IMPERIAL COLLEGE LONDON

UKRI Gateway to Research · FY 2025 · 2025-02

Microorganisms in our environment (e.g. soil bacteria) produce molecules, natural products (NP), that are used to develop important pharmaceuticals, such as antibiotics required to combat antimicrobial resistance (AMR), treat neglected diseases and tackle future pandemics. NP are also used as crop protection agents to boost crop yields and help feed the growing population. Many NP are assembled by nonribosomal peptide synthetase (NRPS) enzymes that couple amino acid building blocks into peptide products, and polyketide synthase (PKS) enzymes that condense malonic acid and other precursors to create polyketides. These huge 'megasynthase' (NRPS & PKS) possess thioesterase (TE) domains that cyclise peptide or polyketide chains to create cyclic structures (macrolactones). Although macrolactones possess exquisite bioactivity, they are prone to hydrolysis cleaving the ring which abolishes their activity. For example, daptomycin and erythromycin are clinically important macrolactone antibiotics from NRPS and PKS respectively, but pathogens have evolved hydrolase enzymes (esterases) which can cleave and deactivate these macrolactones leading to antimicrobial resistance (AMR). The emergence of antibiotic-resistant pathogens is one of the biggest threats we face today. Our government estimate that AMR causes 700,000 deaths each year globally, which is predicted to rise to 10 million, costing the global economy $100 trillion, by 2050. Chemical synthesis can be used to prepare more effective macrolactam derivatives, where the labile lactone is replaced by a more stable lactam bond. Although macrolactams have superior properties, and can evade AMR, their synthesis is very costly, polluting and unsustainable. We will address problems of AMR and food security by developing new methods for bioengineering megasynthase, creating sustainable routes to superior macrolactam antimicrobial agents for medical and agricultural use. The project builds on our recent success developing a new gene editing approach for NRPS reprogramming. Engineering NRPS and PKS, which are amongst the largest and most complex enzymes in nature, is extremely challenging and has met with limited success. However, we showed that gene editing can be used to introduce targeted changes to complex NRPS, enabling alternative amino acids precursors to be incorporated into peptide antibiotics. We envisage our approach could be used to engineer many different megasynthase. Initially, we will use gene editing and other methods to engineer NRPS derived from Actinobacteria (prolific antibiotic producers) delivering more stable lactam variants of the macrolactone antibiotics enduracidin (END) and ramoplanin (RAM), which entered phase III clinical trials for the treatment of vancomycin-resistant Enterococcus. RAM lactam variants have been prepared by chemical synthesis, and shown to be superior antibiotics, but their synthesis took >40 steps, using expensive and toxic reagents, and is not viable for drug development. We will generate improved END/RAM lactams in a clean, cheap, single-step fermentation, making more stable and effective antibiotics widely available. A similar approach will be developed to produce improved lactam variants of DAPT which could be used to treat MRSA and other life-threatening infections caused by antibiotic resistant pathogens. We will also explore bioengineering NRPS and hybrid PKS-NRPS enzymes from Bacillus (another soil bacteria) to produce improved lactam derivatives of cyclic lipopeptide antifungal agents (fengycin & surfactin). The Bacillus strains and lactam products can be used as crop protection agents to kill fungal plant pathogens that damage food crops, including rice which feeds half of the world's population. In addition to reprogramming NRPS/PKS to introduce different precursors, leading to lactam rather than lactone rings, we will also explore structure-guided engineering (fine tuning) of TE domains for more efficient macrolactam formation.

UKRI Gateway to Research · FY 2025 · 2025-02

Natural products are molecules made by plants and microorganisms that have inspired the development of many important pharmaceuticals that we rely on today. For example, soil bacteria, such as Streptomyces from the Actinobacteria family, are particularly prolific in producing antimicrobial agents, which can kill bacterial, fungal, and other microbial pathogens. Many of these natural antimicrobial agents have been widely used to treat life-threatening infectious diseases. However, existing antimicrobial drugs are becoming increasingly ineffective due to antimicrobial resistance (AMR), with microbial pathogens rapidly evolving ways to evade the effects of these compounds. Fungal infections can be particularly problematic, with conditions such aspergillosis and cryptococcosis resulting in millions of life-threatening infections every year. Only very recently, it became apparent that many COVID-19 patients (particularly in India) died of a secondary infection, caused by the "black fungus" mucormycosis. Unfortunately, there are only a small number of antifungal drugs available and very few promising drug candidates in development. Moreover, many antifungals currently in use are largely ineffective against emerging multidrug-resistant fungal pathogens such as Candida auris which pose a major threat to global health. Currently the most effective and widely used antifungals are the polyenes amphotericin B, nystatin and pimaricin, which are all WHO essential medicines. Polyenes are complex natural products derived from Actinobacteria, with similar macrocyclic structures. They show excellent broad spectrum antifungal activity and, unlike other antifungal drugs, resistance to polyenes is less widespread. Despite possessing favourable properties, polyenes suffer from low solubility and exhibit toxicity. This is because polyenes bind to and disrupt the cell wall (membrane) of fungal pathogens, but can also bind to the human cell membrane, leading to toxic effects. Polyene derivatives with reduced toxicity and increased solubility have previously been prepared by chemical synthesis. However, this typically requires laborious and expensive multistep synthetic procedures, which are unsustainable, polluting and too costly to scale-up for manufacture. Recently, we have sequenced the genomes of several Actinobacteria and discovered genes encoding enzymes (catalysts) that are required for the biosynthesis (assembly) of novel polyenes. We were able to isolate and determine the structure of new polyenes. In addition, we obtained preliminary characterisation for some "tailoring" enzymes that add key functionality during the latter stages of polyene biosynthesis. In this project, we aim to further characterise the new tailoring enzymes, testing them with natural substrates (biosynthetic intermediates) as well as precursors from other pathways to known polyenes (amphotericin B etc.). We will also obtain structures or models which we can use to mutate (engineer) the tailoring enzymes to broaden their substrate scope and facilitate catalysis of alternative tailoring reactions. We then aim to combine the different tailoring enzymes in reactions to create a diverse library of polyene derivatives, which will be tested for antifungal activity, toxicity, and solubility. This will provide a detailed structure-activity relationship (SAR), enabling us to establish which combination of tailoring reactions provides polyenes with the best properties. Initially, we will use isolated enzymes (in vitro) to produce new polyenes for testing. However, we will also develop in vivo engineering approaches to create Actinobacterial strains that can produce the best polyene derivatives in a single-step fermentation. These bio-based approaches, particularly in vivo fermentation, can provide much more sustainable, efficient, and cost-effective routes to the improved polyene antifungal agents that we urgently need to combat the emerging drug-resistant fungal pathogens.

UKRI Gateway to Research · FY 2025 · 2025-02

Natural products (NP) are molecules isolated from microorganisms and plants that inspired the development of many leading antibiotics, anticancer, immunosuppressive agents and other essential medicines that are widely used in the clinic today. Often the NP that are isolated from the native organism do not possess the prerequisite properties at the outset. Further synthetic modification is typically required to provide the final drug compound. However, NP are typically highly complex molecules requiring laborious multistep chemical synthesis, which is very expensive, polluting and increasingly unsustainable. The difficulty associated with the synthesis of optimised NP variants presents a major barrier to pharma companies undertaking drug development. This is particularly problematic in the manufacture of drugs required to treat diseases of developing world such as malaria, Leishmania and Chagas disease. These highly infectious diseases, caused by single celled (protozoan) parasites transmitted by insects, effect billions of the poorest people in the world and lead to over 500,000 deaths pa. Currently there are very few effective treatments available for these diseases. A NP artemisinin is used to treat malaria, but new strains of the malaria parasite (P. falciparum) have emerged which are resistant to artemisinin. Promising new NP leads have been identified for malaria and other related diseases, but the costs of synthesising derivatives have prevented new treatments being made available. An alternative for producing optimised NP derivatives, is to manipulate the biosynthetic assembly lines (enzymes) in the microorganisms that construct the parent NP. By reprogramming (engineering) the assembly line to accept different precursors, NP variants with improved properties can be delivered in a more efficient, cost-effective single-step fermentation process. In this project we aim to engineer biosynthetic pathways to produce NP derivatives with antiprotozoal activity that could be used to combat malaria or related diseases. The target NP are peptides, composed of amino acids with a reactive terminal functional group (warhead), produced by Streptomyces and other bacteria. These NP will be designed to bind to the proteasome of protozoa such as P. falciparum. Proteasomes are large multi-protein complexes responsible for degrading other proteins in the cell that are either damaged or no longer needed. The warhead of the peptide NP can cross-link with the proteasome inhibiting its function leading to cell death. We will use novel gene editing and other approaches to engineer the genes encoding the enzymes that assemble the warhead containing peptide NP. This will allow us to change the sequence of the peptides and also include different warheads, to improve their activity, selectivity and other properties for drug development. The biosynthetic assembly line includes nonribosomal peptide synthetase (NRPS) enzymes that condense amino acid precursors. By replacing domains, or subdomains, within the NRPS it is possible to change the sequence of the amino acids in the peptide products. Guided by earlier synthetic studies, we will create warhead containing peptides that are highly selective for the P. falciparum proteasome. Compounds that inhibit proteasomes in human as well as the parasite cell, would be toxic and unsuitable. We will also engineer assembly lines that deliver warhead containing peptides designed to inhibit the proteasomes in human cancer cells. This includes oprozomib a synthetic analogue, which is in clinical trials for treatment of multiple myeloma (bone marrow cancer). By developing an engineered pathway to this type compound, it may be possible to produce anticancer drugs, like oprozomib, in a single-step fermentation making them more widely available at lower costs. The methods we develop are generic and can be used to produce a range of warhead containing peptides for a number of other therapeutic applications.

UKRI Gateway to Research · FY 2025 · 2025-02

Nucleic acids are polymers comprising of nucleotide monomers, with ATCG bases in DNA or AUCG bases in RNA (U & T are equivalent). In cells, DNA exists as a double helix and is transcribed to single-stranded messenger RNA (mRNA), which is then translated to create specific proteins (functional molecules within cells). The Pfizer and Moderna COVID-19 vaccines are mRNA sequences coding for the SARS-CoV-2 spike protein. Upon immunisation the mRNA enters our cells and is translated to produce the spike protein (antigen) leading to the production of antibodies (an immune response) that protect us from future infection. Both vaccines use modified mRNA with a synthetic monomer (N1-methylpseudouridine) in place of U. Although N1-methylpseudouridine and U code for the same information, the slight structural differences improve mRNA longevity in the cell and boost translation levels of the antigen. Similarly, modified mRNAs are also being developed to combat other diseases such as cancer (immunotherapies). Currently mRNA vaccines and therapeutics are produced using a DNA-dependant polymerase enzyme. Whilst this works well, the use of DNA templates prevent selective modification as the enzyme can only use four monomers (AUCG or equivalent). Therefore, inclusion of modifications at specific positions (e.g. terminal regions more prone to degradation) is unachievable using this method. Other examples of therapeutically important modified nucleic acids include short antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). ASOs bind to a complementary mRNA (base-pairing) to block it or induce cleavage, preventing translation of detrimental proteins associated with a disease (e.g. genetic disorders or cancer). siRNA are short modified double stranded RNAs that associate with proteins in the cell and promote breakdown of complementary target mRNAs. ASOs and siRNAs are highly modified to improve their stability to cellular enzymes that degrade nucleic acids. Given their highly modified structures, ASOs and siRNAs are currently produced by chemical solid-phase synthesis (SPS). Although SPS works well on a small-scale, it is extremely costly and very difficult to operate at large-scale, which means that manufacture of ASOs and siRNAs required for large patient populations is not feasible. The synthetic monomers used are also very expensive to produce and require extensive chemical manipulation. Large excesses of monomers are required at each step, along with other costly reagents, and large volumes of organic solvents, most of which are toxic, damaging to the environment and increasingly unsustainable. In this project we will develop novel enzymatic methods for template-free assembly of modified nucleic acids (mRNA, ASOs, siRNA & other therapeutics). Enzymatic methods operate in water, under mild conditions, utilising benign enzymes and renewable monomers and will provide a more sustainable, scalable, and cost-effective alternative to SPS, while also allowing selective modification of longer mRNA. Initially, we will focus on engineering template-free polymerase and ligase enzymes to accept modified nucleotide monomers with blocking groups. A blocking group ensures only one monomer is enzymatically added in each step. Only after deblocking is the next monomer added, which gives complete control over the sequence and position of modifications. We will use X-ray (3D) structures of the enzymes to guide engineering (mutagenesis), making rational changes to the enzyme active site so that modified nucleotides are accepted. We will also use more random approaches to create larger libraries of mutant enzymes. High-throughput fluorescent assays will be developed, where incorporation of a monomer leads to fluorescence, allowing us to screen larger numbers of mutants and select variants with improved properties. The engineered ligase enzymes can also be used to join longer RNA strands to produce mRNA with selective modifications.

UKRI Gateway to Research · FY 2025 · 2025-02

Nucleic acid-based therapeutics comprise a rapidly expanding category of drugs that have the potential to treat a broad range of genetic and infectious diseases, cancer, cardiovascular disorders etc. Several antisense oligonucleotides (ASOs), short interfering RNAs (siRNAs) and mRNA vaccines have recently been approved and many are under clinical trials. Therapeutic oligonucleotides contain modified ribose moieties and phosphorothioate linkages for improved stability in the cellular environment. Many of the world's top pharmaceutical and biotech companies are now engaged in developing ''safe and effective'' nucleic acid (NA) therapeutics. Currently, modified NAs are produced by solid-phase oligonucleotide synthesis (SPOS) which uses toxic/deleterious reagents and solvents, making the scale-up problematic and expensive. Herein, we propose to establish a novel sustainable bio-based route towards modified nucleic acids, which will involve iterative oligo synthesis in water under mild conditions, utilising benign enzymes and renewable precursors. Modified nucleotide monomers will be synthesised and added to an initiator oligo using template-free, engineered polymerase or ligase enzymes with sequential coupling followed by 3'-deblocking steps. Initially, PEG-based watercompatible solid supports will be used to immobilize the initiator oligo to enable easy isolation of the product. This can be later replaced by emerging membrane separation technology enabling oligo assembly at higher concentrations. Our approach uses nucleotide triphosphate or monophosphate monomers that are easier to prepare, store, and handle, compared with the current monomers used in SPS. We envisage that our proposed methodology would enable widespread production of nucleic acids therapeutics and vaccines, facilitating faster, low-cost, and non-toxic manufacturing of essential medicines at an industrial scale.

UKRI Gateway to Research · FY 2025 · 2025-02

Antimicrobial resistance (AMR) (infections that are less responsive to antibiotics) is increasing rapidly around the world and is a major problem for the health service. Vulnerable groups including refugees and migrants to the UK and Europe are particularly susceptible to AMR, and we need dedicated research in this group to better address this issue. Refugees and migrants to the UK and Europe are more likely to have AMR due to higher rates in their countries of origin, liberal policies around antibiotic use, poor infection control practices in under-resourced health facilities, and increased person-to-person spread during their journeys due to living conditions or detention. Bacteria affected by AMR can cause infection or be carried by patients without causing active infection; they can spread person to person, particularly in healthcare settings and over-crowded living centres. Despite the importance of this issue and calls from WHO to take a person-centred approach to AMR, the perspectives of refugees and migrants with AMR are under-explored. This is important as this marginalised population have different challenges to accessing healthcare in the UK. This evidence gap impacts on our ability to develop bespoke strategies for this population and prevent increasing the prevalence of AMR. My overall research aim is to formulate person-centred policy recommendations for tackling AMR among refugees and migrants in the UK by identifying the gaps in policies through in-depth exploration of the perspectives of refugees, migrants, and key stakeholders like policy makers or civil society organisations (CSOs). My first objective is to review documents and policies on AMR and identify gaps in evidence or recommendations for refugees and migrants in the NHS, nationally (UK) and internationally (Europe). Relevant policy documents include National Action Plans on AMR, multidrug resistant organism (MDRO) screening, and antibiotic prescription guidelines. This will identify relevant gaps in addressing AMR among this group to be explored in subsequent objectives. The second objective is to conduct clinical ethnographic studies of the lived experiences of AMR-affected refugees and migrants in the UK. Clinical ethnography is a research methodology that uses clinically-informed and reflective immersion in patient experiences; it involves in-depth interviews with participants and observations, followed by transcription and analysis. It will provide fundamental information about patients' access to healthcare across time and geographies, social, behavioural and cultural influences on antibiotic use and their lived experiences of carriage or infection with resistant bacteria. The third objective is to conduct in-depth interviews with experts on AMR including healthcare workers, policymakers or CSOs to understand their perspectives. I will draw on findings from prior objectives to inform these discussions to begin to form potential policy changes that can be appropriate to the needs of refugees and migrants in the NHS and further afield. From this, I will synthesise findings contextually to identify local and national policy recommendations based on the experiences of refugees and migrants themselves and policy makers. These could span local policy recommendations around antibiotic prescribing and use, screening for resistant bacteria and infection control through to broader recommendations as to how to improve understanding of AMR among refugees and migrants and how we can provide improved care in the NHS. This work is of high relevance to healthcare service strategy in the UK but also internationally (including WHO), as refugees and migrants face challenges in accessing healthcare impacting the development of AMR.

UKRI Gateway to Research · FY 2025 · 2025-02

The AUREUS doctoral network meets the increasing need of a highly qualified work force to counteract multidrug-resistant S. aureus infections by performing cutting-edge, inter-disciplinary research in the multifaceted field of chemical biology. The proposed research program aims at training Doctoral Candidates (DCs) to acquire complementary skills to exploit and develop different and innovative strategies to i) unveil the biosynthesis and structure of unique S. aureus cell wall glycopolymers, the so-called WTA (wall teichoic acids), ii) gain greater insights into the molecular basis of the human immune responses to S. aureus WTA, iii) harness the acquired knowledge to rationally design and develop effective immune-based therapies against S. aureus and related bacterial species. To this end, the AUREUS intersectoral program is based on a unique international team combining expertise in different fields including chemistry, (micro-)biology and immunology. In detail, 9 world academic leaders in the glycoscience and/or S. aureus research world and 4 companies (SMEs) with world-class expertise in glycoscience, cutting-edge diagnostics and therapeutic research programs will be involved in the AUREUS project. Each DC will have their own individual project, based on fundamental science and with practical applications, either in biotechnology or in biomedicine, as will be explored through secondments with our industrial partners. The AUREUS network will provide 14 young scientists with broad, top-class scientific and professional competences and skills, thereby expanding the pipeline of future leaders for both industry and academia.

UKRI Gateway to Research · FY 2025 · 2025-02

At temperatures around a millionth of a degree above absolute zero, atoms and molecules enter a new regime. All their motions follow the laws of quantum mechanics, and can be very precisely controlled. Researchers achieved this control for atoms some time ago, and it is now becoming possible for molecules too. This is important because molecules have much richer patterns of energy levels than atoms, and their complexity can be used for many applications in quantum science and technology. For example, they can be used as building blocks of a quantum computer and to simulate interacting quantum systems that cannot be simulated on a normal computer. They are also being used to study the fundamental symmetries of nature. We are at the forefront of this field. We have a unique capability to laser-cool CaF molecules and Rb atoms to near the quantum regime and to confine them together in magnetic and magneto-optical traps. We have already used this for initial studies of CaF+Rb collisions in these environments. Control of ultracold matter is achieved via collisions. Particularly important are resonant collisions, where the colliding pair can combine to form a larger molecule with no change in energy. Near such a resonance, a magnetic field can be used to control the collision: with only a small change in field, the interaction can be tuned to be attractive or repulsive, or even to zero so that the particles no longer see each other at all. Most of the properties of the ultracold gas depend on the interaction strength, which here can be controlled at will. Our proposal is to locate these resonances for the prototype system CaF+Rb and use them for important applications. We will confine both the molecules and the atoms in an optical trap, where we can apply a controllable magnetic field. CaF+Rb is particularly suitable for this: both species have unpaired electron spins, so that the interactions between them are closely analogous to the well-understood case of pairs of alkali-metal atoms. We have exploited this similarity in a preparatory theoretical study, which has shown that suitable resonances will exist at easily accessible magnetic fields. We will use the resonances to control how quickly the atoms and molecules come into thermal equilibrium. Then, by using the atoms as a coolant, we will bring the molecules further into the fully quantum regime. We will also use the resonances to form triatomic molecules in a controlled manner, and then characterise these new molecules spectroscopically. In these ways, we will bring the tools of quantum control to increasingly diverse and complex systems for the benefit of quantum science and technology.

UKRI Gateway to Research · FY 2025 · 2025-02

Solid phase peptide synthesis (SPPS), first introduced by Merrifield in 1963, revolutionised the way we make peptides and other biopolymers, inspired the development of combinatorial chemistry as well as automated chemical synthesis. The impact of this technology has been enormous, leading to the development of many new lifesaving pharmaceuticals and other materials of great value to society. Despite the tremendous importance of SPPS in science today, the basic principles and technology have not advanced greatly since it was first introduced. Moreover, current SPPS involves the use of large amounts of deleterious reagents and solvents that are damaging to the environment. ENGPEP will provide the first viable alternative enzymatic approaches for more sustainable peptide synthesis, using bespoke engineered ligase enzymes to couple amino acids and other precursors in the absence of protecting groups and other deleterious reagents. The provision of enzymatic methods for peptide synthesis would be a step change and could offer many applications including the cleaner and more efficient production of important and widely used peptide-based pharmaceuticals.

UKRI Gateway to Research · FY 2025 · 2025-02

The deep sea poses major challenges to construction engineering because of a combination of extreme environmental factors: ocean depths typically greater than 200 mm, high water pressure, low temperature and aggressive seawater composition. Recent studies have shown that cement and concrete materials designed for conventional structures can degrade rapidly when exposed to the deep sea and are inadequate for demanding applications that require long service lives. However, the requirement for future sustainable energy production such as offshore wind power, nuclear power generation and waste disposal, and geological carbon capture and storage facilities, means that there is an increasingly urgent need for advanced materials and construction technologies that are suitable for deep-sea applications. DuRACS will fill this critical gap by developing a new generation of advanced cementitious materials for the construction of durable and resilient structures in marine environment, in particular deep-sea infrastructure applications. The research programme consists of six interlinked work packages running over 36 months. It combines material selection, design and development, laboratory-based testing of mechanical properties, microstructure and durability, numerical modelling, and thermodynamic modelling to evaluate and improve candidate materials. The final work package will test the most promising materials in deep sea field sites in Japan at depths up to 3500 m. Field data will be correlated to lab-based experiments and simulations, and the findings disseminated widely to the industry and scientific communities in open-access publications. We will engage with our industry partners throughout the project to ensure practical relevance of the developed materials and leverage their wider industry influence to accelerate impact and uptake. This international partnership will produce new knowledge and material technologies that could lead to significant breakthroughs in the exploration and utilisation of deep-sea resources. The ambitious research laid out in DuRACS will generate the science and engineering needed to unlock the full potential of advanced cementitious materials for deep-sea applications. The collaborative research between leading experts and industry partners from the UK and Japan, if successful, will deliver construction materials that would secure future access to safe, affordable and clean energy for global sustainable development.

UKRI Gateway to Research · FY 2025 · 2025-02

To enhance the cloud capacity provided to IRIS.

UKRI Gateway to Research · FY 2025 · 2025-02

Our vision is to discover the symmetry-violating forces that generated the imbalance between matter and antimatter in the Universe by advancing the state of the art in precision quantum measurement. There is virtually no antimatter in the visible Universe. This asymmetry between matter and antimatter is one of the greatest mysteries in science. It cannot be explained using our best models of physics, implying that the forces responsible for the imbalance have yet to be discovered. Many theories of these new forces have been developed, but they lack empirical support. In almost all theories, the symmetry-violating forces that generate matter-antimatter imbalance also endow fundamental particles with an asymmetric shape. Our aim is to measure the shape of the electron with unprecedented precision and to interpret our results in the context of matter-antimatter asymmetry. The motivation for this work comes from particle physics and cosmology, but many of the tools we need come from the quantum science community. The best approach is to use electrons that are bound up inside polar molecules. To reach the highest precision, those molecules should be cooled near absolute zero and trapped using laser light. We also need measurement protocols that minimize sensitivity to potential errors, and analysis tools that can detect the signatures of errors in the data and correct for them. The objectives of this proposal are: Understand how our measurements will determine or constrain the parameters of new theories. Prepare an array of ultracold molecules. Build a magnetically shielded apparatus suitable for our measurements. Prepare the data analysis tools we will need. To realize our vision, we have assembled an inter-disciplinary team that brings together experts in the phenomena and methodologies of particle physics, which is the domain of STFC, with experts in the quantum control of ultracold matter, the domain of EPSRC. Beyond this specific project, there are many benefits in bringing together these two communities, who have very different practices and do not often work together towards common goals, despite the very great potential of this approach. Particle physics will benefit by learning about the methods of ultra-precise measurements used in quantum science. Quantum science will benefit by acquiring the tools pioneered in particle physics - tools for designing and building complex experiments, and for analyzing complex datasets. Both disciplines will benefit from the very different approaches to managing scientific projects practiced by the two communities. We aim to harness these differences to encourage creativity and unlock new capabilities that would not otherwise emerge.

UKRI Gateway to Research · FY 2025 · 2025-02

In the UK around 100,000 babies are cared for in neonatal units yearly; many are preterm and have a high risk of death and long-term disability. Necrotising enterocolitis (NEC) a dreaded condition affecting the gut, can affect up to 7% of those who are born very preterm (VPT: earlier than 32 weeks of pregnancy). NEC typically affects babies 4-6 weeks after birth, leads to death of the gut wall, often requires surgery and is a leading cause of neonatal death. Amongst those who require surgery one-third will die and a third will have significant long-term disability or complications related to gut. NEC also affects the brain: almost half NEC survivors have long-term problems like cerebral palsy or learning difficulties. NEC is one of the top three research priorities for premature babies, identified by parents, patients, doctors, nurses, and researchers. We know that being born more preterm, small or after slow growth in pregnancy, receiving antibiotics on several occasions or formula milk feeds increase the risk of NEC, but the disease sets in very abruptly and usually unexpectedly. Therefore, recognising signs or predicting NEC a day or two earlier could be critical in reducing the adverse consequences and better outcomes. In the neonatal units we routinely monitor heart and lung health using heart rate, blood pressure and oxygen levels in the blood continuously; this enables us to detect important condition like infection earlier. But there are no established methods to continuously monitor gut health in the neonatal units. From our previous research, we have established normative measurements of oxygen levels in the tissues of the brain and gut. From laboratory-based studies we also know that certain bacterial and chemical changes occur in the stools (poo) of the VPT babies days before the NEC becomes apparent. We want to use these to predict NEC. We will recruit 425 VPT babies over 3 years from two tertiary care hospitals in London. We will record detailed maternal and baby data and observations such as heart rate, oxygen levels in blood, and blood pressure every second during a baby's neonatal stay. We will also measure oxygen level in the brain and the gut and collect daily stool samples from the nappies of the babies to measure bacterial and chemical changes in the stool. We will then combine all these complex data to identify changes that occur before a baby develops NEC. We believe that we will be able to identify changes in these measures before a baby becomes sick with NEC. If we are able to predict NEC in advance, this will open up the possibility of treating to prevent NEC - for example with medications that prevent inflammation or antibiotics - to stop or modify NEC and save lives and improve lifelong outcomes. We are consulting parent focus groups and the UK Bliss baby charity as we design the study. The findings of the study will be shared through healthcare and academic research websites and social media; presented in conferences and published in peer-reviewed scientific journals. We believe that this study will have dramatic short- and long-term health benefits for vulnerable babies and drive better care at national and international levels.

UKRI Gateway to Research · FY 2025 · 2025-01

General overview We imagine a future where a patient is given a drug which is inactive until it is illuminated with light, allowing the precise and targeted treatment of tissues and organs, as described by the emerging area of ‘photopharmacology’. Even beyond new medicines, light-addressable molecules hold significant potential for precision chemical biology across many sectors (agrosciences, personal care, etc). However, there are currently important fundamental mechanistic questions in this field, which are on many technical levels. Here, we show that we have the ability to tackle such key mechanistic questions. To fully realise the success of photopharmacology, it is critical to achieve a large differential binding potency between the light-addressable forms. This would allow for high (light-controlled) specificity for binding and inhibition of a biological target with human health relevance. However, how the binding of the drug to the protein impacts the drug’s photochemistry, and how the structural changes of the drug upon illumination impacts the dynamics of binding and unbinding is not understood on a fundamental level. Gaining such understanding is now possible with advanced X-ray Free Electron Laser (XFEL) based time resolved crystallography and is the focus of this proposal. Biology and medical relevance The human N-myristoyltransferase (NMT) protein is an important drug target. From a therapeutic perspective, NMT is an interesting target for photopharmacology application. It is enzyme that transfers myristate (a 14C fatty acid residue) co-translationally from myristoyl coenzyme A (MyrCoA) to N terminal glycine residues labelling proteins for membrane association, protein-protein interactions or subcellular localisation. NMT has emerged as a target in a wide range of diseases, from fungal infections and malaria to rhinovirus infection and cancer. A light-addressable NMT inhibitor will allow for further insight into NMT biology, such as further elucidation of kinetics of myristate labelling of different substrates and/or changes in substrate subcellular location in a light-dependent fashion. In this application, we use NMT as a representative target and show exciting preliminary work and initial results on a designed and synthesised a light-addressable analogue (LD162). LD162 exhibits strong binding to NMT1 (KD = 6.5nM) in its ‘active’ form and is ~50 fold less active in its ‘inactive’ form. We also present our recent unpublished crystal structure of the NMT:LD162 complex, establishing the feasibility for pump-probe time resolved crystallography of the complex. This proposal will leverage this data to generate a full analysis of the time-resolved structural and energetic changes upon photochemical activation for LD162 and a range of newly designed analogues. Objectives Having developed a potent light-addressable inhibitor of NMT we are in a unique position to enter the next design and characterisation stages. We will combine the expertise of the van Thor group in time resolved serial crystallography and laser spectroscopy with the expertise of the Fuchter group in photopharmacology and synthesis. We will execute a series of time resolved XFEL experiments of crystals of the HsNMT1:LD162 complex. A strategy for the development and synthesis of next-generation compounds is proposed to allow us to fully study changes upon photochemical activation across a range of drug binding modes/potency. Thermodynamics and spectroscopy investigations will test all compounds, which, coupled with the structural data,will reveal the dynamical detail of the molecular interactions with the NMT active site.

UKRI Gateway to Research · FY 2025 · 2025-01

Our vision is to fundamentally redefine the diagnosis and treatment of Pulmonary Hypertension (PH), a multifaceted disease that carries significant diagnostic and prognostic difficulties. Even though there are numerous cross-sectional studies on PH, they cannot be combined because the patients are all at different stages of the disease along with different comorbidities. By integrating high-dimensional molecular profiling into traditional longitudinal cohort studies, we aim to leverage machine learning, genomics, and vascular biology to predict future molecular and clinical measures at any time point in a patient's journey. This approach can potentially discover biological mechanisms that drive disease progression and identify biomarkers in patients even when they cannot visit the clinic to provide data. Aims and Outcomes: 1. Develop machine learning models to predict whole transcriptomes from blood biopsies at any point in a PH patient's journey. This could enable a new form of molecular classification for PH at previously unexamined time points, offering more precision than current clinical classifications. 2. Create an efficient computational system for real-time analysis of high-dimensional data, such as thousands of genes, thus overcoming the current methodological gap for genomic data captured at multiple times. 3. Extrapolate molecular changes observed in blood biopsies to changes in the pulmonary vasculature, providing a non-invasive method for investigating disease mechanisms. 4. Determine the optimal sample size and design for longitudinal molecular studies, increasing these studies' cost-efficiency and statistical power for other diseases. Our interdisciplinary approach begins with computational modelling of gene expression and symptom trajectories across multiple years following a patient's diagnosis. We will begin by combining molecular trajectories with baseline factors, including gender, ethnicity, and socio-economic status. Time-dependent changes in blood transcriptome and methylome will be associated with changes in patient symptoms, such as mean arterial pressure and 6 minute walk distance. Historically measured gene expression profiles will be used directly as longitudinal inputs in our machine learning models to predict future molecular profiles associated with pulmonary vascular remodelling and patient outcome. To ensure scalability to many patient measures and time points, we will evaluate and extend a machine learning technique called Gaussian Processes, which has successfully modelled lower-dimensional longitudinal data such as body weights and CO2 emissions. The algorithm will be trained through an iterative process, by gradually increasing the amount of longitudinal data from patients' molecular profiles and electronic health records. Our multidisciplinary team of computer scientists, epidemiologists, biologists and clinicians, will enable the algorithm to use biologically relevant features and be scalable for clinical applications. The data and methods from this project will not only provide PH patients with better information about their disease progression, but can also be used to understand other complex diseases and age-related disorders.

UKRI Gateway to Research · FY 2025 · 2025-01

Imperial is an internationally leading centre for research, education and translation and the only UK higher education institution to focus exclusively on science, engineering, medicine and business. Imperial is renowned both for world-class fundamental research and for the translation of this research for the benefit of society and the economy. In the latest REF exercise, Imperial obtained a greater proportion of 4* “world-leading” research than any other UK university and ranked first in the UK for research outputs, first in the UK for research environment, and first for research impact among Russell Group universities, recognising Imperial’s approach to ensuring a positive and inclusive culture in which all our staff and students can thrive. This grant will enable the acquisition of eight different items of equipment which will enable the following objectives to be met: Increased capacity and accessibility to core equipment meaning greater efficiency of use Greater sustainability through reduced resource and energy costs Greater engagement with ECRs Providing access to multi-Departmental users and enabling cross-Departmental collaborations Imperial’s new strategy, Science for Humanity aims to achieve enduring excellence in research and to promote the development of world-class core disciplines and multidisciplinary research addressing major societal challenges. The proposed investments align strongly with both Imperial’s and EPSRC’s strategic ambitions and will be significant additions to Imperials provision of world-class facilities. Providing cutting-edge research infrastructure and enabling equipment, with highly skilled technical support that facilitates "hands-on" training for the next generation of world-class talent, is core to the Imperial's mission and embodied in our strategy. This approach is consistent with EPSRC’s view of a World Class Lab supporting the next generation of researchers as a combination of excellent people undertaking cutting-edge research using state-of-the-art, fit-for-purpose equipment underpinned with qualified, well-resourced technical support.

UKRI Gateway to Research · FY 2025 · 2025-01

Amazonian trees play a central role in regulating methane, a potent greenhouse gas contributing to global warming. In wet seasons, when trees are flooded, they release methane into the atmosphere, but in dry seasons, they absorb it, helping lower atmospheric methane levels (Pangala et al., Nature, 2017; Gauci et al., Nature, 2024). The methane emitted in the wet season is largely thought to originate from the soil beneath the flooded trees, but research suggests that microorganisms inside the trees may also be producing methane (Covey & Megonigal, New Phyt., 2019). During the dry season, when the soil is no longer flooded, methane emitted from the tree stems is likely produced by internal microorganisms. Similarly, the methane consumption/uptake observed in trees is driven by microorganisms inside the tree (Jeffrey et al., Nat. Commun., 2021). The knowledge gap lies in understanding how water table fluctuations, which affect methane emissions, also impact the methanogens (methane producers) and methanotrophs (methane consumers) inside trees. While we know that water levels influence methane emissions from trees (Gauci et al., Philos. Trans. R. Soc. A., 2021), we do not fully understand how the activity of these internal microorganisms changes in response to fluctuating water levels. Do methanogens and methanotrophs adjust their functions seasonally, or are they resilient to short-term changes, such as extreme weather events? Understanding these processes is crucial because water table levels directly affect not only methane emissions but also the microbial dynamics that drive them within trees. Currently, the Amazon is facing its most severe drought in over 120 years, driven by climate change and worsened by the transition from El Niño to La Niña. This extreme drought is placing immense stress on trees and could disrupt the balance of methane production and consumption regulated by methanogens and methanotrophs. This disruption could potentially alter methane emissions from the region, but there is no current data showing how drought impacts this delicate balance inside trees. Addressing this gap is essential to predict how carbon-dense ecosystems like the Amazon will respond to extreme environmental pressures as climate change accelerates. The 2024 drought provides a timely opportunity to investigate how these extreme conditions affect methane emissions from Amazonian trees and their microbial communities. In 2022, our Royal Society-funded research collected extensive baseline data on methane emissions and microbial dynamics from Amazonian trees during wet and dry seasons under typical hydrological/weather conditions. This baseline allows for a unique direct comparison between normal seasonal variations and the effects of the 2024 drought. Importantly, this study must be conducted before the rainy season begins, ensuring that the drought's effects are captured without being masked by typical seasonal changes. By comparing these datasets, we can identify shifts in methane production and consumption within trees and how microbial communities react under extreme drought conditions. This study will offer novel insights into how climate change-driven droughts might alter the Amazon's role in regulating methane emissions. It will also improve climate models used to predict regional and global methane budgets and guide efforts to reduce greenhouse gas emissions. Beyond its policy implications, the data generated will be invaluable to the broader scientific community, providing a deeper understanding of how ecosystems and microbial communities respond to extreme weather events and the long-term resilience of the Amazon rainforest.

UKRI Gateway to Research · FY 2025 · 2025-01

Downstream processing (DSP) of biopharmaceuticals is dominated by chromatographic steps which suffer from low throughput, poor scalability and elevated energy consumption, as well as high equipment and materials costs. To this is added the low stability and high degradability of liquid formulations. The training program "Crystallisation towards efficient and sustainable biomanufacturing" (PROCRYSTAL) vision is that of crystallisation as a simple, sustainable, cost-efficient and scalable alternative to current DSP techniques and liquid formulations, once it allows to separate, purify and stabilise in a single step. Nevertheless, integrated training to exploit biocrystallisation full potential is currently not available, only fragmented research activities. Within this training program, 13 Doctoral candidates (DCs) are expected to go beyond current practise to respond to the near future biopharma manufacturing needs. And only possible leveraged by the expertise conveyed in this consortium on biomolecules crystallisation, biochemistry, chemical and process engineering as well as advanced modelling. The PROCRYSTAL training program for the DCs has been framed with special attention to fundamental understanding of the underlying phenomena, from the molecular scale to process scale, and advanced experimental and modelling techniques specific to crystallisation technology. The DCs will acquire a wide range of subject specific and general transferable skills, in an interdisciplinary and inter-sectoral environment and by multinational collaboration which enhances the early-career DCs long term employability and competitiveness.

UKRI Gateway to Research · FY 2025 · 2025-01

Antimicrobial resistance (AMR) is a growing public health threat. Not only does it create the risk of untreatable bacterial infections, but also increases the likelihood of serious complications from the essential procedures of modern medicine, such as transplants, chemotherapy, or even childbirth. Our understanding of AMR has improved dramatically with the advent of next-generation sequencing (NGS), enabling us to gain insights into the mechanisms of AMR and identify these mechanisms directly from clinical samples, such as blood, sputum, or urine. This subsequently allows us to target each infection with the precise treatment specific to it and improve the efficacy of the existing antimicrobials, as almost no new classes of antimicrobials have entered the market in the last 40 years. However, the insights necessary for understanding the mechanisms causing AMR and identifying them directly from samples are highly dependent on the data used for their analysis. Efforts to carry out large-scale analyses have been hindered by multiple factors; one key factor is that publicly available combined datasets containing NGS data and AMR data are presented in a variety of formats, and follow different conventions with regards to their interpretation. This project, Comprehensive Assessment of Bacterial-Based Antimicrobial resistance prediction from GEnotypes (CABBAGE), attempts to provide a solution by collecting and curating all the publicly available data containing both NGS information and AMR information, transforming it into a standard format, and making it accessible it to the research community and the general public as a resource to be maintained by the European Bioinformatics Institute (EBI). In a pilot project, we collected more than three times as much data as is currently available from the single largest public database, in a reconciled, uniform format. We have also conducted an initial benchmarking for one of the pathogens, Klebsiella pneumoniae, showing both the importance and the subtleties of interpretable prediction of AMR phenotypes. Whilst this initial effort required considerable manual processing, one of the project's goals will be to automate the process so that the results of future studies can be directly incorporated into this database, and work with stakeholders such as the World Health Organisation to facilitate the adoption of our standards. Additional goals of the project include investigating the limitations of the ability of NGS information to predict AMR, to systematically compare existing approaches for carrying out these predictions, to set out quality criteria for the evidence required to identify novel resistance mechanisms in a data-driven way, to check experimentally that any mechanisms discovered according to these criteria are accurate, and lastly, to create initial draft catalogues of genomic determinants of AMR for each of the 7 most commonly found bacterial pathogens on the WHO's priority pathogens list. The outcomes from this project will include a comprehensive resource on NGS and AMR, a better understanding of the limits restrictions of AMR prediction predictive ability from NGS information, and quality criteria required for the evidence supporting novel resistance mechanisms. These outcomes will serve several communities working on AMR. First, they will help diagnostics developers assess the performance of their proposed tests. Second, they will help public health microbiologists assess the risk posed by specific infections in real-time. Lastly, they will help clinicians prescribe the optimal drug regimen for each infection they treat.

UKRI Gateway to Research · FY 2025 · 2025-01

This Fellowship will enable the rigorous study of a fragile structural form that has long left the comfortable confines of the laboratory scale and is increasingly critical to our renewable energy independence. This Fellowship will, for the first ever time: develop open-source solvers for the high-performance simulation of structural systems with sharply nonlinear behaviour suffering from numerical deterioration in partnership with the Edinburgh Parallel Computing Centre (EPCC); develop protocols for the digital twinning of massive shell structures where the quality of the twinned midsurface is paramount and sub-mm geometric features can be critical, in partnership with reality capture specialists Leica Geosystems (LGS); gather the first terabyte-sized datasets of digital twin inputs representing state-of-the-art offshore wind support structures based on unprecedented access to facilities planned for construction starting in 2025 granted by project partners Siemens Gamesa Renewable Energy (SGRE), ScottishPower Renewables (SPR) and COWI; complete the scientific understanding of the nonlinear response of very long tubular structural forms prone to ovalisation phenomena; generate extensive datasets of synthetic buckling resistances of digitally-twinned shells; calibrate actual safety margins of current and future planned offshore wind support structures and disseminate this within the international Eurocode design framework; ('Plus') found a permanent indexed data journal to accumulate empirical and numerical dataset pairs for the wider computational engineering community to validate simulations used in research and safety-critical design. The open-source software development will push the boundaries of computational structural engineering and support an emerging research culture increasingly employing digital twinning. The financial benefits of quantifying actual safety margins of current and future-scale offshore wind support structures are significant: a single modern tower saved from failure saves ~£2M, while even a ~10% reduction in steel saves ~£10M across a 100-tower offshore installation (assuming ~£1k / tonne for structural steel, not including carbon cost).

UKRI Gateway to Research · FY 2025 · 2025-01

Clean energy access will be key for achieving the global development goals; it has clear links to health, education, water access, etc... Many regions, particularly in Sub-Saharan Africa, have low electricity access today. Scalability, cost-effectiveness and abundance of solar irradiance make solar the best technology for this endeavour. Solar Home Systems (SHS) have successfully provided basic services like lighting and mobile phone charging to many communities. However, SHS offer low power output, which limits their ability to support more energy-intensive applications such as electric cooking. Electric stoves, which could significantly reduce reliance on wood stoves, offer health and environmental benefits but require much more power than what SHS can provide. Connecting multiple SHS to form a larger grid has been considered but is often impractical due to high costs and limited scalability. Instead, community-scale solar mini-grids, with larger generation and storage, present a viable alternative. These mini-grids can be designed to support household cooking and industrial and agricultural uses such as grain milling and cooling. They can also provide power for electric vehicle (EV) charging stations, an important development in many African cities where motorbike taxis are common. Electric motorbikes offer a cleaner alternative to fuel-powered engines but require reliable and substantial power sources for charging. Integrating mini-grids with local distribution networks can enhance their efficiency and reliability. By connecting mini-grids to these networks, they can share resources and provide power during peak demand times or when the main grid is down. This integration can benefit both the mini-grids and the distribution system, creating a more resilient energy network. The installation of solar panels requires a significant land area, which can conflict with agricultural activities and conservation efforts. However, solar panels can power agricultural equipment like water pumps and with appropriate co-design (agrivoltaics) the panels can provide shade and support soil temperature control and water conservation. Additionally, the revenue from mini-grid services can support local farmers and enhance their economic stability. Our project will explore how mini-grids with EV charging infrastructure for small vehicles can be integrated into agricultural areas and support various community needs. We will develop geographical models to identify optimal locations for these mini-grids and evaluate how different technologies and applications can be combined. Our research team, with expertise in infrastructure planning, political geography, and electrical engineering, will focus on how mini-grids can interact with local distribution networks to maximize their benefits. We plan to test these concepts in real-world settings by deploying a small set of EVs and suitable charging infrastructure. The interaction with the community, industrial developers and national regulators based in Ghana, Rwanda and Kenya will provide steering and inform the development of models and systems required in our work. The project is led by Imperial College London with a consortium of researchers from the University of Strathmore (Kenya), University of Energy and Natural Resources of Ghana, the University of Leeds, the University of Rwanda, the African Institute for Mathematical Sciences and the Kigali Centre for Collaborative Research (Rwanda).

UKRI Gateway to Research · FY 2025 · 2025-01

Photosynthesis uses sunlight to provide the energy for life. It takes CO2 from the atmosphere to make the carbon polymers that are the fuels and building blocks of living things. The electrons required are taken from water, and the oxygen released energizes the atmosphere, thus allowing complex life to evolve. Over time, much of the biomass produced was sequestered in sedimentary rock, lowering atmospheric CO2 concentrations, and establishing a climate on this planet appropriate for the current inhabitants. Mankind caused the climate crisis by reversing photosynthesis through an over-zealous enthusiasm for combustion. Because of the poor efficiency of photosynthesis, biofuels cannot (at present) replace fossil fuels. However, by understanding photosynthesis, we can improve its efficiency for less energy-intensive production of food and of other complex biomaterials for the bioeconomy. This project takes advantage of the unexpected discovery of low-energy, long-wavelength forms of oxygenic photosynthesis. Some species of cyanobacteria can swap their usual 100% chlorophyll-a-based photosynthetic apparatus for one in which 10% of the chlorophyll-a molecules are replaced by chlorophylls-f, which absorbs light of longer wavelength. This only occurs when the cyanobacteria find themselves shaded from visible light but still irradiated by far-red/near-infrared light, a not uncommon occurrence given the dominance of conventional chlorophyll-a photosynthesis. This far-red (FR) photosynthesis does the same chemistry as conventional, visible-light photosynthesis, but it runs on light with less energy. In this project we shall use biochemical, biophysical (spectroscopic, structural, and computational) and molecular biology approaches to study the far-red version of Photosystem 2 (FR-PS2), the water/plastoquinone photo-oxidoreductase of far-red photosynthesis, and compare it to the PS2 of conventional photosynthesis. Conventional PS2 is already limited by the energy available in red light. Thus, FR-PS2 is expected to be even more limited. We have shown however that it works almost as efficiently as conventional PS2. Here we shall determine how evolution has tuned FR-PS2 to overcome the energy shortfall. We shall determine the structure of the FR-PS2 and compare it to conventional PS2. Our earlier work and unpublished preliminary work has identified several changes specific to FR-PS2 in close proximity to key elements of the enzyme. To study specific intermediates in the enzyme cycle, we will set up a flash/freeze cryo-EM apparatus. This may be the first flash/freeze cryo-EM set-up in this field and possibly in the UK. This apparatus will be applicable and available to study a range of other light-driven enzymes outside of this project. The PDRA will develop this flash-freeze cryo-EM set-up, perform a range of other biophysical methods (spectroscopy and computational modelling) and isolate functional far-red PS2. The PDRA will also engineer each tuning modification into conventional PS2 and characterize the mutants. Overall, the PDRA will contribute to understanding photosynthesis while gaining a unique portfolio of expertise at the forefront of 21st century molecular bioenergetics and molecular enzymology. The modifications in FR-PS2 studied here will be required in when engineering far-red crop plants. This study will also provide an improved mechanistic understanding of the key features in normal photosynthesis which are tunable for function in a range of conditions. Knowledge of these adjustment-points will allow optimization of normal plants growing under specific growth-conditions, different light regimes (different intensities and colours, under different stress conditions, etc.) relevant to changes in climate and changes in agricultural methods (such as growth under artificial light).

UKRI Gateway to Research · FY 2025 · 2025-01

When we break an ankle, further damage is prevented through the protective sensation of pain; we avoid weight bearing. Unfortunately on occasion, after damaged body parts have healed, pain persists. This kind of pain, termed chronic pain, has no protective function. Current pain relieving drugs do not always work and as such chronic pain affects up to 20% of the adult population. This results in a significant economic strain on the healthcare system as well as a huge socioeconomic burden on the individual. To identify new drugs that make chronic pain patients feel less pain we must identify new therapeutic targets based on novel mechanistic insight. My research ultimately aims to provide such insight. The process of pain perception is highly complex. It involves many different nerve signals travelling from the brain to the spinal cord. These nerve signals comprise regulatory pathways that, in the normal situation, make us feel less pain. However, in chronic pain, the function of these regulatory pathways can go wrong leading us to feel more pain. This grant seeks to investigate the functionality of these pathways a) in health and b) in a rodent model of chronic pain. Chronic pain can manifest in patients suffering from cancer; the growth of secondary cancer tumours in the bone may lead to cancer induced bone pain (CIBP). Due to improvements in cancer treatments coupled with largely ineffective pain relieving options, the prevalence of CIBP is high. In my laboratory I have developed a rodent model of CIBP that encompasses early and late stages of the disease. I have collected preliminary data showing that regulatory pathways, from the brain to the spinal cord, do not function in the proper manner in these rodents in the early stage of disease. I wish to use NIRG MRC funding to prove whether or not the nerve signals that comprise the regulatory pathways have gone wrong in a manner that is specific to the stage of disease progression. My hypotheses are that multiple distinct regulatory pathways exist and that regulatory pathways are impacted negatively in a stage-specific way. I propose that this negative impact on regulatory pathways is an underlying cause of the pain associated with this disease, and if true it would mean that directed therapies, intended to relieve suffering in, for example, cancer pain patients, could be more easily formulated according to, for example, the stage of disease. To this end I will study the influencing factors and function of brain to spinal cord inhibitory pain pathways in health and in CIBP rats. Through comparison it will be possible to pinpoint where regulatory pain pathway connections have gone wrong. Ultimately, pain-relieving agents could be prescribed more effectively if we understand what regulatory pain pathway we should target for chronic pain relief.

UKRI Gateway to Research · FY 2025 · 2025-01

Characterizing the shallow subsurface of Mars remains a challenge due to the existence of a sensing gap at the depths of meters. iPMS will close this gap by utilizing the fact that the surface of Mars is continuously bombarded by meteoroids which excavate material from those depths. The theoretical foundations of impact cratering indicate that the spatial distributions of ejecta are sensitive to the material properties. As over 1000 fresh impact craters and ejecta formed in the period of spacecraft observation were imaged with the highest resolution camera orbiting Mars (NASA MRO HiRISE), I propose to study these sites in theory and in reality in order to i) establish how ejecta spatial distributions vary with latitude, elevation and terrain types, ii) describe the theoretical dependency of these distributions on subsurface rheology and impact conditions, iii) constrain the subsurface rheology near selected impact sites, including human-made ones formed via controlled release of ballasts by spacecraft. This will be achieved by performing 1) analysis of ejecta in HiRISE images, 2) numerical impact experiments into a variety of layered subsurface targets with shock physics code iSALE. By combining the two approaches, I will tackle some key unanswered scientific questions in planetary science outlined by Decadal Survey 2023-2032. This project contributes to the bigger challenges of mapping water ice on Mars, is relevant for planetary protection, and will reinforce Europe's leadership and autonomy in space sciences.

UKRI Gateway to Research · FY 2025 · 2025-01

Newborns are colonized by microbes at birth and during the first months of postnatal life. In order to establish symbiotic relationships with microbes, newborn immune cells must tolerate beneficial microbes, while limiting invasive pathogens (1). This ancient process, shaped by evolution, may be altered by antibiotic exposure, C-section delivery and infant formula, all of which associate with an increased risk of immune-mediated disease like allergies, asthma and inflammatory bowel disease (2). The mechanisms whereby symbiotic immune-microbe interactions are established remain poorly understood in humans. In mice, a transient immune reaction to commensals occurs after weaning, inducing regulatory T cells and tolerance which prevent immunopathology later in life (3). Whether a similar response occurs in humans early in life is not known. Interactions with commensals are also important for generating a diversified repertoire of cross-reactive lymphocytes able to recognize and respond to pathogens and vaccines. Here I propose multimodal analyses of adaptive lymphocyte responses towards colonizing microbes early in life by single-cell analyses and antibody profiling of serial blood samples already collected from a human birth cohort (6–8). By monitoring the specificity, clonal structure and transcriptional regulation of commensal-reactive T and B cells, we hope to learn how tolerance is ensured, and colonization allowed, and how commensal-specific lymphocytes are diversified, maintained and regulated to secure long-term immune-microbe mutualism. This program holds the potential for greatly expanding our knowledge of newborn immune systems and the development of healthy immune microbe interactions, with important implications for understanding immune-mediated disease, susceptibility to infections and the protective effects of vaccines.