IMPERIAL COLLEGE LONDON

UKRI Gateway to Research · FY 2024 · 2024-09

Poor sleep and anxiety affect many people worldwide. One hypothesis is that good sleep reduces the impact of stress, and that poor sleep may itself trigger serious depression. Rapid Eye Movement (REM) sleep may be particularly important in promoting emotional resilience and guarding against depression. We have discovered new circuitry in the hypothalamus and basal ganglia that contributes to generating REM sleep, and this circuitry overlaps with circuitry that regulates stress, depression and motor movements. Can this circuitry be exploited to learn about the function of REM sleep, and ultimately improve mental health by lowering stress and anxiety levels? Three of the brain regions we have found to regulate sleep-wake states (the lateral habenula, the entopeduncular nucleus, and the subthalamic nucleus) are already used clinically to treat Parkinson's disease via deep brain stimulation, to alleviate major depression or motor symptoms. Some patients report that deep brain stimulation at the three sites we mention above also improves their sleep. On the other hand, deep-brain stimulation in these regions can also trigger depression/anxiety. Therefore, we plan to understand more about the parallel wiring in this complex system, and isolate the specific sleep-inducing components. It may be possible, for example, to selectively enhance REM sleep. Currently our work is at a "blue skies" phase. But understanding more about how sleep could boost emotional resilience and feelings of well-being could ultimately improve human health, both in patients living with severe depression and posttraumatic stress disorder and those living with neurodegenerative disease.

UKRI Gateway to Research · FY 2024 · 2024-09

One of the most pressing challenges for healthcare is that many patients do not respond to treatment, which produces physical, social, and economic suffering. Moreover, variable treatment response contributes to the cost of drug development. A major driver of these inefficiencies is the cellular heterogeneity existing within and between patients in complex diseases such as cancer. Altered behaviours can involve only a few cells, but to-date such changes are often profiled at the population level, which masks functionally and clinically relevant intercellular variations. Modern single-cell technologies allow the tracking growth and intracellular concentrations in hundreds of cells simultaneously. The outcomes of these experiments are difficult to interpret because they vary drastically from cell to cell, even within genetically identical cell populations grown under the same conditions. Predictive models are needed to make sense of these experiments and to understand how cells exploit this heterogeneity, for instance, to survive drug treatment. It will be crucial to address this question with the wealth of single-cell data becoming available to tackle problems of drug tolerance and diseases, as well as to improve therapies for the health sector. Current mathematical approaches quantify the stochasticity inherent in reactions by which molecules are synthesised in the cell, but they cannot predict how these heterogeneous affect cell growth, division, and death. To understand this effect, I will develop new mathematics and models that enable us to understand the complex interplay between cell growth and the reactions in single cells. These models treat cells as individuals and allow tracking the state of every cell and their histories in a growing cell population. They thus provide a quantitative understanding of biological data at the experimental single-cell resolution. Using these mathematical methods, the project will uncover the causes and consequences of heterogeneity in bacterial and cancer cell populations, which has important implications in a range of biotechnological and medical applications. Using a combination of theory and experiment, we will explain how cellular heterogeneity affects essential cellular functions such as cell division, growth and the cell cycle that ultimately drive proliferation and cell survival. In particular, we will investigate cell division and cell cycle kinetics to explore how heterogeneity allows bacteria to cope with stress and cancer cells to evade chemotherapeutic treatment. The project thus presents a transformative and quantitative single-cell perspective on the role of cellular heterogeneity in cell proliferation and its implications for disease.

UKRI Gateway to Research · FY 2024 · 2024-09

Chronic Obstructive Pulmonary Disease (COPD) is the 3rd cause of mortality worldwide, causing 3.23 million deaths in 2019. Acute exacerbations of COPD (AECOPD) are the major cause of COPD morbidity, mortality and healthcare costs. Developing novel targeted treatments for AECOPD requires a better understanding of AECOPD mechanisms. Respiratory virus (mostly rhinovirus [RV]) infections are the major cause of AECOPD. Studying disease mechanisms in naturally-occurring AECOPD is difficult because of variability in: time from AECOPD onset to clinical sampling; causative agent; therapeutic background and interventional treatment and repeated lower airway sampling during naturally occurring AECOPD is impractical/potentially dangerous. We therefore developed experimental RV challenge in COPD as an experimental model of AECOPD (the model is unique worldwide), in which the above factors are standardised, and repeated lower airway sampling is safely and easily performed. Previous studies in this model demonstrated that RV infection induced prolonged (~5 weeks to full recovery) AECOPD in 95% of successfully infected subjects. Further, 60% of RV-induced exacerbations were followed by secondary bacterial infections, with more severe RV infection increasing risk and severity of secondary bacterial infection. Thus, strategies that reduce severity of virus infection in COPD, are likely to reduce secondary bacterial infections, thereby enhancing antibiotic stewardship. These COPD subjects had increased susceptibility to RV infections due to deficient interferon-responses and RV-infection in COPD, but not control subjects, provoked bronchial neutrophilia, but surprisingly also marked bronchial eosinophilia in 16/17 COPD subjects, which correlated with adverse clinical outcomes.

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

Cerebral small vessel disease is the most common cause of neurological disability, seen on MRI scans as damage to the deep regions of the brain in over half of people by 65 years old. It causes 30% of strokes, falls, frailty, late-onset depression and up to 40% of dementia. However, it has no treatment due to limited understanding of the underlying mechanisms of the disease. Small vessel disease is strongly related to long-standing high blood pressure and to its effects on the body, including stiffer blood vessels and an increased variation in blood pressure during and between each heart beat. It is also related to reduced responsiveness of blood vessels in the brain, limiting their ability to compensate for blood pressure changes. Finally, genetic studies support the role of blood pressure but also identified genes responsible for the integrity of the tissue of the brain. As such, some patients may have more severe disease because their brains are more vulnerable to being damaged. We propose that small vessel disease is due to a balance between increased transmission of variable blood pressure to the brain, a reduced ability of the brain to compensate for this and an increased vulnerability of the brain to being damaged. However, no study has measured all these elements together in a large enough population to test this, and thus to identify and test potential treatments. This project will combine our groups' expertise to measure all aspects of this mechanism in UK Biobank. This study includes brain scans in more than 100,000 people, detailed medical history and lifestyle information and genetic testing. However, it has lacked measurement of changes in blood flow to the brain and its ability to compensate. By adapting the brain scans in UK Biobank, we have developed novel measures of variation in blood flow to the brain with each heart beat and the ability of the lining of the blood vessels in the brain to control blood flow, measured by spontaneous fluctuations in blood flow and blood flow responses whilst performing a visual task. The first part of this project will improve these measurements of control of blood flow to the brain. It will improve how specific they are to blood flow control rather than changes in cognitive function, focus on specific brain regions and will add direct tests of how fluctuations within blood vessels are transmitted to blood flow within the brain. Secondly, we will work with our collaborators to refine genetic measures of tissue vulnerability, including both single genes associated with vulnerability of the brain to injury and combined scores reflecting many genes to produce an overall estimate of an individual's vulnerability to injury, independently of genes affecting blood pressure. We will combine these new, unique measures with extensive medical history and lifestyle data, imaging measures of injury to the brain and resulting effects on cognitive function, risk of stroke and risk of dementia. This will allow us to screen >1000 risk factors for their effects on control of blood flow to the brain, and compare them with the same relationships with damage to the brain, stroke and dementia. We will use advanced statistics to test our proposed mechanism in a single mathematical model of this pathway. This will assess whether real data is more consistent with the hypothesised mechanism causing the disease, compared to alternative theories. Finally, we will use this model to identify new factors that affect this mechanism, particularly whether medications commonly used for other illnesses may improve the pathway, thus identifying potential new treatments to be tested in future studies. Overall, we will be able to test our hypothesised mechanism of small vessel disease within a single large population, improving our understanding of the cause of the disease, identifying new potential treatments and assessing their potential for testing in clinical trials.

UKRI Gateway to Research · FY 2024 · 2024-09

Offshore wind farms (OWFs) have become an important way of renewable energy utilization due to the advantages of rich resources, high utilization hours of power generation, and land saving. The produced power is often transmitted to the onshore power system by modular multi-level converter (MMC)-high voltage DC (HVDC) technologies. Therefore, both sides of the AC tie line between OWF and MMC are interfaced through power electronic devices having high controllability. OWFs often adopt the grid-following controller, and it has two control structures: decoupled current control (DCC) and decoupled sequence control (DSC). They are required to ride through a fault in modern power systems, so some innovative fault ride-through (FRT) strategies must be used so that the fault behaviors of OWFs are significantly different from synchronous generators (SGs). In addition, the MMC has two typical control modes: voltage-frequency (VF) control and grid-forming control. The control objective of the MMC is to provide a voltage and frequency reference for the OWF-MMC system. When the traditional VF control is used, the MMC does not have the current limiting function, so the MMC is easily blocked within an extra short time due to overcurrent if a fault occurs. To limit the fault current and control the system voltage, the grid-forming controller has been developed and become a research hotspot. However, the research on fault characteristics of the OWF-MMC system and their impact on protection performance is still in its infancy. Some incidents have happened outside and within the European Union (EU) since the protection scheme is not configured well. In the UK, the world's largest operating offshore wind farm-Hornsea was disconnected from the onshore grid in 2019 due to the wrong operation of the protection system. During this accident, the system frequency declined below 49 Hz and almost one million people across England and Wales experienced blackouts. Some blackouts and equipment damage have also been reported in the Germany Bard1 project partly due to improper protection and control configurations. Therefore, protection technologies for the OWF-MMC system are extremely important to maintain power supply reliability, device safety, and grid stability.

UKRI Gateway to Research · FY 2024 · 2024-09

FITNESS is a Doctoral Network at the intersection of electric power distribution networks optimization, electricity markets, communications, and control systems. The project will develop new methodologies for active distribution networks services in the era of smart grids. FITNESS is the first training network dedicated to this challenge and involves 4 Beneficiaries and 6 Associated Partners from 7 EU countries, guaranteeing a pan-European approach in a multi*sectoral context (universities, research centres, and SMEs). FITNESS will train a new generation of scientific professionals who can transition between disciplines and between the public and private sectors based on (i) Recruited Researcher (RR) projects; (ii) courses and workshops, with the emphasis on hands-on, collaborative learning and attention to transferable skills; (iii) mobility, knowledge transfer, all within a training network that includes some of Europe's finest researchers.

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

Improving Heart Rhythm Treatment: Innovative Catheter Technology for Better Outcomes Heart rhythm problems in the upper chambers of the heart, called the atria, can make the heart less efficient.  Atrial fibrillation (AF) is the most common rhythm problem, affecting 1 out of 5 people in their lifetime. It is responsible for more than 20% of all strokes, as well as causing reduced life expectancy and reduced quality of life. Despite its global importance and healthcare costs (estimates vary from $6 billion - $26 billion in the US alone), the mechanisms of AF remain poorly understood. We cannot reliably find the ‘circuits’ and ‘drivers’ that cause this arrhythmia to persist. This hampers our ability to treat the condition and to research new pharmacological and interventional treatments. (1) A treatment called ablation therapy can help. It involves using special wires called catheters, which are put into a vein and guided to the heart. Some catheters help doctors understand how the heart's electrical signals work. Other ‘ablation catheters’ are used to create small scars in specific areas of the heart to fix the problem. Sometimes, it's hard for doctors to find exactly where the problem is in the heart. This makes treatment less effective and less personalized. This procedure has success rates in the region of 50%. Our team is making progress by developing new ways to analyse the heart's signals and creating a new system for recording them. However, to make a bigger difference, we're also designing a new catheter that can put 50 tiny electrical sensors on the heart's surface all at once. Our new catheter uses advanced technology to include wires inside a tube that also carries the ablation catheter (2-4). This makes the procedure simpler and safer because it allows doctors to both diagnose the problem and treat it through one access point. We've made prototype parts for the catheter and plan to develop it further into a working device. We'll then undertake testing to make sure it's safe for use in people. Eventually, we'll combine the catheter with the electronics, signal processing, and visualization techniques we've developed (5-7). This will help guide doctors to the right area in the heart for treatment and improve outcomes for people with atrial fibrillation (8). This innovative approach to AF treatment represents a significant leap forward in cardiac care. By integrating diagnostic and therapeutic capabilities into a single catheter, we aim to enhance the precision of ablation therapy, increasing its success rate beyond the current 50%. The ability to place 50 sensors directly on the heart's surface offers an unprecedented level of detail to map the heart's electrical activity. This is crucial for identifying the arrhythmia's specific origins, which have remained elusive with current technologies. The catheter will be combined with electronics and signal processing methods that we have already developed. This will not only enable more carefully targeted ablation treatment but will also provide a platform for international research.

UKRI Gateway to Research · FY 2024 · 2024-09

All cells have intrinsic immune defences against viruses: to survive in a given species, viruses must evolve matched counter-measures. To block DNA viruses that reproduce in the nucleus, cells require: A sensing strategy that can differentiate between invading viral genomic DNA, and cell DNA. An output of this sensing that can prevent the viral DNA from executing its functions. Our understanding of how cells distinguish host and viral DNA in the nucleus is sketchy: we know some proteins that help repress viral gene expression, and some that induce production of antiviral signalling molecules (particularly interferon). However, none of these proteins have a defined mechanism for distinguishing between foreign and cellular DNA. The "Speckled protein" Sp100 is part of a nuclear protein complex (ND10) known to repress DNA viruses. Sp100 has a short isoform (Sp100A) and several longer isoforms. The longer isoforms have a DNA-binding SAND domain, and can inhibit diverse DNA viruses. The Sp100 SAND domain binds unmethylated DNA, but not the methylated DNA that makes up most of the cell's genome. Sp100 also accumulates at sites of DNA damage, but is not required for DNA repair. Most or all herpesviruses have protein(s) that act against Sp100: Herpes simplex virus (HSV1) protein ICP0 degrades Sp100 alongside the other ND10 components; herpesvirus saimiri (HVS - a squirrel monkey virus) uses ORF3 to degrade Sp100 but not ND10; Epstein-Barr virus (EBV) uses EBNA-LP to bind Sp100 and disrupt its function. Corresponding mutant viruses lacking these countermeasures exhibit reduced viral gene expression upon infection. By knocking out cell genes in combination, we have discovered that: Another speckled protein - Sp140L, found only in primates - also represses these viruses; Repression by Sp100 does not need functions downstream of the SAND domain; Sp100A expression can rescue mutant viruses; EBNA-LP inhibiting long speckled protein isoforms prolongs survival of proliferating naïve B cells. demonstrating both overlapping and opposed functions of different Sp100 isoforms and homologues. We propose to determine fundamental properties of speckled proteins, using EBV, HVS and HSV1 infection to define their roles during DNA virus infection, with the following aims: Identify which parts of which speckled proteins help inhibit virus genes or interferon production, and identify which other antiviral proteins work with Sp100/140L functions. Determine the binding specificity of the SAND domains of the four speckled protein isoforms, to see which might distinguish viral DNA from cellular DNA in the nucleus. Establish whether Sp100 long isoforms and Sp140L associate with infecting herpesvirus genomes. We will produce antibodies against Sp140L and Sp100 long isoforms to help us (and others) study these proteins. Use the sequence variation primate EBNA-LPs and corresponding speckled proteins to provide insights into how speckled proteins function. This study will be the first to assess speckled proteins as a family. Understanding whether and how speckled proteins sense and respond to viral (and other abnormal) DNA has broad implications for DNA virus biology, immunology and gene therapy, as well as repair of damaged DNA - relevant for cancer development particularly in high radiation environments from the beach to outer space. Additionally, a novel potential role in limiting naïve B cell lifespans has implications for EBV-associated lymphomas, vaccinology and autoimmunity, including primary biliary cholangitis (which often exhibits auto-antibodies against speckled proteins) and the involvement of EBV in multiple sclerosis and other autoimmune diseases.

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

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

UKRI Gateway to Research · FY 2024 · 2024-09

Improving solar fuel generating technologies and industrial catalysts are two essential aspects of tackling the ever-increasing issue of climate change. Electron bifurcating enzymes are systems which provide a blueprint to tackle both of these areas. SPECIMEN sets out to elucidate the catalytic mechanisms and electron transfer pathways in the electron bifurcating [FeFe]-hydrogenase HydABC from Thermatoga maritima (Tm) via a combination of advanced CW/pulsed electron paramagnetic resonance (EPR) spectroscopies paired with state-of-the-art spectro-electrochemistry (SEC) and biochemical techniques. These advanced physical characterisation techniques, tightly coupled with biochemical methods for manipulating and tailoring samples, provide the most advanced toolkit for identifying and interrogating enzymatic electron transfer pathways, and the key structural/chemical factors that govern their involvement in electron bifurcation. The 44 FeS clusters and four flavin mononucleotide (FMN) sites of HydABC will be exploited to understand the electron bifurcating mechanism in the enzyme. Firstly, the role of FMN in electron bifurcation will be determined by hyperfine spectroscopy (ESEEM, HYSCORE, ENDOR, EDNMR and THYCOS), which will distinguish between the type of FMN radical produced (neutral vs. anionic), elucidating the mechanism. Next, these hyperfine techniques will be employed to investigate how the radical intermediate is stabilised by interactions with amino acid residues of the protein sequence, and the role of conformational changes in this process. Finally, pulsed dipolar EPR spectroscopy will be used to determine how these protein conformational changes operate within the electron bifurcating mechanism, with particular emphasis on the formation of electron transfer pathways, elucidating the synergy between changes in the electronic structure of FMN and the conformation of the protein to achieve bifurcation.

UKRI Gateway to Research · FY 2024 · 2024-09

Our vision is to replace need for animal testing in bone research with lab-based bioreactor analyses of human tissue. The immediate benefit will be replaced animal burden for bone research and orthopaedic intervention development at technology readiness levels 1-4. The method will also lead to better interventions as treatments are optimised with human bone, sourced from patients with relevant demographics and disease history. Advancing interventions to promote favourable bone remodelling is important for the 200,000 people who require joint replacement, or the 70,000 that fracture their hip each year in the UK, with similar numbers affected worldwide. The research is timely: animal burden is growing as the field transitions from passive implants tested in cadavers, to orthobiologics, tissue engineered implants, drugs and active stimulation technologies that influences living tissue pathways. An appropriate preclinical test method is needed to facilitate the development and translation of these technologies to deliver improvements in patient care and socioeconomic benefit. The core idea that underpins the proposal is that tissue can stay viable for 1-24 hrs after being removed from the body; something that is widely accepted in the field of transplants. With bioreactor technology, we will keep the bone viable for weeks, allowing for novel interventions to be tested against viable human bone, in the lab. This research will investigate the sensitivity of bone bioreactors to tissue preparation methods and bioreactor settings to comprehensively characterise best practice for the novel approach. Then, we will conduct a direct validation against previous in vivo data, to quantify the extent to which the method can replace live animal testing. Finally, with the method validated, to build the 3Rs case for adoption, we will analyse the effect of species (animal vs human) on bone remodelling around implants. This would demonstrate the scientific benefits that could be gained from replacing animal testing with an alternative that is more relevant to humans.

UKRI Gateway to Research · FY 2024 · 2024-09

A novel and promising approach to understand the evolution of animal communication and human language is to identify the semantic content of animal calls. However, many significant aspects of animal linguistic theories and methods remain unexplored in ecology. SPANTICS aims to elucidate the semantics of avian communication through spearheading experimental research on the closed and monitored population of house sparrows in Lundy Island, UK. SPANTICS is a comprehensive and thorough project that will determine the core meaning of alarm calls, the units that carry the information, and the ecological factors that shape call production. The core meaning of elements will be determined using a series of controlled stimulus presentations that will notably distinguish riskbased semantics from category-based semantics. To identify the vocal units carrying information, sparrow vocal production will be analysed by focusing on spectral and temporal features. This will enable me to test a recent and untested coding theory which proposes that combinations of acoustic features can convey semantic content in a way comparable to combinations of notes (i.e., Featural Compositionality). Finally, I will examine the potential impact of social factors by determining if sexual selection and/or kin selection have an effect on birds' semantic production. To ensure thorough analysis and interpretation of results and provide valuable knowledge for future ecological projects, I will quantify for the first time the sparrows' repertoire and potential individual signatures in their calls. SPANTICS is truly multidisciplinary, combining linguistics and ecology to produce robust and replicable results. SPANTICS will improve the scarce knowledge of avian semantics and enable comparative linguistic research across clades.

UKRI Gateway to Research · FY 2024 · 2024-09

On a daily basis, our lungs are exposed to an array of environmental insults including viruses, bacteria and toxic particles. Specialised 'epithelial' cells run from our nose all the way down to the depths of our lungs, forming a barrier to the external environment and protecting us from these insults. However, these epithelial cells are frequently and sometimes severely damaged by these exposures. It is critical that after injury, the epithelial cells are quickly repaired to restore this barrier. If epithelial cells are not efficiently repaired then we are more prone to infection, and our ability to breathe is compromised. The lungs are able to repair themselves when damaged but this ability deteriorates as we get older and in some people the repair process doesn't work properly, leading to disease. Currently, there are no treatments able to restore damaged lung tissue, and this is clearly an urgent clinical need. A greater understanding of how the lungs repair themselves is required to promote long term lung health and to identify new treatments that can promote lung repair. The extracellular matrix (ECM) is a three-dimensional meshwork of proteins and other factors that supports the structure of the lungs and acts as a scaffold for cells that populate the lungs. We are interested in a small fragment of this ECM called Pro-Gly-Pro (PGP), which is normally hidden but becomes released from the ECM in response to infection or injury. We have exciting data that demonstrates that PGP is potent at promoting repair responses in lung epithelial cells. Furthermore, PGP can also operate to drive the influx of cells called neutrophils into the lungs. Neutrophils are essentially the soldiers of our immune system that can kill any invading organisms that have entered the lung as a result of injury. Therefore, we believe that PGP is a fragment of the lung tissue that is released in response to injury and then subsequently acts to direct localised epithelial repair to seal the breach to the external environment, whilst simultaneously causing the influx of neutrophils to sterilise the lung tissue. We also believe that pathways governing the levels of PGP may be disrupted in disease settings. Consequently, understanding how PGP promotes repair responses could yield novel treatments to counteract lung injury. Because the ECM is a critical component of all tissues, our data is highly likely to also be relevant for repair of other organs in the body. In this proposal, we want to understand more about how PGP drives repair in epithelial cells and ascertain the relative importance of PGP as a mediator of repair following lung injury. We will use epithelial cells isolated from the lungs of healthy individuals to probe how exactly PGP is able to drive repair responses, thus revealing potential strategies for therapeutic intervention. Subsequently, we will induce micro-injuries in slices of human and mouse lung tissue that are essentially 'mini lungs' and assess how manipulation of PGP in this more complex 3D setting modulates subsequent repair responses. The use of human lung cells and tissue is critical if we are to understand the importance of PGP to human lung injury and repair. However, to truly demonstrate the capacity of PGP to instigate lung repair and minimize pathology over a prolonged period of time, it is also necessary to assess the role of PGP in a mouse model of lung epithelial cell injury. We will determine the importance of naturally generated PGP in supporting epithelial repair and also ascertain to what extent supplementation of PGP can enhance repair. The results of this proposal could lead in future to new treatments that can promote lung repair via modulation of PGP.

UKRI Gateway to Research · FY 2024 · 2024-09

Despite many promises that connected automated vehicles (CAVs) would be imminent on our roads, it is widely recognized that the control algorithms supporting such technology are not mature. Indeed, control algorithms in CAVs only operate in linear regimes, being fragile to nonlinear operation like cooperative steering; tests show that CAVs are unable to interact safely on the road with human-driven vehicles, e.g., to form mixed platoons. The CO-ADAPT project aims to develop a comprehensive theory of co-adaptation for CAVs, by leveraging control concepts of "nonlinear, robust, non-stationary adaptive control". CO-ADAPT will design nonlinear functionalities beyond mere linear regime; to achieve robust operation, control algorithms will be embedded with the capability to adapt inside non-nominal boundaries. To promote co-adaptation on the road with human-driven vehicle, CO-ADAPT will design provably stable control algorithms that continuously adapt to the non-stationary behaviour of human drivers. The adaptive control tools developed within CO-ADAPT will prove technical robustness and enhanced autonomy of CAVs in nonnominal traffic with nonstationary human-driving behavior. To target prompt technology transfer, CO-ADAPT will create an open source platform where the theory and adaptive control algorithms are verified through open-source autopilots and traffic simulators, via use cases like platoon merging and splitting, cooperative avoidance/lane change, mixed traffic with human-driven and automated vehicles. CO-ADAPT will be carried out at Imperial College London under the supervision of Prof. Astolfi, a world-leading expert in nonlinear and robust adaptive control, nonholonomic mechanics, adaptive time-varying control. The project will involve a two-way knowledge transfer between the expertise of Prof. Astolfi and the expertise of the applicant in CAVs, cooperative adaptive cruise control, mixed traffic and autopilots.

UKRI Gateway to Research · FY 2024 · 2024-08

Calcium carbonate (CaCO3) scaling of pipeline and flow systems is a long-standing and intractable problem, affecting many critical industries. Current descaling approaches involve labour-intensive manual scraping of scales, or the use of specialized chemicals to dissolve the scales or to stop them from forming. Unfortunately, these approaches incur cost and time, are not universally applicable to all kinds of flow configurations and have otherwise raised environmental concerns as well. ENSSLED builds instead on an alternative approach of using nanoparticles that can nucleate scales on themselves, rather than on the pipe walls. These sacrificial nucleants (SN) after scaling can be removed from the flow stream. But in practice, they often stick to the pipe walls due to their random and disordered shapes (rhombohedral crystals or RC) attained during scaling. Conversely, ENSSLED proposes to investigate the use of spherically shaped SN, synthesized from a bio-based environmentally friendly material called chitosan. Owing to its aminerich surface property, chitosan can induce film-wise mineral growth (by a biomimetic process called biomineralization). ENSSLED applies these principles to control scaling around the SN in the form of films rather than disordered RC. By retaining the spherical shape of the SN during scaling, the adhesion of the SN with that of the pipe walls could be minimized, thereby deterring scale formation on the pipe walls and enabling complete recovery of the SN afterwards. This distinctive biomimetic strategy could offer an industrially acceptable and sustainable approach toward passive descaling. ENSSLED plans to achieve these goals through a multidisciplinary approach involving SN synthesis, chitosan (biopolymer) processing, scaling analysis, and contact mechanics-based adhesion measurements (between SN and the pipe walls).

UKRI Gateway to Research · FY 2024 · 2024-08

Forces are ubiquitous in biology; they allow organisms to survive under extreme conditions, are involved in giving shape to early embryos or control cellular organization; and they can also drive pathological processes including cancer, malaria or atherosclerosis. Therefore, there has been a long-standing interest in understanding and replicating the mechanisms by which cells react to these physical cues. Fundamental knowledge of how cells respond to mechanical stimuli promises to open new ways of understanding, diagnosing, and treating diseases and, in addition, could significantly impact the engineering and development of artificial cells. Synthetic or artificial cells are man-made constructs designed to mimic, or extend, the capabilities of biological cells. By combining biological building blocks - such as lipids, proteins, or nucleic acids - artificial cells have been designed to replicate biological processes including energy transduction, motility, decision making, or communication; and have found applications in biomedical therapies, or energy production. Overall, synthetic biology - including artificial cells - is believed to be instrumental in the fifth industrial revolution, where biotechnology is expected to play a pivotal role. However, development of fully biomimetic synthetic cells has not yet been achieved. In this Fellowship, I aim to address one of the challenges in engineering artificial cells: How to make them sense, and react, to external forces; similar to their biological counterparts. While cellular membranes are highly dynamic, the membranes of artificial cells mostly resemble a passive chassis which displays a limited response to extracellular forces. In this work, I will combine DNA nanotechnology, membrane engineering, environmentally sensitive membrane dyes, advanced microscopy, and simulations to develop a molecular toolkit capable of sensing the forces acting on biological membranes and reacting to this stress by altering the membrane's biophysical behaviour. In this Fellowship, I will: 1) Investigate how lipid-lipid and protein-lipid interactions occurring within membranes are affected by mechanical forces. 2) Implement a circuit capable of releasing a chemical signal in response to an applied force onto the membrane. 3) Develop a synthetic scaffold supporting the artificial cell membrane, capable of modulating its biophysical behaviour. 4) Integrate the above systems to provide artificial cells with the ability of sensing and reacting to changes in extracellular mechanical cues, replicating the capabilities of their biological counterparts. This Fellowship is set to advance our ability to monitor and manipulate molecular interactions within cellular and artificial membranes. Altogether, this will lead to a better understanding of fundamental biological processes involving membrane deformation, including viral infection or cell migration. Given that membranes and membrane proteins account for >50% of current druggable targets, this research could be a game-changer in the drug discovery market. Furthermore, the proposed technology could lead to the production of advanced drug delivery vehicles that respond to mechanical cues, such as the increased stress in atherosclerotic regions. Additionally, by controlling the biophysical behaviour of lipid membranes, we could engineer rugged synthetic cells that are more durable and better suited for scaled-up industrial applications, such as vaccine delivery vehicles.

UKRI Gateway to Research · FY 2024 · 2024-08

Vaccination is crucial to control of bacterial meningitis because of its devastating 15% mortality rate despite antibiotic intervention, and the development of significant neurological sequelae (deafness, limb amputations, learning disability) in up to 50% of survivors. Currently available vaccines are limited by coverage; the changing genetic epidemiology of the two main aetiological agents of bacterial meningitis, Neisseria meningitidis and Streptococcus pneumoniae, therefore mandates continuous vaccine development efforts. Application of the Reverse Vaccinology 2.0 (RV 2.0) strategy to meningococcal and pneumococcal vaccine antigen discovery in our lab led to the successful identification of highly conserved membrane proteins of novel vaccine candidacy. Other collaborative efforts led to successful glycosylation of a meningococcal surface protein with the pneumococcal serotype 4 glycan using in vivo glycoengineering, thereby providing a platform for cheap production of our novel and exciting vaccine antigens as glycoconjugates. Following from highly promising preliminary work, this research program aims to produce next-generation, low-cost prototype vaccines that will engender further significant decline in the incidence of bacterial meningitis, globally, by: (1) utilising intelligent structural biology tools in the rational design of our exciting targets as hybrid, multi-epitope antigens for enhanced potency of the vaccine-induced immunity; (2) glycosylate these hybrid antigens with the pneumococcal glycan via protein-glycan coupling technology (PGCT), since glycoconjugation offers longer-term protection from disease and asymptomatic infection; and (3) harness the power of synthetic cell (SynCell) engineering for the in vivo production and delivery of these glycoconjugate vaccines into human systemic circulation. The success of this programme would not only result in the successful production of a prototype synthetic cell vaccine (one of the firsts of its kind in the entire field of infectious diseases) to be progressed through follow-on human clinical trial studies, but also a step change in our capability for combating bacterial diseases, in a broader sense.

UKRI Gateway to Research · FY 2024 · 2024-08

My proposal will explore non-perturbative aspects of conformal field theories (CFTs) with applications to both high energy and condensed matter systems. In condensed matter, CFTs describe quantum materials that are the target of current and future experiments. In high energy, CFTs provide the only known non-perturbative description of quantum gravity via the famous AdS/CFT duality. These CFTs are often strongly coupled, however, so they cannot be studied using standard perturbative tools such as Feynman diagrams. My plan is to combine cutting edge non-perturbative methods such as the conformal bootstrap, supersymmetric localization, and harmonic analysis to answer long standing questions in strongly coupled physics. This proposal is divided into two related strands: Strand I. Non-perturbatively study quantum gravity via the dual CFT. For string and M-theory, the goals are to compute graviton scattering to all orders in the Planck length expansion, and study black hole states that appear in this scattering. For the simpler case of higher spin gravity, the goals are to extend my recent derivation of AdS/CFT, which applies to negative spacetime curvature, to the cosmologically relevant case of positive spacetime curvature, and to connect to string/M-theory AdS/CFT. The outputs of this strand will realize the dream of the holographic principle by computing exact physical observables in quantum gravity. Strand II. Study quantum chromodynamics in 2+1 dimensions as an emergent description of algebraic spin liquids, deconfined criticality, and the transition between fractional quantum hall states. The goals are to determine when these theories are conformal, compute critical exponents, verify recently proposed dualities, and find new dualities. The outputs of this strand will predict physical observables that can guide ongoing and future experiments. Since these CFTs are dual to higher spin gravity, the output of strand I will also inform the research of strand II.

UKRI Gateway to Research · FY 2024 · 2024-08

Antibiotics are life-saving treatments for bacterial infections, but there may be (collateral damage) with overuse upon the gut microbiome (i.e. the billions of microorganisms within the gut). Specifically, any associated loss of (beneficial) commensal gut bacteria results in loss of their ability to protect against disease-causing (pathogenic) bacteria causing gut infections, e.g. Clostridioides difficile infection (CDI). Similarly, recurrent antimicrobials (select out) gut bacteria with antimicrobial resistance (AMR), increasing vulnerability to the presence of intestinal multidrug resistant organisms (MDROs). Currently, we have limited therapeutic strategies to minimise this problem; however, one approach to restore the antibiotic-damaged microbiome is faecal microbiota transplant (FMT; stool microbiome transfer from healthy screened donor into a patient). FMT is an established treatment for CDI, and shows promise in patients colonised with (carriers of) intestinal MDROs. However, we do not fully understand how antibiotics produce these (side effects), and have limited knowledge about mechanisms of action of FMT, although the more donor microbiome engrafting (taking hold) within the recipient, the more likely success. Better understanding of how antibiotics and FMT impact the gut microbiome to respectively increase vulnerability to/ protect against (antibiotic-associated infections) - including factors influencing FMT's engraftment - could be exploited to develop more effective (microbiome therapeutics). One mediator of FMT's effectiveness are metabolites (small chemical molecules). My research demonstrates that patients with an antibiotic-damaged gut microbiome have alterations in various lipid (fat-related) gut metabolites related to the microbiome compared to healthy people, and these are restored (to normal) by FMT. This includes a post-FMT reduction in certain lipids containing sulfate groups, including a group called sulfatides. Further research demonstrates that FMT restores 'beneficial' bacteria possessing (sulfatase) enzymes (which remove the sulfate group from gut lipids, as well as molecules on our own (host cells called glycans); FMT also restores bacterial enzymes that chemically alter glycans. This is interesting, as sulfatides and sulfated glycans - but not desulfated versions - are associated with gut colonisation of disease-associated bacteria or common MDROs (such as C. difficile, E. coli and K. pneumoniae), and binding of their toxins (poisons), enabling them to attack the gut. I hypothesise that antibiotics causes loss of beneficial gut bacteria (containing sulfatases and glycan-altering enzymes) which protect against gut colonisation with pathogenic bacteria and their toxins; successful FMT reverses this and restores engraftment with these beneficial bacteria instead.

UKRI Gateway to Research · FY 2024 · 2024-08

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

UKRI Gateway to Research · FY 2024 · 2024-08

Research context: Unlike other cancer types, which have recently seen significant improvements in their treatments and survival, pancreatic cancer continues to have extremely poor patient outcomes. Less than ten percent of patients diagnosed with pancreatic cancer survive more than five years after diagnosis. A major contributing factor is that pancreatic cancer is often detected at an advanced (incurable) stage. In the United Kingdom, nearly half of patients have Stage 4 disease at the time of diagnosis, which has a profound effect on treatment options and, ultimately, survival. Improving early detection of cancer is essential for improving survival, by providing patients with a window of opportunity to undergo treatment with curative intent. However, diagnosing pancreatic cancer at an early stage remains a challenge, as the signs and symptoms of early pancreatic cancer are often similar to those of many common illnesses. This makes it hard for doctors to identify which patients should be tested for pancreatic cancer. One solution for improving early detection of pancreatic cancer, being developed by our laboratory, is a simple breath test that detects small molecules, called volatile organic compounds (VOCs), which are different in the breath of patients with and without pancreatic cancer. This breath test could be offered to patients visiting a General Practitioner with non-specific symptoms, which for many patients will be due to one of a number of common illnesses, but in a minority may be due to undiagnosed pancreatic cancer. Challenge this project addresses: An important aspect in developing this breath test is to identify how the breath VOCs that are used to detect pancreatic cancer are produced within the cancer environment. This project aims to address this by studying VOC production from pancreatic cancer using a laboratory model. This will help us to identify specific VOCs produced from pancreatic cancer, even when occurring at very low concentrations in breath, thus making the breath test more accurate. To ensure the model is as representative of pancreatic cancer as possible, it will contain both cancer cells and the surrounding cells that are known to promote the growth and spread of these cancers. This allows the model to resemble more closely the interactions occurring between these cells in the human body, which may influence VOC production. Overall aim: To study VOC production from pancreatic cancer using a laboratory model. This model will use cells from 15 human pancreatic cancer samples and 5 normal human pancreas samples that are grown as groups of cells (organoids), as well as their surrounding supporting cells (cancer-associated fibroblasts) to mirror their interactions in the human body. This project will be based at Imperial College, with additional work taking place at the Cancer Research UK Convergence Science Centre. Objectives: To identify pancreatic cancer specific VOCs, compared with normal pancreas VOCs, using groups of pancreatic cells. To grow groups of pancreatic cancer cells together with supporting cells found inside the pancreatic cancer environment, to see whether this affects overall VOC production. To use the above laboratory model to identify biological pathways contributing to VOC production in pancreatic cancer. Potential applications and benefits: Alongside the results of parallel clinical studies, this research will support a future breath test that will offer an opportunity to improve earlier detection of pancreatic cancer, with benefits to both patients and the health service.

UKRI Gateway to Research · FY 2024 · 2024-08

'Reconnect' addresses the problem of reconstructing complex systems' network dynamics from data to understand and predict critical transitions. Using the framework of complex systems, it pioneers methods for characterising the network dynamics that can feature in diverse fields such as geology, climate science, chemistry, and neuroscience by blending tools from the fields of Dynamical Systems (DS) and Machine Learning (ML). Interactions between network components often lead to unexpected behaviour. For example, the functioning of an individual neuron is relatively well understood, yet the behaviour of neural networks and their emergent collective dynamics remain elusive. Data-driven reconstruction of network structure facilitates the prediction of switching behaviour in such complex systems from data. This proposal will investigate mathematical brain networks.