantitative historical semantics. Uniquely integrating computational methods in a novel corpus annotation system to analyse Latin words’ meaning quantitatively at scale, COALA can transform the way historical lexical semantics research is done. The impact spans multiple fields: in corpus linguistics, addressing open challenges for consistent sense annotation at scale for a historical language; in computational semantics, advancing state-ofthe-art methods as a reliable basis for lexical semantics research; in Latin and historical semantics, answering open questions on how polysemy varies by text genre, how words in the same lexical field change their meaning, and how the timing of semantic innovations relates to lasting changes. Our analysis will also be the first extensive empirical semantic investigation of Latin’s status as a fossilised language throughout its history.

UKRI Gateway to Research · FY 2025 · 2025-02

The individual electrons in a metal, or the qubits in a quantum computer, are subject to peculiar but well-understood quantum mechanical laws. But metals/quantum computers have many electrons/qubits respectively and they all interact with one another, giving rise to a very complicated system. By implication, if you really want to understand a material or the operations of a quantum computer, you must grapple with the following question: What behaviours emerge when many quantum bodies (i.e., spins, electrons, qubits) interact with one another? The answer is fascinating. Surprising new behaviours can emerge due to both the complexity of many-body systems and the strangeness of the underlying quantum mechanical laws, and the continuing effort to chart this terrain accounts for two vast intersecting fields: condensed matter and quantum information theory. One insight from the study of condensed matter is that many-body systems are organised into phases. In addition to the prosaic (liquids, solids, gases) there's an ever-growing list of exotic quantum phases including superconductors and topological orders, many of which are useful. Much of condensed matter is dedicated to the search for new phases, and here it intersects with quantum information theory. For example, discovering new phases can help us to design more robust quantum computers, which may one day revolutionise computation (and will produce interesting physics in the mean-time). Indeed, the topological orders mentioned above now form the backbone of the most prominent digital quantum computers. This fellowship extension focusses on two themes within this area. 1) Find and characterise new open quantum phases The theoretical search for new phases has tended to assume that they are in thermal equilibrium. We aim to find new phases which emerge when we remove that assumption, and subject the system to driving, measurement, and dissipation. This is a timely question because the resulting so-called "non-equilibrium" or "open" systems describe well the conditions in a modern quantum simulator. Open systems are relatively understudied, but we already know that they can give rise to qualitatively new behaviours which can neither be realised in equilibrium nor in classical systems. We also now know more about the mechanisms that stabilise these phases, due to progress made in the first part of the fellowship. Going forward, our aim is to find and characterise new open quantum phases. The payoff is that if you find a new phase, then you have identified a new robust -- hence potentially useful -- quantum phenomenon. For example, new such phases may prove useful for protecting quantum information from noise, which is the main barrier to performing useful quantum computations. 2) Develop and use new classical (and quantum) algorithms for simulating many-body systems Transport properties (e.g., charge conductivity), are among the most practically important features of materials. Yet our ability to predict these properties from first principles in interacting quantum matter has until recently been limited. In the first part of the fellowship we used insights gleaned from quantum information theory to develop a new such technique (called `DAOE'), which efficiently simulates quantum transport in a range of systems, and which can probe transport in previously inaccessible regimes. This fellowship extension will further develop the algorithm, make an optimised version of it publicly available, and use it to understand new physics and experiments. DAOE is presently run on classical computers, but we will also explore the possibility of running analogous software on a quantum computer. The result may greatly enhance our ability to use quantum computers to predict experiments and, ultimately, the properties of materials.

UKRI Gateway to Research · FY 2025 · 2025-01

This proposal aims to develop gene therapy for degenerative eye disease whilst investigating the molecular mechanisms required for regeneration in the central nervous system (CNS). Our recent work demonstrated that delivering a molecule called Protrudin to the eye allowed for regeneration in the optic nerve and neuroprotection in the retina, after an injury used to model optic nerve disease. Glaucoma is a common optic nerve degenerative disease affecting 80 million patients worldwide. It is associated with raised intraocular pressure (IOP), however IOP is relevant in as little 60% of patients (varying between countries) whilst the common pathology is progressive dysfunction and loss of optic nerve fibres (axons) and retinal ganglion cells. These are the neurons that connect the retina to the brain through their axons in the optic nerve. Neuroprotective strategies for glaucoma are of great therapeutic need. Ocular gene therapy could be a viable approach, with its success in the clinic already demonstrated for genetic eye diseases. In the case of glaucoma, an ideal gene therapy would need to be protective, as well as capable of promoting the regeneration of lost axons. Protrudin can provide both regenerative and protective functions, but these effects could be improved. We have identified related molecules that also stimulate regeneration or neuroprotection, and we aim to use these to synergise and amplify Protrudin's effects. A first part of the work will evaluate Protrudin-focused gene therapies for the visual system in well-established models of optic nerve injury and retinal disease. We aim to develop gene therapy tools that would allow for Protrudin and a partner gene to be delivered in a single vector to increase efficacy and promote dual therapeutic benefit. These studies would provide pre-clinical validation of a gene therapy for treating degenerative eye disease. Protrudin is a scaffold-type molecule that localises to the axonal endoplasmic reticulum (ER). This is a cellular organelle that extends as an extremely fine tube throughout axons. We previously found that Protrudin can stimulate regeneration by increasing the amount of ER in axons. The ER is a complex organelle. It could provide many functions that might be therapeutically useful, but we have not characterised these. We have been studying the functions that the ER and Protrudin might be providing in axons and have discovered a potential role for an organelle called Golgi Satellites. A second part of the work will use cutting edge cell biology techniques to test a key mechanistic hypothesis: Protrudin drives axon regeneration by coordinating an axonal interaction between ER and Golgi Satellites. We will investigate Protrudin as a linker between the axon ER and Golgi Satellites and will characterise this important machinery and its role in axon regeneration. An axonal interaction between these organelles could indicate that axons rely on more diverse cell biology than currently considered. The work will characterise the cellular machinery at this interaction site and determine its functions. We will investigate a role for Golgi satellites in regeneration and examine whether they can also be targeted therapeutically. This molecular research will expand the implications of the study, uncovering targets for promoting axon regeneration and neuroprotection that could have relevance in the CNS beyond visual impairment.

UKRI Gateway to Research · FY 2025 · 2025-01

We request funding to support the purchase of a single crystal X-ray diffractometer, to address a key gap in our EPS research facilities which has been identified through a thorough assessment of equipment need across King’s. Single crystal X-ray diffraction (SCXRD) is a critical technique for determining the structure of small molecules (e.g. drugs, polymer building blocks, metal catalysts), macromolecules (e.g. proteins), and solids (e.g. extended materials). We propose to purchase an SCXRD instrument which will be focused specifically on enabling the structural analysis of small molecule samples, for which there is significant and growing demand across King’s. There is currently no locally available instrument which can efficiently and reliably provide high quality data for such small molecule samples, and researchers requiring this technique currently make extensive use of regionally available facilities, both in London and at the National Crystallography Service in Southampton. However, this approach is costly, slow and unsuitable for sensitive samples which readily degrade or decompose during transportation. As a stop gap measure, King’s has recommissioned a 15 year old instrument acquired from another institution, but this is not a sustainable solution as the instrument provides poor quality data with long acquisition times and is at the end of its service life. The purchase of a new SCXRD instrument focused on small molecule research, and housed in the Department of Chemistry, will have significant benefits for researchers at King’s, and King’s partners, such as the Francis Crick Institute. We have identified a broad user base for such a facility and expect the instrument to substantially benefit the careers of early career academic researchers in the Department of Chemistry, as well as enabling the research of users across natural sciences, biomedical engineering and pharmaceutical sciences. In addition, the provision of an instrument locally will significantly enhance our ability to train postdoctoral researchers and PhD students in this critical analytical technique.

UKRI Gateway to Research · FY 2025 · 2025-01

Amyotrophic lateral sclerosis (ALS) is caused by a combination of genetic and environmental factors. Many advances have been made in identifying genetic changes involved in the development of the disease. However, there is still much to be understood about the changes in our DNA that increase the risk of developing ALS as there is still no identified causative DNA risk which has been identified in the majority of ALS. An overlooked source of genetic change in the human genome is the presence, absence or expansion of large DNA sequences called Structural Variants, despite one of these in the C9orf72 gene being the most common cause of ALS responsible for ~6% of all cases in European populations. One type of Structural variants is called human endogenous retroviruses. These sequences integrated in our genomes up to millions of years ago as a result of ancient infections and currently comprise ~8% of our genome, whereas proteins comprise only 1%. Recent studies demonstrated that the expression of these elements, expression is toxic to cultured motor neurones, and causes a motor neurone disease in mice supporting their potential key role in the development of ALS. However, many questions remain, for example, it is not clear if these effects are the consequence of a specific type, a group of them, or even if they occur in ALS patients. Moreover, the study of Structural variants and endogenous retroviruses is complicated and requires sophisticated bioinformatics and new sequencing technologies are able to characterise them with unprecedented accuracy and resolution. In the recent years our laboratory has developed computational tools and laboratory protocols to study them and our preliminary results show that some the genome of some patients carry genetic variation compatible with their presence. However, the analysis of larger groups of people with and without ALS and a deeper investigation on their biological effects on other genes are required to prove their effective role on the development of ALS and clarify potential new avenues of treatment. This proposal will enable us to expand our analysis to the wider Project MinE dataset which currently has over 8000 patient and 1400 control DNAs available. We will capitalise on data already generated through Project MinE to allow us to identify definitively if these elements are correlated with or are playing a role in development of ALS. We will also use a new technology, called long-read sequencing, to characterise their sequences with high resolution and accuracy and to understand what is their effect on the expression of other genes. This will help us to understand wether they are a cause of the disease and how to design experiments that can help us understand how to trat them. This is a novel study that will complement traditional genomic analyses to address an important gap in our understanding of the genetic basis of ALS. Expanding the knowledge of the genetic causes of ALS will help in the understanding of the processes occurring in the disease and to develop targeted therapies which otherwise would remain elusive.

UKRI Gateway to Research · FY 2025 · 2025-01

Human Immunodeficiency Virus type 1 (HIV-1), the causative agent of the AIDS pandemic, encodes two accessory proteins (Vpr and Vpu) that potently suppress proinflammatory signalling via the NFkB family of transcription factors during the early and late phases of viral replication in CD4+ T cells and macrophages. This appears, at least in part, to be a mechanism to inhibit the induction of innate immune to viral replication at vulnerable stages of the lifecycle. Despite this, the integrated HIV-1 provirus is an NFkB-regulated gene which requires NFkB to be activated to initiate viral gene expression. Our recent publications on Vpu and unpublished work on Vpr from clinical isolates shows that the potency of NFkB suppression by these proteins has been underestimated. Both exert their functions through markedly different mechanisms that are incompletely understood at the molecular and cellular level. We have shown that Vpu promotes the degradation of the bTrCP1 adaptor of the SCF ubiquitin ligase, leading to a potent block of both classical and alternative NFkB pathways. But how this specificity is achieved is unclear. By contrast Vpr appears to block nuclear transit of inflammatory transcription factors by association with the nuclear pore and karyopherins. However, the requirement for its cognate ubiquitin ligase Cullin4DCAF1 implies Vpr targets an unknown factor to exert this activity. Since Vpr is a constituent of the incoming viral particle and Vpu is expressed 'late', these data imply that HIV-1 dynamically regulates NFkB across its replication cycle to balance innate immune evasion and viral production. A key barrier to curing individuals of HIV-1 is the presence of a pool of infected CD4+T cells harbouring transcriptionally silent integrated proviruses - the so-called latent reservoir. While individuals living with HIV-1 are take combined antiretroviral therapy (cART) this latent reservoir is of little consequence. However, upon therapy withdrawal re-activation of some of these reservoir cells leads to rapid re-emergence of the virus. Therefore, aside from a handful of cases where HIV+ blood cancer patients were transplanted with bone marrow stem cells genetically resistant to infection, people living with HIV cannot be cured and must take cART for the rest of their lives. Thus, purging or silencing of this reservoir is viewed as the key goal of HIV-1 cure research, and ultimately this is dependent on the level of NFkB activation in individual latently infected cells. However, a key gap in knowledge is what viral and cellular factors promote the establishment of latent proviruses in the first place and whether these activities limit the success and sustainability of latency-reversing agents (LRAs) currently being developed to facilitate reservoir reduction - so called 'shock and kill' strategies. It is our hypothesis that dynamic manipulation of NFkB in HIV-1-infected primary cells by Vpr and Vpu tips the balance to promote the establishment of a latent provirus. Furthermore, their potency at inhibiting NFkB may limit the sustained gene expression required for sufficient reservoir purging by LRAs/cure strategies activating these pathways. We therefore seek MRC programmatic support for interlinked basic and translational studies to understand: 1. The consequences of dynamic regulation of NFkB for both viral and host gene expression across the viral replication cycle 2. The molecular mechanisms underlying the suppression of NFkB by HIV-1 accessory proteins 3. How accessory protein function affects the establishment, maintenance, and sustainable reversion of HIV-1 latency.

UKRI Gateway to Research · FY 2025 · 2025-01

Amyotrophic lateral sclerosis (ALS) is a complex disease which differs between individuals in terms of 1) symptoms and progression over time, and 2) biological causes. Although there are features common to all ALS patients in the latter stages of disease, it is thought that in the pre- symptomatic and early stages of ALS, these can vary greatly based on the individual's underlying biology. Therefore, grouping patients into subgroups with similar biological characteristics, can increase our chances of finding genes and processes which could be used as personalised indicators of ALS progression. Our previous work demonstrated that we could group patients into three molecular subtypes, based on brain specific gene expression signatures which were identified using machine learning. These subtypes are ALS-specific, can differentiate patients from non-affected individuals with high accuracy and are also present in independent ALS datasets from different populations. This means that they show potential as indicators of ALS diagnosis and progression. In this project we will validate this method on a large-scale dataset as a diagnostic and stratification tool based on blood sample analysis that can be used by all people with ALS.

UKRI Gateway to Research · FY 2025 · 2025-01

In the realm of quantum information technology (QIT), scalable qubit platforms with long coherence times and high-fidelity gates are essential for achieving quantum computational power. The project 'QUIQ' aims to explore the potential of double quantum dot (DQD) qubits controlled at attosecond timescales by combining QD quantum information process modeling expertise with the attosecond physics expertise of the attosecond quantum physics group at King's College London (KCL). By operating DQD qubits at attosecond timescales, we can significantly reduce processing time and enhance performance in ultrafast QIT. The project focuses on studying the coherence of DQD qubits through the implementation of Rabi oscillations triggered by ultrafast laser fields. We aim to realize atto-qgates, representing the first attosecond quantum gates. The achievement of basic atto-qgates, including Pauli X, Y, Z, and Hadamard gates, will provide a crucial stepping stone towards future attosecond quantum operations on DQD qubits. Furthermore, we will investigate quantum circuit design and develop quantum error correction techniques to minimize errors in the DQD qubit platform. The project combines theoretical investigations with the experimental capabilities of the KCL host group to optimize system parameters, improve coherence times, and enhance control over the proposed DQD qubit platform. Additionally, we will investigate quantum resources, such as entanglement and discord-like correlations, in bipartite DQD qubits. By proposing the use of the quantum path interferometric technique based on High Harmonic Generation (HHG) for atto-qgate readout, this project bridges the fields of attosecond physics and quantum technology, enabling significant advancements in attosecond quantum information processing.