KING'S COLLEGE LONDON

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

At present, lithium-ion batteries (LiBs) are most commonly used for electric vehicles and grid storage applications. However, LiBs have come under severe scrutiny for their environmental and social impacts caused by exploitative mining in the Global South. Moreover, they face severe challenges with regards to their supply chain including the ever-increasing demand of critical raw materials and the emergence of mining and manufacturing monopolies, which in turn has created significant price volatility. These supply chain weaknesses put the battery demand satisfaction, and with it the energy transition at risk. This fellowship proposal aims at advancing the development of aluminium-ion batteries (AiBs) as an innovative, sustainable, and resilient alternative to LiBs. To this end, I will employ a multidisciplinary research approach combining materials science with environmental, economic, policy, and supply chain considerations. Compared to LiBs, AiBs have the advantage of increased volumetric energy densities (increased amount of energy without increasing the size of the battery), lower supply chain risks (abundance of raw materials) and lower environmental footprint (the use of recycled aluminium can avoid the burden of ore processing). Despite these important advantages, AiBs are still under-researched and the battery performance falls short of its potential. Two primary challenges hinder their progress: 1) the cathode (electrical conductor) materials tested to date for AiBs demonstrate low performance and short lifetime, and 2) there is a significant knowledge gap regarding the underlying reactions that determine and hamper performance, impeding precise control of battery performance. With this fellowship, I lay out an ambitious programme to address these key technical challenges holding back AiB development. Here, I propose a novel materials design approach to explore a previously untapped pool of materials that could serve as potential AiB cathodes. The in-depth investigation of their fundamental electrochemical and molecular reaction mechanisms via sophisticated characterisation techniques during battery usage will create new knowledge that will be leveraged to identify performance bottlenecks, enabling the engineering of high-performance cathode materials for AiBs. This research proposal is strongly embedded in and guided by sustainability and resilience considerations of AiBs. My team and I will research synthesis methods informed by green chemistry principles to avoid lengthy and energy-intensive manufacturing processes. Moreover, we aim to use battery materials that are not only abundant and evenly distributed geographically, but also have minimal social and environmental impacts. We will apply life cycle assessment and techno-economic models evaluating the impacts across the AiB value chain to inform the battery materials design process. During the fellowship extension (+3 years), the development of AiBs will be continued towards up-scaling and prototyping, where the main challenges to be tackled will be the development of materials manufacturing processes suitable for up-scaling and the design of the battery cell. This research will benefit from a strong cross-disciplinary academic and industry network supporting the advancement of this exciting technology and the generation of global impact. This research not only pushes the limits of an emerging battery technology and sees through its advancement towards prototyping, but it will also support the alleviation of supply chain bottlenecks and geopolitical risks associated with current lithium-ion batteries. This will have significant academic impact via the creation of new knowledge while fostering societal and environmental benefits. Through the establishment of a robust green battery supply chain, this research will contribute to a resilient energy future.

UKRI Gateway to Research · FY 2024 · 2024-09

The detection of chemical cues from the outside world is fundamental to animal survival. In mammals, sensing of the external chemical environment governs diverse behaviours including selection of food, social interactions, and avoidance of predators. Decoding the complex chemical milieu of odorants in the environment into functionally relevant responses requires similarly complex detection systems and, in many animals, this is achieved through two principal chemosensory systems: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO) in the nose. These evolutionary conserved olfactory organs contain millions of olfactory sensory neurons and vomeronasal sensory neurons that express arrays of chemosensory receptors each activated by a specific chemical signal. Sensory neurons of the MOE and VNO are the only neurons in mammals that are in direct contact with the external environment, which includes the specialised microbial communities of the nasal tissues. Given this direct contact, these sensory neurones are permanently exposed to oxidative stress, pathogens, or xenobiotics and, consequently, have a limited lifespan, compensated by continuous neurogenesis throughout adulthood. Increasingly, it is appreciated that development and maintenance of host tissues is influenced by the microbial communities that live in and on our skin, gut, mouth, and nose. This can be due to direct contact, as in the gut, or via the production of microbial metabolites that have an indirect influence on development of organs such as the brain. Recent evidence from humans and mouse suggests that the microbiome can also impact smell, and chemosensing. For example, a number of viral and bacterial infections can lead to loss of the sense of smell. Anosmia is an early sign of COVID-19, with ACE2, critical for SARS-CoV2 entry into cells, being expressed in the olfactory support populations. Disturbed nasal microbiome and metabolites have additionally been discovered in patients with olfactory dysfunction. The gut microbiome metabolites can also impact the olfactory system, such that mice with low gut microbial TMA production have altered olfactory perception. Importantly, germ-free (GF) mice have an impaired olfactory function when compared to conventionally reared specific-pathogen free (SPF) mice, taking longer to find hidden food pellets, and showing reduced expression of olfactory receptors. In this application we will investigate the role of the host and maternal microbiota in the development and maintenance of chemosensing using mouse models. Three aims will be addressed: Aim 1. To map the distribution of microbiota in the nose over time and correlate to gene expression patterns: mapping the host and microbiome together. Aim 2. To understand when and how the microbiota impact chemosensation. Aim 3: To assess whether chemosensation can be rescued or reduced by timed introduction/loss of microbiota and/or metabolites. The results will highlight the under-explored impact of the microbiome on chemosensation, teasing apart metabolite versus direct effects, and developmental changes versus maintenance. Of particular importance, the findings will open potential avenues to manipulate and rescue chemosensation through control of the microbial environment or provision of metabolites. This could lead to new therapeutics and recovery of chemosensation in affected patients. The research falls within the remit of Research committee C "Genes, development and STEM approaches" and the overall BBSRC strategy of supporting bioscience discovery and understanding the rules of life. Knowledge of microbiome interactions has the potential to catalyse the creation of novel therapeutics, but it is first important to understand the underlying mechanisms.

UKRI Gateway to Research · FY 2024 · 2024-09

While Gender-based Violence (GBV) occurs everywhere, countries such as Brazil are especially badly affected. GBV is a key development challenge with its elimination being central to the achievement of Sustainable Development Goal (SDG) 5 on gender equality. Although existing research acknowledges that younger women bear the brunt of GBV, their experiences as activists are poorly understood and under-researched despite a 'feminist spring' of protest among youth across Latin America over the last decade. The combination of art and activism has been key to this, suggesting possibilities for preventing GBV through engaging with feminist 'artivism'. This project develops an innovative translational arts-based approach to prevent GBV in Brazil and creates engagement and policy pathways that can be scaled-up transnationally. Drawing on established successful international collaborations, it will be conducted in the favelas of Maré in Rio de Janeiro with Redes da Maré (Redes) (a community-based human rights NGO), together with People's Palace Projects (an arts centre using creativity for transformation - PPP) and Women of the World Foundation (a global movement creating a gender equal world - WOW). Focusing on young people (mainly cisgender and trans women as victims but also some men as perpetrators aged 16-25) as the key to preventing GBV among future generations, it will work in Maré where the team has developed pioneering research on GBV since 2016. This showed that 57% of cisgender women experienced GBV, especially young (aged 18-29) and Afro-descendant women. Working with Redes and their Women's House, this project explores the drivers of GBV in terms of social norms and structures and how to build feminist youth activism. Inspired by Latin American feminist decolonial scholarship and protest, the study theorises how to transform protest against GBV into feminist activism for prevention and the role of co-produced arts-based approaches within this. It does so through applied arts workshops with young people encouraging conversations around GBV using poetry, photography, dance, and digital storytelling led by local artists. It will culminate in a co-curated multi-media installation and a creative youth encounters toolkit to maximise awareness and profile raising. Through focus groups, storytelling and video-making, the young people will develop digital educational materials on preventing GBV to be disseminated in secondary schools across Brazil and Latin America through south-south collaboration facilitated by Redes, PPP and WOW as a way of informing the next generation on how to prevent GBV in the future. A key aspect of the engagement pathway is the curation of a Day of the Girl Festival in Rio co-curated by youth from Maré showcasing their creative youth encounters. Developing south-north, south-south and transnational linkages, the project will also stage an International Girls Festival in London with WOW featuring a learning workshop led by Maré youth communicated through their global partnerships network reaching 63.5 million people each year, across 45 locations and six continents. These young people will be included in the WOW Young Leaders Directory, and two transnational exchanges among youth between Rio and London will be developed Finally, the project develops a transnational policy pathway through Redes' ongoing work with the Municipal Council of Policies for Women in Rio where they are policy champions on their advisory council and WOW's work with the Young People's Action Group (YPAG) as part of the Violence Reduction Unit at the Greater London Assembly.

UKRI Gateway to Research · FY 2024 · 2024-09

Most proteins need to self-assemble into well-defined, specific 3D structures to be functional. Failure of proteins to fold correctly, or to remain correctly folded, is the origin of a wide variety of diseases. However, to shuttle between different cellular compartments separated by lipid membranes (such in mitochondria, chloroplasts or the endoplasmic reticulum) proteins need to transiently unfold through narrow pores that act as highly-evolved molecular gateways. Similarly, disaggregation and proteasome-mediated degradation also requires proteins to traffic across narrow pores. This is an active process that uses ATP energy to mechanically unfold the protein as a prerequisite for translocation. These directional unfolding pathways followed by proteins when crossing pores are very different from those sampled when proteins are free in solution. In fact, the stretched shape required to navigate these narrow pores is reminiscent of the conformations visited by proteins when unfolded mechanically using in-vitro single-molecule nanomechanical techniques, such as the atomic force microscope or the optical/magnetic tweezers. Yet, direct experimental verification of the mechanical determinants underpinning protein unfolding during translocation in the cell has remained largely untestable, mostly because the vast pre-existing knowledge on protein folding that we have using classical bulk biochemistry is not relevant in the mechanical context. The challenge lies in developing cross-scale experimental approaches able to correlate the nanomechanical properties of proteins measured in-vitro with their behaviour when functioning within the cells – and apply it to the particular context of their translocation across biologically-relevant pores. In this work programme we aim to elucidate the molecular mechanisms by which protein nanomechanics regulates the cellular translocation of proteins across biological pores as diverse as the proteasome, the nuclear pore complex or the peroxisome. We will do this by developing and applying a combination of state-of-the-art optogenetics experiments inspired by the nanomechanical properties of individual proteins, complemented with steered molecular dynamics simulations (SMD) and crystallography. In particular, we aim to uncover whether the force-induced mechanisms regulating the translocation of proteins across the narrow proteasome pore hold true for other much wider pores such as peroxisomes or the nuclear pore complex – for which we have recent tantalising evidences that, contrary to previous belief, mechanical unfolding accelerates protein translocation. Our ambition is to uncover a potential general mechanism to address how the structure and conformational dynamics of proteins under force regulate their translocation across a suite of structurally- and functionally distinct biological pores. The fundamental and mechanistic knowledge we generate will enable us to directly test the macroscopic and functional effects of precise molecular perturbations. It will also forge new territory to connect ‘molecular gymnastics’ with cellular mechano-response – potentially leading to new insights into molecular transport. This overarching approach provides the exciting and unique opportunity to design new molecular strategies and biotechnological tools towards the engineering of nuclear transport, drug delivery and nuclear mechanotransduction, and to regulate protein homeostasis through mechano-control.    

UKRI Gateway to Research · FY 2024 · 2024-09

Analytic number theorists study how arithmetic sequences are modelled by random processes. This project aims to show that a property of the square numbers (involving gaps between dilated squares) is approximated by a Poisson process. Doing so would resolve a deep 25-year-old conjecture, and provide rigorous justification around the mysterious phenomenon of quantum chaos. Context Start with an irrational number x, e.g. the square root of 2, and consider x, 2x, 3x,... etcetera. Restricting to the part after the decimal point (i.e. working ‘mod 1’), the sequence becomes 0.414...,0.828...,0.242...: what is its behaviour? In 1916 Weyl proved that nx mod 1 is equidistributed, meaning that the proportion of numbers n for which nx mod 1 lies in a fixed interval is approximately the length of that interval. For example, nx mod 1 begins 0.375569... for about 1 in a million values of n. A sequence of N independent uniformly distributed random points between 0 and 1 is also equidistributed (with high probability). Thus, Weyl demonstrated a pseudorandomness property of the sequence nx mod 1; he also proved the same result with n replaced by the sequence of square numbers. These results have become central number-theoretic tools, as (when combined with analytic techniques) they help to count solutions to equations. Consider again the N random points. The average gap between consecutive points is 1/N, albeit with some much tighter clusters. These clusters can be precisely calculated: for instance, the proportion of gaps of length at most s/N is about 1 - exp(-s). Now, take the first N squares 1,4,9,16... and consider the sequence x,4x,9x,16x, etcetera. The sequence mod 1 runs 0.414...,0.656...,0.727...,0.627....Weyl showed the sequence is pseudorandom, in the sense of equidistribution. But does its gap distribution agree with the random points? Rudnick-Sarnak conjectured that the distributions do agree, at least for a generic x. This is a profound and influential observation, positing a vast generalisation of Weyl's work. Aims, challenges, and objectives The ultimate goal of this project is to prove the Rudnick-Sarnak conjecture. This would be a major result in arithmetic pseudorandomness. There is a natural approach, using so-called 'k-correlation functions', and in earlier work I advanced the study of 2-correlations and 3-correlations associated to this problem. The project's sub-goals build on this work, before generalising to all k-correlations. The Rudnick-Sarnak prediction is backed by convincing data. However, little has been rigorously proved, the main challenge being that the scale length 1/N is so short. Potential applications and benefits The main beneficiaries will be academic, as the topic intersects with many mathematical areas: number theory, harmonic analysis, probability, additive combinatorics, and dynamics. There is also a potential application to physics. The sequence of dilated squares can be viewed as the eigenvalue energy levels of a quantum system; Berry-Tabor observed in experiments that the gap distributions of such eigenvalues are determined by the dynamics of the corresponding classical system. Integrable classical dynamics should correspond to a 'poissonian gap distribution' (our case): chaotic dynamics should correspond to gap distributions arising from random matrix theory. Though there is strong empirical evidence, precious little has been rigorously proved: this project aims to provide such proof in an explicit case. As this project studies pseudorandom properties of concrete sequences, there could also be potential applications to Monte Carlo methods: in mathematical finance, engineering, and beyond.              

UKRI Gateway to Research · FY 2024 · 2024-09

We combine a range of research capabilities (new portable MRI scanner and our AI tools), and draw on multi- and interdisciplinary teams (clinicians and scientists from different faculties and different hospitals as well as a patient with relevant lived experience), to conduct early-stage translational medical research with the potential for patient benefit. Two technological developments underpin the proposed work. First, we developed an Artificial Intelligence (AI) tool that can accurately sort magnetic resonance imaging (MRI) brain scans into normal and abnormal (i.e., there appears to be disease). The AI "triage" tool that we built allows radiologists to report abnormal brain scans preferentially before normal scans which results in faster management of patients with disease. The downstream effect of our AI tool is to reduce the effects of disease, and related healthcare costs. Second, recent technology allows MRI scans to be performed using a small, portable MRI scanner that does not require a dedicated hospital room with a fixed MRI scanner. Furthermore, unlike fixed MRI scans, it is also safe to use the portable MRI scanner next to metalwork. As such the portable MRI scanner can be used in GP surgeries, Community Diagnostic Hubs or wheeled to the bedside of a patient in an Intensive Care Unit who may be very unwell and therefore at high risk for transfer to the standard MRI department. The portable MRI scanner is also very cheap to buy and to run when compared to a fixed MRI. The "trade off" is that the images obtained are not as clear as the scans obtained in fixed MRI scanners. Nonetheless, the clarity of the images for relatively simple tasks such as sorting patients into normal and abnormal is sufficient - if abnormal, patients can be prioritised for onward referral for standard (fixed) MRI where the superior images can be used for more complex assessments. Our aim is to use an AI trick called "transfer learning" to combine knowledge from our AI tool for triage (which was built for standard MRI scans) with a small number of research scans from the portable scanner in order to build an accurate portable MRI AI "triage" tool. Our proposal will plausibly provide the initial evidence required to support the next translational research step that would bring the portable MRI AI "triage" tool to the clinic. Potential use-cases for translation are considerable. Because putting an intensive care patient inside a standard MRI scanner is both hazardous and laborious, a bedside portable scanner with an AI "triage" tool might indicate to the treating team whether it is sensible and necessary to proceed to standard MRI. Additionally, the portable scanner would allow an initial triage in the community where patients have nonspecific clinical features. For example, many types of headache are a common problem but rarely associated with an abnormality. Community triage with an AI "triage" tool would plausibly allow more rapid onward referral for targeted imaging in those with an abnormality, for example, specialised MR imaging for possible brain tumour patients. The research has immense potential to contribute to hospital and community medicine in countries like the UK. We also emphasise that low-income countries with almost no access to standard MRIs might benefit disproportionately from such a tool, as the portable scanner is cheap (~£200k compared to ~£1-2M for a standard MRI scanner).

UKRI Gateway to Research · FY 2024 · 2024-09

Lasers and optical amplifiers in the near- and short-wave infrared regions (700 nm to 3000 nm) are are a key enabling photonic technology in modern technologies. They span many relevant technological windows such as telecommunications bands (1250 nm to 1625 nm), LIDAR wavelengths (905 nm & 1550 nm), eye-safe wavelengths (>1400 nm), and the NIR-IIc (1700 nm to 1880 nm), NIR-III (2080 nm to 2340 nm) biological windows and atmospheric gas sensing spectroscopy (~2000 nm). However, the integration of traditional vacuum deposited semiconductor laser diodes and silicon microelectronics/photonics is notoriously difficult due to material incompatibilities, preventing the very-large scale integration of these technologies and the development of on-chip quantum communication/information devices. Solution processed PbS colloidal quantum dots (CQDs) could better serve these applications in the infrared as they can be readily integrated into silicon technologies, lend themselves to cost-effective large scale production of photonic devices and have tunable optoelectronic properties. However, the first generation of PbS lasers suffer from large FWHM (~ 4 nm) and low q-factors, limiting their application. High q-factor cavities, such as those generated from plasmonic strucures. are therefore also required to maximize the potential of PbS CQD lasers. The aim of this project will be to make a crucial step in advancing PbS CQD laser technology for integrated photonics and explore their viability as future photonic devices, through the development of plasmonic caivites.

UKRI Gateway to Research · FY 2024 · 2024-09

The role of media is key to shape public understanding of humans' impact on the planet, raising awareness of environmental issues and motivating social and policy actions to tackle them. Within the field of environmental communication, and more specifically climate change communication, news media coverage has received an increasing amount of scholarly attention. However, most of the studies that delve into the practices, effects, impediments, and successful strategies to frame content about the environment are centered on the Global North. In contrast, this research (acronym ECOLA) is focused on Latin America, home to one of the most diverse ecosystems on the planet and a region particularly susceptible to the impact of climate change. Amid the widespread threat of misinformation in countries such as Brazil, this study moves beyond traditional news media enquiries to investigate how a broader range of communicators across different media and national contexts, such as reporters, photojournalists, documentary filmmakers and community leaders, are disseminating mediated discourses about the environment that can push for solutions. Understanding the debates raised by a diverse group o regional media actors is essential to build connections between global researchers, media producers and other stakeholders interested in strategic communication to facilitate society's engagement with ecological problems. Environmental communication is a growing field of research that bridges natural sciences and the humanities, crossing different disciplines such as media, journalism, cultural, social movements and urban studies. ECOLA aims to expand the interdisciplinary knowledge of the field by critically analysing the landscape and the dynamics of environmental communication in an underrepresented region and beyond large media corporations. The main research questions address the type of news stories that Latin American producers are disseminating online to inform society about ecological crises beyond "breaking news"; the extent to which they include the voices of those who are among the most affected and the main challenges of environmental coverage in a regional context of economic and political instability. The project will use semi-structured interviews with journalists and other environmental communicators across Latin America, to establish their views on their innovative practices, their perceived role, the responses from the audiences and the challenges to inform society about climate change. Their accounts will help to identify unifying aspects of their practices and to shed light on transnation obstacles such as anti-enviromental discourses driven by misinformation, political polarisation and/or economic pressure. Interviews will be combined with participant observation in Brazil and analysis of the coverage of climate change, using seminal case studies.

UKRI Gateway to Research · FY 2024 · 2024-09

The Parliamentary Thematic Research Lead on International Affairs and National Security, will be embedded in the UK Parliament, working alongside parliamentary staff. This lead role will bring the research perspective to work carried out by select committees, libraries and Parliamentary Office of Science and Technology (POST). The role will include leading horizon scanning and futures work and supporting parliamentary staff to take a strategic approach to planning their work programmes, including supporting the development of committee Areas of Research Interest. The Thematic Research Lead will identify upcoming needs for Parliamentary Academic Fellows and opportunities for co-production of briefings between academics and Parliamentary staff. They will connect and expand their networks (including research, learned societies and industry) to support parliamentary activities and will liaise with those in the Government CSA Network team. This will enhance engagement with those working in research to policy, fostering collaboration and knowledge exchange. The Thematic Research Lead will liaise with UKRI and its research councils to enable increased parliamentary impact of UKRI investments. They will share insights from Parliament back to the research councils and UKRI; by doing so, they will contribute to the development of the research-policy ecosystem. The Thematic Research Lead will support with identifying the skills and experience needs of members of the parliamentary thematic team and relevant development and training opportunities. They will also help to identify opportunities for secondments, placements or people-exchanges both into and out of Parliament. Beyond working in their policy area, the Thematic Research Lead will work as part of a network with the other Thematic Research Leads to identify cross-cutting opportunities or issues and develop strategic responses, share information, learning, insights and best practice.

UKRI Gateway to Research · FY 2024 · 2024-08

Eukaryotes use sterols to modulate biophysical properties of cellular membranes, whereas some bacteria produce hopanoids as sterol mimics. Unlike sterols, hopanoids do not require oxygen for their biosynthesis. Interestingly, some eukaryotic organisms populating hypoxic environments, including several species of pathogenic fungi, appear to have acquired squalene-hopene cyclase (SHC), the enzyme responsible for hopanoid production, through horizontal gene transfer. How SHC is "domesticated", and how the regulation of hopanoid and sterol production is coordinated, is unknown. I will probe these fundamental questions using a comparative biology approach. The fission yeast Schizosaccharomyces japonicus relies on SHC to grow anaerobically, whereas its relative, Schizosaccharomyces pombe, is an obligate aerobe lacking SHC. I will use a combination of molecular genetics, cell biology, protein and lipid biochemistry, and next generation sequencing approaches to explain 1) how hopanoid production is regulated; 2) how hopanoids contribute to cellular and organismal physiology in the presence and absence of oxygen; and 3) how S. japonicus balances the production of ergosterol and hopanoids depending on environmental conditions. Understanding how hopanoid synthesis is regulated and how it contributes to cellular physiology may help define new targets for antifungal therapies. It may also become useful in industrial biotechnology applications, for instance to support yeast growth in anoxic environment of bioreactors. Importantly, probing this rich biology will also provide wider insights into the principles of membrane organization and function and shed light on the mechanisms underlying "domestication" of horizontally transferred genes in eukaryotes.

UKRI Gateway to Research · FY 2024 · 2024-08

Our multidisciplinary team, positioned at the nexus of advanced microscopy, optical design, Fluorescence Lifetime Imaging Microscopy (FLIM), adaptive optics, sensor technology, and biological research, aims to usher in a new era of biological imaging. As we integrate three-photon microscopy with FLIM, our goal is to provide an unparalleled depth of understanding into 3D cell cultures. This effort is crucial for shedding light on physiological interactions, key developmental processes, and the intricate mechanisms underlying disease progression. While 2D monolayer cell cultures have historically been the primary tool for understanding cellular processes, they offer only a limited perspective. These flat cultures often miss out on capturing the depth and complexity of cellular interactions found within living organisms. Recognizing these limitations, there has been a growing emphasis on the use of 3D cell cultures. These cultures more accurately mimic in vivo conditions, replicating authentic cellular interactions, structures, and behaviours that are central to understanding live developmental stages. Two-photon excitation (2PE) microscopy, despite its transformative contributions to cellular imaging, has faced challenges, notably its penetration depth in complex biological media. To address this, our team is leveraging three-photon excitation microscopy (3PE) with novel laser sources in tandem with high-speed fluorescence lifetime imaging (utilising the innovative 1D FLIM SPAD array sensor). This combination promises faster acquisition speeds and enhanced functional imaging capabilities, paving the way for high-throughput biological investigations. By incorporating advanced holography and temporal focusing techniques, we aim to optimize photon generation and maintain precise alignment on the detector array. This ensures that we can delve deeper into biological samples, capturing details previously out of reach. In collaboration with life scientists at King's College London, we plan to showcase the potential of our technology across various biological research areas. We are particularly keen to explore cellular dynamics in 3D cultures and probe the biochemical intricacies of developmental biology. At King's College London's Comprehensive Cancer Centre, our team has access to top-tier imaging infrastructure. This environment, combined with our collaborative and innovative spirit, places us in a strong position to further the field of biological imaging. As we push forward, we are committed to bridging the gap between traditional 2D models and in-depth in vivo studies, driving new revelations in cellular behaviour, developmental biology, and beyond.

UKRI Gateway to Research · FY 2024 · 2024-08

Organ transplantation remains the only definitive treatment for end-stage heart, lung, liver or kidney disease. Early transplant outcomes are now generally excellent, dramatically reducing patients' mortality and morbidity. Nevertheless, transplantation still faces significant obstacles, especially long-term immunosuppression-related toxicity and chronic decline of transplant function, which are the leading causes of transplant failure. To break these barriers, which represent a very significant societal and economic burden in the EU, there is a need for innovative therapies to lessen our reliance on conventional immunosuppression and better control non-resolving inflammation. Extracorporeal photopheresis (ECP) is now being investigated as a personalized, adjunct immunosuppressive therapy in some organ transplant settings. However, ECP is regarded as a controversial therapy, primarily because current understanding of its pharmacological actions is incomplete, but also because there remain questions about optimal manufacturing processes, quality-control and personalized clinical indications. The exTra project asks whether a better mechanistic understanding of ECP can guide us more efficiently towards novel applications. Specifically, exTra brings together European experts in clinical transplantation, immunology, pharmaceutical development, computational biology and medical device manufacture to address key questions through a coordinated, interdisciplinary effort. exTra proposes 10 independent doctoral research projects with the ambition of providing its trainees with a comprehensive understanding of basic and translational immunology, especially relating development and licensing of new immunotherapies. Through its research and training activities, the exTra project will contribute to scientific advancement and innovation in Europe, ultimately leading to societal and economic benefits stemming from clinical innovations in transplant immunotherapy and beyond.

UKRI Gateway to Research · FY 2024 · 2024-08

Vector-borne diseases (VBDs) are among the most wicked of climate change-driven global health threats. Increasing temperatures and extreme rainfall patterns are extending the range and disease-carrying capacity of key mosquito vectors, amplifying the global risk of infection. At the same, mass migrations, deforestation and rapid, unplanned urbanisation are seeding new contexts VBD exposure and endemicity. The large-scale roll out of Insecticide Treated Nets (ITNs) and Indoor Residual Spraying (IRS) have succeeded in making major gains against malaria—the VBD responsible for the greatest number of deaths globally—but in recent years, progress has stalled (WHO, 2023). Increasing insecticide resistance is a major driver of this worrying trend, but these frontline tools, which require consistent use, continual reapplication, and comprehensive coverage, have limitations inherent in their design. Above all, ITNs and IRS can do little to offset the mosquito biting risks attendant to substandard, and poorly constructed housing, where the vast majority of those most vulnerable to VBDs are most likely to reside (WHO 2017). Tackling VBD epidemics under warming conditions requires safe, climate-resilient, housing capable of conferring protection from mosquitoes but without reliance on expensive and energy-intensive mechanical systems. This proposal responds to that clear need by harnessing the untapped potential of the 'humble brick.' The world's most commonly used building material, earthen bricks are durable, modular, low-maintenance, heat and insect resistant, with great potential for recycling and reuse. Bringing together expertise in anthropology, entomology, architecture, engineering, vector biology, urban planning, epidemiology, stakeholder engagement and climate adaptation, we seek to develop a research programme transforming this unassuming building material into a tool for epidemic preparedness, investigating adaptations to brick design, geometry and composition that can facilitate airflow and prevent mosquito entry, while aligning with local construction methods, priorities and markets. The proposal builds upon an extensive track record of collaboration between team members and the Ifakara Health Institute, a preeminent Tanzanian research organisation and a pioneer of community-based approaches to vector research, surveillance and control. Our empirical brief responds to the priorities of the Pan-African-Mosquito Control Association (PAMCA), which seeks to promote regional R&D in house improvements as means of vector-borne disease prevention. During this development phase, we will consolidate intersectional lines of inquiry on sustainable housing design, citizen science, urban vector ecology, and equity-driven climate change mitigations to develop a proof of concept for a user-led brick design process, involving students, masons, craftsmen and builders. Leveraging the teams' research networks, we will integrate collaborators in South Asia, South and Latin America to identify research questions, strategies and incorporate new case studies to adapt that process and identify opportunities for VBD resilient brick-design to be brought to scale. Interdisciplinary attention to the material components of housing and the synergistic relationships between disease, heat, emissions, energy use and domestic investments can help ensure global health resilience through a commitment to climate equity. Tackling epidemics through humble bricks situates preparedness within the local priorities, everyday needs, and capacities of communities-a process of innovation where global health, urban resilience, environmental sustainability, and dignified existence converge.

UKRI Gateway to Research · FY 2024 · 2024-08

In partnership with BORO Solutions Ltd., this project explores the commercial applications of research developed in connection with the AHRC grant "Properties, Paradox, and Circularity. A New, Type-Free Account" [grant number AH/V015516/1] (abbreviated as PPC hereafter). Cutting across boundaries, the project exploits the practical, commercial potential of abstract philosophical ideas and methods arising in formal philosophy, especially philosophical logic and formal ontology. One of our principal aims is to aid BORO Solutions in improving its commercial products and services by addressing current commercial challenges faced in the development of information and business systems, where multi-level domains tend to result in fragmented descriptions of data patterns and structures. These challenges are currently dealt with through pragmatic processes, not underpinned by a rigorous foundation. We provide this rigorous foundation. In so doing, we demonstrate the practical, commercial benefits of these abstract ideas and methods. More specifically, the project aims to: (1) demonstrate the commercial benefits of applying formal methods and technical tools developed in PPC; (2) enable commercial knowledge exchange about improved processes for handling and cleaning data in business systems; (3) aid BORO Solutions in improving its commercial products and services related to information re-engineering. Based on these aims, the project has the following primary objectives: (A) providing a rigorous formal foundation for pragmatic processes used to unify currently multi-level typed data structures in information systems; (B) using this rigorous foundation to (i) review existing processes for handling and cleaning data in business systems and (ii) uncover new opportunities to improve such processes; (C) documenting and sharing publicly information about the improved processes, thus enabling commercial knowledge exchange; (D) embedding of the formal methods developed in PPC into BORO Solutions' bCLEARer™ methodology, which underpins many of the company's commercial products and services related to information re-engineering; (E) testing the enhanced version of bCLEARer™ using data from BORO Solutions' commercial projects.

UKRI Gateway to Research · FY 2024 · 2024-08

Following a successful first phase of my fellowship, this proposal has the aim of further understanding and curbing the complexity of legal systems, from a dual standpoint: on one hand, we will develop and add important features to our 'Graphie' visualisation interface, which allows users to navigate the UK legal corpus beyond the traditional purely 'textual' paradigm. On the other hand, we will deepen our theoretical investigation on what makes a legal text 'complex' -- from the point of view of how difficult it is for a generic reader to locate a piece of information hidden in a hierarchical structure (modelled as a complex network). The phases of the project entail data collection, visualisation/user experience design, theoretical modelling, and development of novel quantitative tools to assess the complexity of dynamically interacting and ever-evolving units of a network of provisions (for instance, the articles or chapters of a living Act). The 'legal complexity' problem is long-standing and hard-felt by legal scholars, practitioners, and even untrained users, and my project has the ambition to address it via an innovative and truly interdisciplinary approach, which leverages tools from complexity science as well as state-of-the-art techniques and frameworks for data visualisation. The final goal is to demonstrate that the current way legislation is produced, displayed, and offered to end-users is highly suboptimal, and that an alternative is possible. This cultural switch will rest on recent developments in network theory and complexity science, which for the first time mark a transition between 'qualitative' and 'quantitative' approaches to legal complexity. One of the primary sources of legal complexity is the sheer volume of legal provisions in force at any given time. A rough estimate points to the existence of about 50,000,000 words of law currently in force in the UK legislative system (in comparison, there are only about 25,000 genes in the human genome) and 100,000 being produced or amended each month. Another issue concerns the way individual acts of parliament are written: the original structure as well as the subsequent amendments make it very difficult for a general reader to follow all the implications of a given provision, because multiple hops across different 'nodes' of the network are typically needed to form an exhaustive view of an act's content. The fact that legal provisions are continuously created, amended and repealed, and typically point towards other ones, either older or located elsewhere, makes the legal corpus a dynamical and highly intra-connected entity -- which is surprisingly still accessed via the same tools used for centuries: manual word searches and references to numbered paragraphs. In 2013, the Office of the Parliamentary Counsel launched the ''Good law" initiative "with a shared objective of making legislation work well for the users of today and tomorrow". However, the options proposed there to curb the complexity of the corpus as a whole -- for instance in the standard Red Tape or 2-out-1-in initiatives -- are generally based on a naïve 'item-removing' strategy, which is not guaranteed at all to achieve the goal of keeping the intricacy of the law under control. Finally, a further issue contributing to the problem of legal complexity is the fact that lawyers and legal practitioners do not usually have the necessary training in complexity science and quantitative methods to be able to effect a meaningful change on the way their own professionals go about their daily business in a more efficient and rational way. My vision is that advanced network theory, digital tools and analytical techniques from Complexity Science -- as well as the creation of an interdisciplinary training programme blending law and basic science together -- should be combined in an unprecedented synergy to set new measurable standards in the drafting, accessibility, and user-friendliness of the law.

UKRI Gateway to Research · FY 2024 · 2024-08

Up to 1 in every 3 adolescent girls will experience a mental health condition during the pregnancy and the year after birth (known as the perinatal period). While the majority of adolescent pregnancies occur in sub-Saharan Africa, there is limited evidence as to what interventions can improve mental health outcomes in this setting. The Innovative approaches for adolescent periantal wellbeing (INSPIRE) project sought to address this gap in knowledge and care by developing solutions to improve adolescent perinatal mental health outcomes in rural and peri-urban settings in Kenya and Mozambique. Through this project the Thriving Mamas programme was developed. The programme is an enhanced antenatal course designed to provide adolescents with skills and knowledge related to pregnancy and child birth, caregiving, life skills, and family planning. During the course of the INSPIRE project, our engagment with key stakeholders highlighted the difficulties policymakers, health planners, and service providers had in integrating new interventions into existing services. Existing implementation guidelines and frameworks lack utility for those without practical integration experience. The current project (Scaling-up co-designed adolescent mental health interventions) focuses on this challenge. It aims to develop an effective and useable tookit to guide stakeholders through the process of adaptation and integration of adolescent mental health interventions. A draft operational toolkit for adaptation and delivery will be developed through a series of workshops with policymakers, techinical experts, service providers, and young people. The agreed toolkit will then be tested through the adaptation of the Thriving Mamas programme for delivery in Mombasa (Kenya) and Maputo (Mozambique). Throughout these processes, qualitative and quantitative data will be collected to better understand participants' experiences of engaging in co-design activities, the utility and comprehensiveness of the operational toolkit, and the percieved feasibility, acceptability, and appropriateness of the Thriving Mamas programme in a new, urban setting.

UKRI Gateway to Research · FY 2024 · 2024-08

CAR-T therapy is a "living drug" used to treat cancer. The main component of CAR-T therapy are T cells, a type of immune cell which can directly kill diseased or infected cells. T cells are collected from the patient and redirected towards their cancerous cells by engineering them to carry a CAR (Chimeric Antigen Receptor) on their surface. This CAR allows the T cells to recognise cancer-associated proteins and direct the T cells to kill the cancer. These therapies have currently been approved for patients with blood cancers, where they can lead to long term survival in up to half of patients. CAR-T therapy has been significantly less successful in treating solid tumours. Key challenges include the failure of the CAR-T cells to survive long enough in the patient, the loss of CAR-T cell killing function and a lack of biomarkers which would allow patient-specific tailoring of the product. We will address these challenges by building on our previous research in the field of immune-metabolism. The metabolism of a cell is the way in which it turns nutrients into energy. To produce an effective immune response, it is vital for T cells to adjust their metabolism to fuel their function. T cells use a range of nutrients, such as sugars, proteins and fats; their preference varies depending on the functions that need to be supported. The CAR-T products on the market are built slightly differently, they contain different co-stimulatory domains - either CD28 or 4-1BB. These two domains differentially impact T cell metabolism and can therefore affect their function. We and others have shown that if the metabolism of a T cell becomes impaired, the T cell will lose its function. However, it is not known which types of metabolism, and the nutrients that fuel them, are required to support effective CAR-T cell function over time and how these could be manipulated to increase treatment success. To address this gap in knowledge my proposal has three aims: 1) We will investigate the metabolism of patient-derived T cells both before and after they are engineered to become CAR-T. We will assess current CAR-T (CD28 and 41BB) and a novel CAR-T which we have contributed to developing and which will be used in patients for the first time in an upcoming clinical trial. We will determine how CAR-T cell metabolism changes over treatment course and how this correlates to clinical outcome, with the aim of biomarker discovery. 2) We will determine the unknown nutrient requirements of human CAR-T cells, which is of great scientific interest, but could also allow improved CAR-T cell production by providing the correct fuel. 3) Finally, we will explore how to optimise CAR-T cell function by a) choosing the product that leads to the best CAR-T cells from any given patient and, b) use specific drug treatment during production of CAR-T cells to achieve optimal function. By defining the fundamental requirements of optimally fuelling CAR-T cell anti-cancer responses, our project will address the key challenges of improving CAR-T cell function and defining much needed biomarkers to predict treatment outcome in human patients.

UKRI Gateway to Research · FY 2024 · 2024-08

Nerve cells, or neurons, are essential building blocks of the brain. They are responsible for acquiring, storing, processing, and transmitting information. Neurons develop from stem and progenitor cells through meticulously orchestrated changes in gene expression. Gene expression typically involves (1) creating RNA copies of gene sequences in the cell nucleus, (2) modifying the RNAs using various nuclear factors, and (3) dispatching fully modified RNAs to the cytoplasm, where they serve as 'messengers' for protein synthesis. The second step of this process comprises several distinct reactions. One of them adds a chemical group called the 'cap' to the beginning of the RNA copy, while another appends the RNA end with a molecular 'tail.' In addition, there is a reaction known as splicing, which removes one or several internal portions of the original RNA sequence and joins the remaining segments together. Previous studies have shown that the same RNA copy can be spliced in more than one way. The developing neurons often utilize such alternative splicing to regulate their gene expression. One particular type of alternative splicing affects the initial, cap-modified segments of RNA sequences. How they are regulated and what they do in neurons remains poorly understood. Our work leading to this proposal revealed that cap-adjacent alternative splicing extends the initial sequence segments in hundreds of RNA messengers expressed in neurons. We found that some of these events are controlled by SRRT, a cap-associated protein abundant in stem cells but downregulated in neurons. Here, we propose to test the hypothesis that this reduction in SRRT abundance helps neurons alter cap-adjacent splicing patterns and extend the initial sequence segments in many RNA messengers. We will examine whether such extended sequences determine the localization of RNA messengers inside the neuron, and control their engagement with the protein synthesis machinery. We will develop our research program by pursuing the three objectives. Firstly, we will investigate the extent of cap-adjacent alternative splicing in the developing neurons, using both traditional and novel RNA sequencing approaches. Secondly, we will employ genetic, biochemical and computational techniques to dissect the mechanisms utilized by SRRT and other factors to control such splicing events. Finally, we will discover the biological functions of the extended messenger RNA sequences. This will be achieved by determining if they enable specific RNA localization within the neuron, or modify their messenger function. We will also probe the functional outcomes of perturbing the natural splicing regulation by genetic engineering. It is worth noting that, although these objectives are clearly related, each of them can be achieved independently. The significance of our work is highlighted by the frequent deregulation of alternative splicing in the context of human diseases and aging. Defects in cap-adjacent RNA sequences have been linked to devastating neurological disorders, including Huntington's Disease, Fragile X Syndrome, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia. In our preliminary work, we have identified specific targets of cap-adjacent alternative splicing, including an Alzheimer's Disease biomarker and a gene mutated in Tuberous Sclerosis patients, who often develop epilepsy, autism spectrum disorders, and learning disabilities. We are confident that the proposed study will uncover new fundamental mechanisms underlying normal brain development and function. This, in turn, will contribute to ongoing efforts to improve the diagnosis and treatment of medical conditions that cause significant suffering to patients and impose a substantial economic burden on society.

UKRI Gateway to Research · FY 2024 · 2024-08

Context: Invasive insect species have the potential to outcompete or predate native species and bring disease. As mobile devices increasingly support biodiversity monitoring, acoustic detection and identification of insects opens up a new avenue to expand the coverage of biodiversity monitoring in the United Kingdom. Such technology is ideally suited for surveillance of invasive species, where the species density is initially low, meaning surveillance effort can be costly and uncertain but still has to be balanced against the potential economic cost of successful invasion. Challenge: A major challenge, in tandem with the great potential offered by mobile acoustic sensing, is the gap between the large volume of raw acoustic recordings generated through passive monitoring and the data processing capacity necessary to promptly extract valuable information from audio contents. Moreover, positive detections must be relayed swiftly to alert research communities, the wider public, and policy makers. Delays can grow excessively in a nationwide mobile acoustic monitoring programme where thousands of mobile devices record sound events as they monitor for invaders. Failing to address this challenge will limit the adoption of a mobile acoustic system for monitoring of invasive species and constrain our ability to deliver timely insights into habitat connectivity and species mobility based on acoustic sensing.

UKRI Gateway to Research · FY 2024 · 2024-07

The UN Intergovernmental Panel on Climate Change promotes conservation agriculture as a cost-effective way of mitigating climate-related risks to food production. However, smallholder women farmers in low- and middle-income countries (LMICs) face barriers to adopting this strategy, including limited access to land, capital, training, and gender-based societal stereotypes. Global policy initiatives have often prioritized the viewpoints of advanced economies, overlooking the realities and constraints of vulnerable communities in LMICs. Smallholder women farmers are particularly marginalized and left out of crucial discussions regarding the effectiveness of climate-resilient agricultural systems. Our project uses a participatory action research methodology to investigate how conservation agriculture can empower smallholder women farmers and mitigate climate-related risks to their (a) living standards, (b) food security, and (c) health. This advanced qualitative approach is designed to engage participants throughout the research process, allowing us to co-produce a practical set of policy interventions to tackle climate change in LMICs. The project team includes an interdisciplinary group of experts from Nigeria, Brazil, the UK, and Canada seeking to address the following research objectives: i. To understand the various conservation agriculture practices used by smallholder women farmers in two LMICS, Nigeria and Brazil, focusing on their benefits, limitations, and the socioeconomic resources needed for better outcomes. ii. To empower smallholder women farmers by addressing their socioeconomic vulnerabilities (e.g., poor access to funds and skill enhancement opportunities) and physical challenges (e.g., limited access to modern agricultural tools). iii. To co-produce an actionable set of evidence-based policy recommendations to promote climate change resilience and enhance the socioeconomic status of smallholder women farmers in LMICs. Our work plan is divided into two research phases. Phase 1 will focus on exploring the lived experiences of smallholder women farmers using qualitative methods such as in-depth interviews and focus groups. In Phase 2, we will organize multi-stakeholder workshops, training, and pilot funding to enhance climate change resilience among smallholder women farmers in LMICs. Our goal is to identify practical adaptation strategies and best practices that can be implemented in other national and global settings.

UKRI Gateway to Research · FY 2024 · 2024-07

Unmet need. Viral infections are a global threat and the source of substantial social and economic burden. There is an increasing trend in the emergence and re-emergence of new viruses with high infectivity and mortality rates. Lessons learned from past pandemics, e.g. the global pandemic of SARS-CoV-2, demonstrate that a substantial amount of investment is needed to refine the science and technology to develop new early treatment antivirals. These antivirals should be based on a plug-in technology to be rapidly repurposed for treating the next fast-spreading virus and successfully managing pandemics. Approach and market. Among different technologies, pharmaceuticals based on nanoparticles show a high added value with an estimated compound annual growth rate of 22%. Protein-based nanopharmaceuticals are estimated to have a market size of $ 15 billion. NANOPROV will create novel protein-based prophylactic nanomedicines. The primary target group (> 8 million individuals in the UK alone) will be public servants and immunocompromised patients (e.g. cancer patients) and those requiring primary care. Innovative solution and background. NANOPROV will use a plug-in nanocage technology we have patented and built upon available data regarding antiviral binding proteins. It creates proof-of-concept efficacious antiviral prophylactic nanocages for early treatment. The plug-in technology can be quickly modified using genetic engineering and repurposed to create prophylactic nanocages against a new rapidly spreading virus. The project will generate the proof of concept product for developing inhalable formulations and preclinical tests. Our plug-in nanocage technology is based on the ubiquitous iron-storage protein of life ferritin. This naturally occurring nanocage protein is biocompatible, safe and stable and has shown an acceptable safety profile for making other therapeutics, such as vaccines. Team and environment. NANOPROV is a unique collaboration between experts in ferritin nanocages and those in antimicrobial therapeutics working at King's College London and the UK Health Security Agency (UKHSA). The Team has extensive experience developing antimicrobial products and collaborates with world-leading experts in inhalation drug delivery, formulation, and manufacturing and with biopharmaceutical companies. Expected impact. NANOPROV will refine the science and technology for developing early treatment protein-based nanopharmaceuticals. This unique cross-fertilisation of expertise and experience will create prototype antiviral nanomedicines and technological advances for rapid repurposing to counter a fast-spreading new virus. It will generate confidence in using our nanocage technology to develop other nanomedicines, including multivalent mosaic vaccines and multivalent anti-cancer immunotherapeutics.

UKRI Gateway to Research · FY 2024 · 2024-07

Structure and function are intimately linked in chemical and biological systems, and understanding their relationship underpins technological progress. Knowledge of the different conformations adopted by molecules is crucial to gain insight into their chemical and biological functions. However, despite its tremendous importance, conformational analysis remains an outstanding challenge for many processes. In this project we propose a novel approach to account for conformational flexibility and apply it to the long standing question of musk-olfactory receptor (OR) interactions. Musk odorants are key compounds in perfumery due to their distinctive sensual notes and fixatives qualities. Natural musks are macrocycles with ketone and lactone functional groups. They have been used in perfumery since the beginning of the 20th century but they were very expensive due of the difficulties in their extraction and their complex synthesis. There were thus numerous attempts to develop new compounds with similar olfactory and fixative properties, which led to the appearance of other classes of musks. Many of these were found to be toxic and environmentally harmful, and are gradually being removed from use in consumer goods. Therefore designing and developing new biodegradable musks is still of huge industrial interest. Progress on understanding the molecular features that determine musk-OR binding and musk smell has been hampered by the lack of structural data on macrocyclic musks and musk ORs. Conformational flexibility, an important characteristic of both odorants and ORs, is a major factor. Macrocyclic musks are expected to adopt many conformations, which has prevented their analysis by traditional spectroscopic techniques. ORs are also expected to be structurally flexible. Their importance has grown over the years, since they have been found in tissues outside the nose and have been proposed as drivers of cancer. In this project we will address the challenge of advancing our understanding of musk smell by identifying macrocyclic musks' conformations for the first time, and determining their docking and binding trends on a refined model of a human musk OR. We will use a cutting-edge spectroscopic technique and multiscale computational methods. Our partnership with one of the leaders in the fragrance and flavor industry will allow us to investigate musks of industrial relevance and to get advantage of the industry's viewpoint on the application of structure-activity relationships. Our results will make a significant breakthrough in our knowledge of the molecular features and interactions mediating musk smell, and will pave the way to a rational design of environmentally safe musks. The tools and results we will develop will be of further benefit to other areas of research including sustainable synthesis, perfumery, structural biology and molecular modelling.

UKRI Gateway to Research · FY 2024 · 2024-07

The protein p53 guards against cancer by orchestrating the self-destruction of precancerous cells. Accordingly, p53 in most cancers is malfunctioning and permits the unchecked cellular growth central to the disease. Understanding the molecular mechanisms underlying p53's function is thus crucial, and researchers now know that p53 is regulated in part by a plethora of post-translational modifications (PTMs). In this project, I will investigate the functional consequences in p53 of an atypical PTM: the reorientation of a protein's backbone by the isomerisation of a proline between cis and trans stereoisomers (Pro-Iso). Specifically, I hypothesise Pro-Iso acts as a "conformational switch" which drives p53 into distinct functional states. This hypothesis is untested due to the difficulty of obtaining chemically well-defined p53 variants and p53's recalcitrance towards structural biology techniques. To overcome these challenges, I will explore the role of Pro-Iso in p53's function via an interdisciplinary chemical biology and biophysical approach. First, I will use the protein semisynthesis techniques pioneered by my supervisor Dr. Manuel Müller (King's College London) to produce full-length p53 variants bearing precise chemical modifications that probe different aspects of Pro-Iso. Second, I will subject these variants to a host of biochemical assays to ascertain differences in key properties and functions. Finally, I will use single-molecule Förster resonance energy spectroscopy to investigate the effect of Pro-Iso on the conformational dynamics underlying p53's molecular interactions. This project will provide me with the transferable skills, training and track record needed to pursue a career as an independent research group leader. More importantly, this research will help further decode how p53 makes cellular life-and-death decisions and thus expand the knowledgebase from which global stakeholders seek to tackle growing cancer rates in an aging world.

UKRI Gateway to Research · FY 2024 · 2024-07

Cryo focused ion beam scanning electron microscope (FIB-SEM) tomography allows 3-dimensional (3D) sections of biological materials to be serially milled and imaged at the nanoscale [1]. These experiments are however limited by time, both in the removal of material and in imaging, and by damage due to the inherently destructive nature of both the ion and electron beams. Compressive sensing (CS) [2,3] and a novel targeted sampling method [4] are proposed to be valuable tools in overcoming these limitations of cryo FIB-SEM tomography. These have been successfully simulated in silico to test the validity of the method (Figures 2 and 3) [4]. Compressive sensing is a method of forming incomplete optimally acquired data followed by a form of data reconstruction to allow the data to be analysed. CS has seen positive applications to transmission electron microscopy and scanning transmission electron microscopy in recent years, in particularly through the application of probe subsampling; the manipulation of the electron beam scanning coils to follow a sampling pattern, rather than a traditional space-filling raster scan [5]. The data is then typically recovered using an inpainting algorithm, of which many exist. These methods provided an overall increase in reconstructed image quality, as determined by the calculated structural similarity index measure (SSIM), at all sampling percentages tested and were particularly effective at low sampling rates, where the most benefit of CS can be gained. Unlike deep learning approaches to de-noising and increase resolution applied to the final 3D reconstruction, Inpainting addresses the individual micrographs, massively reducing the electron dose, and data processing demands, required to form an individual micrograph and the number of micrographs required to form the final 3D reconstruction. If developed and implemented for cryo FIB-SEM volume EM (vEM), it has the potential to overcome the limitations of chemically processed tissue, with their associated artefacts, the electron dose limitations of vitrified samples and challenges associated with charging of the sample surface and acquired data being of low signal to noise. This enabling research technology, has the potential for transformative impact by allowing cells and tissues to be studied close to their native biological state, generating 3D ultrastructural information in the low nanometre range, at shorter acquisition times over extended x-y-z ranges for the study of the interrelationship between multiple cells and their individual subcellular compartments.