University of Cambridge

UKRI Gateway to Research · FY 2025 · 2025-03

The Bacterial Flagellar Motor is one of nature's rare rotary molecular machines. It enables bacterial swimming and is a key part of the bacterial chemotactic network that enables bacteria to direct their movement given the chemical environment. This network is one of the best-studied chemical signalling networks in biology, sensing down to nanomolar concentrations of specific chemicals on the time scale of seconds. The motor's rotational speed is linearly proportional to the bacterial electrochemical gradients, most notably of proton or sodium ions, while its direction is regulated by the chemotactic network. Recently, it has been discovered that the motor is also a mechanosensor. Given these properties, the motor has the potential to serve as a multimodal biosensor with unprecedented speed and sensitivity, and thus a tool for characterizing and studying the external environment, but also bacterial physiology itself. However, at the resolution needed, motor speed and rotational direction are currently detected optically, one motor at a time. A step-change in harnessing the unprecedented potential of this rotary molecular machine would be to detect each motor's rotation electrically and with high throughput. Here I propose to achieve this by specifically attaching individual bacteria to a precise location on the surface and testing two electrical means of detecting the motor's rotation: an integrated circuit and a graphene surface. The detection method will also be employed to fully characterize the three different sensing modalities offered by the flagellar motor: that of cells own physiology, of mechanical forces and of a given set of chemicals. The success of the project we will enable portable biosensor-on-a-chip configuration of the motor speed and rotational direction detection, which can be a game-changer in the biosensing field.

UKRI Gateway to Research · FY 2025 · 2025-02

Epithelial cells stick together to form the sheets and tubes that make up most tissues, where they act as barriers between compartments (e.g. blood vessels) or between the inside and outside of the body (digestive system). Epithelial sheet formation depends on the polarisation of the cells with their apical surfaces facing outside. This polarity localises the impermeable cell junctions that act as barriers to pathogens and fluids; directs the exocytosis of signals and receptors to the correct side of the epithelium; and controls changes to the sizes of apical, basal and lateral domains as epithelia undergo morphogenesis to form more complex structures. Furthermore, >80% of cancers arise from epithelia and alterations in polarity drive metastasis. Thus, understanding epithelial polarity underlies many aspects of cell physiology, development and tumour biology. Work mainly in Drosophila has identified a conserved set of polarity proteins that define the apical, junctional and lateral domains of epithelial cells and has shown that antagonism between apical and lateral factors determines the relative sizes of each domain. However, there are major gaps in our understanding of how polarity proteins function and the logic of the system is still obscure. This proposal aims to answer these outstanding questions using a super-resolution microscopy technique, called DNA-PAINT. Almost all super-resolution imaging is performed on thin samples using high intensity illumination, and imaging thick samples poses several challenges. We have spent the last 5 years building the tools to overcome these challenges and can now image with 10-20nm resolution at the apical side of our model epithelium, the Drosophila follicular epithelium (~8µm above the coverslip). Furthermore, we have developed techniques and algorithms to count the absolute number of molecules in a structure of interest (qPAINT). We now propose to use DNA-PAINT to address the following questions: 1) Biochemical studies have identified numerous protein-protein interactions between polarity factors, but where and if these interactions occur in vivo is unclear. We have endogenously-tagged every polarity protein with SNAP and HALO so that we can label them with oligonucleotides for DNA-PAINT. Imaging all pairs of polarity proteins will show which proteins interact and reveal where the antagonistic interactions occur. This will also distinguish between competing models for the nature of the boundary between the apical and lateral domains. 2) Our preliminary data and recent work in C. elegans indicate that several polarity proteins cluster at the membrane. We will use qPAINT to determine the stoichiometry of polarity protein clusters and investigate the mechanisms that drive cluster formation. Work on Par-3 suggests that they may form by phase separation. We will use a novel approach to test this hypothesis, in which we vary the amount of a protein and measure its cytoplasmic concentration and cluster size. 3) The polarity system regulates cell shape, which depends on the underlying actin cytoskeleton, but little is known about how polarity factors control actin organisation.  We have developed techniques to visualise F-actin at 20nm resolution using the LifeAct peptide. By combining this with DNA-PAINT on polarity proteins and actin regulators, we will determine the relationship between polarity factors and cortical actin organisation. This project will advance our understanding of epithelial polarity, while demonstrating the power of qPAINT to provide quantitative data at the nanoscale. It therefore falls within two BBSRC priority areas: "Understanding the rules of life" and Transformative technologies.      

UKRI Gateway to Research · FY 2025 · 2025-02

Atmospheric CO2 is now higher than at any point in the last three million years. To understand how the Earth responds to these extreme CO2 levels, we can examine how the climate operated in the distant past, when CO2 was last this high. Our understanding of CO2 this long ago is based on chemical 'proxy' records preserved in the geological record. These proxies are informative, but none are perfect; even the best established proxies must rely upon uncertain assumptions about how the total concentration of carbon in the ocean has changed through time to calculate atmospheric CO2. Crucially, there is no proxy that allows us to directly determine the concentration of carbon in past oceans, which limits the accuracy of long-term atmospheric CO2 reconstructions. We aim to address this major knowledge gap by developing a new proxy for past ocean carbon conccentrations based on the Sr/Li ratio in the shells of marine plankton.

UKRI Gateway to Research · FY 2025 · 2025-02

Persistent stress can shift cell fate in somatic cells, in which cells gain a new functional identity through 3D chromatin rewiring. Emerging high-resolution 3D epigenomic studies have uncovered the critical role of chromatin loops for cell identity by orchestrating functional transcription units. However, the mechanisms by which cells overcome epigenetic barriers remain elusive. We reason that by implementing diverse chromatin modifications within a specific biological context, we can engineer somatic cells with chromatin conformational landscapes that do not exist in vivo to adopt optimal cell fates. Here we choose the senescent microenvironment: senescent cells communicate with neighbouring cells by secreting soluble factors and direct contact, amplifying and maintaining senescent neches. Timely management of this process by immune clearance in vivo is critical as the accumulation of senescent cells promotes tissue degeneration and age-associated disorders. We aim to generate cell populations that actively engage with this challenging milieu by neutralising the senescence-associated secretory factors or targeting the senescent cells themselves. The engineered cells will constitute a novel anti-ageing therapeutic avenue. To manipulate the fates of off-the-shelf diploid cells, we propose two complementary approaches: Aim 1. Genetic Approach: Utilising genome-editing techniques, we aim to selectively disrupt functional chromatin loops in diploid cells. We devised a computational approach to estimate which loop anchors (particularly CTCF binding sites) are most likely to contribute to functional transcriptional units through a comprehensive analysis of Hi-C datasets. By targeting the predicted loop anchors, we will systematically engineer cells with combinatorial disruptions in these key regulatory units. Aim 2. Epigenetic Approach: We are developing novel chromatin manipulating probes, by engineering our unique panel of Mintbodies (GFP-scFV) that recognise specific epigenetic marks. The panel of Mintbodies will be fused with chromatin modulatory enzymes. We will stably express the Mintbody-derived chromatin manipulating probes (MCMP) in the diploid cells, establishing novel chromatin states that adapt to the specific microenvironment. Aim 3: Functional validation of the novel chromatin-modified cells with anti-senescence features in vitro and in vivo. We will first employ innovative in vitro evolution screening techniques in the presence or absence of ‘senescent cell feeders’, leveraging the loop-Perturb-seq (Aim 1) and MCMP libraries (Aim 2) and the advanced single-cell multi-target ChIL-seq (scmtChIL-seq), which allows for simultaneous mapping of CTCF and Pol-II binding sites in each cell. Through screening within the senescent microenvironment, we will identify the single-cell resolution trajectories of the cells with selective advantages in the senescent environment. We seek to identify cell populations exhibiting desirable anti-senescence traits and retrieve the specific combinations of CRISPR targets and MCMPs for direct cell engineering for usage in vivo. To functionally validate our engineered cells in vivo (Aim 3), we will focus on mouse models of ageing and sarcopenia, an ageing-linked disorder characterised by diminished skeletal muscle mass and strength. We will introduce the modified cells in mice and test for improvement in ageing markers and muscle regeneration. We have assembled a team with diverse expertise in biology, technology and mathematics. By integrating these two approaches, we will develop a therapeutic strategy of creating cells with alternative regulatory circuits and subsequent functionality, and gain insights into how chromatin modulation contributes to cell identity. While our goal is engineering somatic cells into anti-senescence entities, this strategy is readily applicable in other biological contexts, e.g., cells with improved differentiation potential.

UKRI Gateway to Research · FY 2025 · 2025-02

Research conducted with learners educated in or through a second language has shown that the use of regional or home languages in the classroom benefits both language and content learning. However, the embracement of a multilingual model of language teaching and learning does not currently map to a multilingual approach in assessing language and content, partly because the construct of multilingual assessment is yet to be adequately defined and operationalised. The present project intends to design, implement and evaluate the construct of multilingual assessment in primary government schools in India in which English is taught as a subject or as the medium of instruction (EMI). Children attending these schools grow up and live in a highly linguistically diverse society which embraces multilingualism in the individual speaker primarily in oral language usage with code-mixing/translanguaging as a natural mode of communication. The vast majority of learners in government schools come from underprivileged socioeconomic backgrounds associated with no or minimal home literacy support and lack of any input in English in spoken or written mode. Thus, code-mixing with English and the regional languages is common in teacher-talk and teacher-pupil interaction as a reflection of sociolinguistic practices and a way to scaffold language and content learning. School-based assessment, however, has always been unilingual. This project aims to promote continuity among teaching, learning and assessment through the active exploitation of learners' entire language repertoire. A step to this direction is the use of dynamic assessment (DA), which forms an integral part of students' learning process: students unable to provide a correct answer are supported with prompts that facilitate progression with the assessment tool in use and with follow-up assessments. DA thus offers a more fine-grained picture of students' content and language abilities than traditional, static forms of assessment, since it considers actual learning outcomes as well as learning potential. Furthermore, DA creates an opportunity to learn by making assessment equitable, particularly for underprivileged learners with poor home literacy support. The first objective is to quantify and qualify the use of code-mixing in pedagogical activities in English language classrooms using audio recordings. The second objective is to examine whether DA affects students' English language and content learning over time, and whether a multilingual vs. unilingual (English-only) DA differentially affects learning progress and outcomes. We will recruit three groups of children attending Grade 4 in government schools in two sites, New Delhi and Guwahati, where different regional languages and educational policies related to the promotion of regional language literacy have been implemented so far. The students will be assessed with a) traditional, static assessment b) English-only DA and c) multilingual DA following a longitudinal design and using tasks that will engage learners' listening and reading comprehension. The findings will have ground-breaking implications for the assessment of content and language learning outcomes, promoting a paradigm-shift in multilingual DA. This new model is informed by equity in education and a holistic view of learning, whereby learners are allowed to rely on the totality of their language resources. There is high potential for extending the findings to multilingual contexts outside India, particularly in the Global South, where language education policies seek to address conflicting demands of high linguistic diversity in the population, English as a global language and the need to promote local languages in the curriculum.

UKRI Gateway to Research · FY 2025 · 2025-02

What does it feel like to have a memory? We know surprisingly little about how we can vividly relive past events, which functions of the brain are involved, and how these processes vary across individuals, societies and cultures. Scientists have struggled to know how to frame testable hypotheses about the subjective experience of remembering, which is why it is essential to draw on insights from the humanities about the cultural and intellectual contexts in which subjective experience is shaped. There has been rich literary and historical scholarship on many aspects of memory, interpretations that can benefit from engagement with empirically founded accounts from the cognitive sciences. In this project, scientists and humanities scholars will collaborate across disciplines to drive a step-change both in understanding memory vividness and its brain mechanisms across the life-course, and in enhancing the interpretation of vividness in literary and historical works dating back to the early modern era. The proposed work develops an interdisciplinary and translational approach to the study of human experience, building on a collaboration between four experts in psychology, cognitive neuroscience, literary studies and history, who will interact regularly with a wider established Memory Club group from across the sciences and humanities. Our method is genuinely interdisciplinary, a bidirectional process of knowledge co-creation and research design from the humanities to the sciences and vice versa. Using this approach, we will investigate how the psychological and neuroscientific understanding of memory vividness can be transformed by conceptions of memory from the humanities, and explore what literary, historical and other humanities perspectives on memory vividness can gain from engagement with the modern cognitive neuroscience of memory. This timely interdisciplinary project promises transformative outcomes that will change fundamentally our understanding of memory vividness. It will provide science and humanities researchers with new paradigms and tools for the interdisciplinary study of human experience, and allow them to address new 'third-space' questions about the vividness of memory that would not be possible within traditional disciplinary boundaries.

UKRI Gateway to Research · FY 2025 · 2025-02

ComeInCell will establish a novel integrated Synthetic Cell platform to provide cost- and resource-efficient, environmentally friendly, widely applicable and quantitative model systems to elucidate key cellular mechanisms of health and disease based on the integration of condensate and membrane models. Understanding membrane-condensate interactions is vital for deciphering their functional roles in cellular processes. Our consortium employs synthetic vesicles as model systems to explore these interactions. These tailor-made mimics of cellular compartments offer a platform for studying membrane dynamics and the impact of compartmentalization on the activity of reaction networks and the assembly of complex machinery. We will design synthetic cells as life-science prototyping tools to decipher the role of membrane-associated condensates in essential cellular processes linked to membrane transport, membrane transformation, metabolic networks, and repair. The network will confront global challenges, providing solutions in drug development, therapeutics, green-related issues, and synthetic biology. Our goal is to equip junior scientists with cross-disciplinary expertise for developing integrated synthetic cellular testbeds encompassing condensates and membranes, revolutionizing prototyping systems. We will train the next generation of biophysicists, biochemists and bioengineers in rigorous quantitative and mechanistic thinking, while establishing strong ties to young and emerging European SMEs in the health sector for efficient dissemination towards new therapies

UKRI Gateway to Research · FY 2025 · 2025-02

In the last 25 years, there has been spectacular progress in the mathematical study of the random planar geometric structures which arise from statistical mechanics models in two dimensions.  Important developments include: - Schramm's invention of the Schramm-Loewner evolution (SLE), the canonical model of a conformally invariant random curve. - Lawler-Schramm-Werner's theory of conformal restriction and its application to the study of planar Brownian motion. - Smirnov's proof of the conformal invariance of critical percolation and the Ising model. - Le Gall and Miermont's construction of the Brownian map, the canonical continuous model of a uniformly random surface. - Duplantier-Sheffield's rigorous proof of the KPZ formula for Liouville quantum gravity, the canonical model of a random two-dimensional Riemannian manifold. - Kupiainen-Rhodes-Vargas's construction and analysis of Liouville conformal field theory. The purpose of this project is to study the metric and analytical aspects of the random planar geometric structures which can be built from SLEs.  The goal is to use these results to answer long-standing questions about the discrete models from statistical mechanics whose scaling limits are described by SLEs and related processes.  The key objectives include: - Construct the canonical conformally covariant planar metric which describes the scaling limit of the intrinsic metric for critical planar statistical mechanics models, including percolation. - Construct the canonical Brownian motion on these spaces and use it to solve long-standing questions on diffusions in random media, in particular de Gennes' ``Ant in a Labyrinth'' problem for critical percolation. - Use random planar geometric structures to answer questions about embeddings of metric spaces which are in turn motivated by algorithms used in computer science.

UKRI Gateway to Research · FY 2025 · 2025-02

Tamoxifen (TAM) is widely used as a powerful approach to achieve conditional gene knockout (alteration) in mice by inducing temporal and spatial gene expression or deletion using Cre/loxP models. Standard administration protocols for TAM involve repeat dosing by Intra-Peritoneal (IP) injection or Oral Gavage (OG) over several days, both of which are invasive and have the potential to cause pain and stress in experimental animals. The oral feed route is also challenging due to poor palatability of TAM, causing food aversion. Mice dosed with TAM using traditional methods experience marked weight loss during the dosing period, leading to risk of morbidity in animals. Additionally, TAM’s limited solubility in dose vehicles complicates dose preparation, resulting in inconsistency and poor reproducibility of experimental results. Fluid Pharma, a UK biotech, have developed a highly palatable and easy-to-administer oral feed formulation of TAM, comprising drug coated micro-pellets. Preliminary data from this new product have demonstrated that there is no apparent weight loss in animals administered at effective dose of TAM via the feed route and that similar gene recombination efficiency can be obtained when compared to an equivalent OG dosing regimen. Fluid Pharma aims to establish partnership with a new user, CRUK Cambridge Institute (CRUK CI) to implement the product in their laboratories and to further validate that it is fit-for-purpose for wider adoption. CRUK CI use TAM induced gene expression routinely in the study of cancer and are very familiar with the challenges of TAM administration. The Institute operates with an infrastructure of independent core facilities, bringing together technical specialists from different scientific disciplines to support the academic research groups. This has resulted in a proven track record to deliver grant-funded innovation projects, making the CRUK CI ideal for this partnership. In this proposal, CRUK CI will conduct a series of stepwise experiments to achieve the following scientific objectives, for research groups to have the confidence to adopt this new technology: Standardisation of feed administration protocols for practical bead use in a preclinical animal unit Product characterisation through investigation of the TAM pharmacokinetics (blood concentrations) when delivered in feed, providing evidence that the beads are delivering adequate and reproducible TAM exposure to mice Validation of gene regulation using the palatable TAM beads via oral feed The project is driven by an urgent 3Rs need in preclinical research and aims to achieve immediate and wider, long term 3Rs impact. In the last 3 years, there have been over four thousand IP injections of TAM to mice at the CRUK CI. A successful validation of this new technology would have the immediate Refinement impact of reducing the number of IP injections and associated stress to the animals. In the longer term, fewer animal interventions and adverse effects associated with TAM administration have the potential to result in higher quality data outputs and a Reduction in animal numbers used. The wider impact would be the adoption of this technology both nationally and internationally in preclinical research. A new product proven to deliver a similar TAM induction effect to the more traditional routes of administration has the potential to result in very significant 3Rs benefits.

UKRI Gateway to Research · FY 2025 · 2025-02

Accelerating global biodiversity loss, along with the deterioration of critical ecosystems and the release of greenhouse gases, together demand a radical reconsideration of existing responses. We need to better measure the impact of human activities on biodiversity and ecosystems globally, while also tracking shifts in the spatial distribution of habitats and organisms as a result of climate change. Existing systems are not up to the task: they aggregate fragmented and misaligned data derived from expert opinions and field inventories, and most digitisation efforts cannot model the hugely complex dynamics involved nor address these problems at scale. Hence, policymakers and the private sector cannot accurately identify the potential impact of critical decisions such as where and how to focus conservation activities, while still supplying food, wood, energy and water to people. We propose a planetary insights system for policymakers, business and scientists that can radically improve decision-making for achieving biodiversity conservation and restoration goals alongside meeting human resource needs. We will draw from computer, ecological, conservation and remote-sensing science to combine extensive earth observation data (satellites, drones) with terrestrial data (sensor networks, citizen science, habitat maps) to create a new "Terra" model of the world using self-supervised AI training. Terra will provide predictive properties for very many terrestrial plant and animal species with sparse data and enable monitoring of biodiversity metrics at fine spatial and temporal scales and at much higher resolution and accuracy than is currently possible. We will use Terra to build a suite of critically important predictions about life across our planet: - Deep species distribution modelling will classify changes in global land use and the plants and animals that live there, providing much-needed insights for policymakers to factor into their decision making. We plan to use Terra to create high-resolution, regularly updated databases that accurately classify habitats for wild species and agriculture crop and pasture types, providing a unified classification and change map. - Linking data on long-running as well as contemporary changes in species' area of suitable habitat together with information on their habitat preferences will allow us to model how human actions impacts extinction risks, and crucially where and how these might be most efficiently mitigated. These new datasets exist for ~30K species of terrestrial vertebrates; we plan to also apply these methods, for the first time, to first ~10k and then ~150k data-deficient plant species. These datasets will be ultimately used to analyse the impacts of human food consumption on nature with much greater accuracy and breadth than currently possible. Our system will combine Terra with additional information about the world, such as supply chain datasets about how food travels from field to fork, to identify the spatial distribution of the threat to biodiversity from a unit of consumption of each of a set of agricultural commodities. This will, for the first time, allow decision makers to accurately analyse the impact of their food production, procurement distribution and processing decisions on biodiversity worldwide, and do so on an evidence-driven basis from planetary scale observations that are transparent and reproducible.

UKRI Gateway to Research · FY 2025 · 2025-02

When cells divide, it is critical that each daughter receives a balanced set of chromosomes. Failure to segregate chromosomes accurately can cause genome instability and cancer. Each chromosome contains a dedicated region, called the centromere, that is required for correct segregation during cell division. The centromere acts to load a large complex of proteins called the kinetochore. The kinetochore is responsible for attaching the chromosomes to spindle fibres, called microtubules, that form during cell division. The microtubules act to pull the chromosomes to opposite sides of the cell and thereby achieve balanced segregation during division. Centromeres perform a deeply conserved cellular role across animals and plants. Despite this deep functional conservation, centromeres evolve extremely rapidly, and comprise divergent DNA sequences within and between species. This deep functional conservation, yet diverse sequence composition, is termed the centromere paradox. A further challenge to the study of centromeres, is that they are frequently composed of complex repeated sequences. Centromeric repeats have been impossible to correctly assemble with the previous generation of short-read sequencing technologies. However, new long-read sequencing methods allow the complete resolution of centromere repeats for the first time. For example, we have used long-read sequencing to assemble and study 330 centromeres from the model plant Arabidopsis, which has revealed extremely high levels of within-species sequence diversity. In this project, we aim to build on our foundational maps of the Arabidopsis centromeres, to functionally understand how their complex organization relates to their function during cell division. In recent years, the CRISPR/Cas9 system has emerged as a powerful system to direct pinpoint changes to the genome. For example, CRISPR has been used as 'molecular scissors' to delete target genes in a wide range of species. In this work, we will harness the CRISPR system in a novel approach that will target the centromere repeats. We have shown that this can cause dramatic deletions and rearrangements within the centromeres, which causes cell division defects. We will use CRISPR/Cas9 to dissect how centromeres remodelling influences their role in chromosome segregation. Beyond the DNA sequence, the centromeres are known to acquire epigenetic marks that are essential for their function, including DNA methylation. The CRISPR system can be further adapted to tether proteins of interest to target regions of the chromosome, including the centromeres. Therefore, we will use modified CRISPR systems to tether effectors of epigenetic information to the centromeres. This approach will allow us to test how epigenetic information influences centromere function during cell division, when the DNA sequence otherwise remains the same. A major theory for why centromeres evolve so fast, is that different centromere variants can selfishly compete. For example, during female reproductive development, it is common for an asymmetric cell division to form the egg cell. Selfish centromeres that can bias their inheritance into the egg cell have the potential to achieve an unfair transmission bias into the next generation. Consistent with this model, we have used sensitive fluorescently marked chromosomes to show that diverged European and African Arabidopsis centromeres show unequal transmission between generations. In the proposed work, we will use our remodelled centromeres to extensively test how they compete with both unmodified centromeres and between themselves. The proposed work will provide a comprehensive study of centromere genetic and epigenetic organization using a tractable model plant, and will reveal how this influences their role during cell division. Our work will have cross-cutting significance for centromeres across plant and animal species, with broad relevance for fertility and genome evolution.

UKRI Gateway to Research · FY 2025 · 2025-02

Quantum materials host collective phenomena that defy a semi-classical description, for example because they arise from strong correlations or involve topological order. The diversity of these collective phenomena, their reach into practicable temperature regions and their tunability enable new technologies. Foremost among them is superconductivity, a macroscopic quantum phenomenon with multiple applications ranging from powerful magnets used in MRI scanners, fusion research reactors and particle accelerators to lightweight motors and generators, low-noise rf filters, low-power electronics, and quantum devices used in sensing or computing. In most superconductors, the required electronic interactions are produced by dynamic lattice distortions. Alternatively, these interactions can be caused by more complex quantum processes similar to those which give rise to magnetism. Such unconventional 'superconductivity without phonons' is associated with a rich range of properties, some of which are highly desirable, such as resilience to high magnetic fields, current densities or temperatures. The challenge the project addresses and how it will be applied to this Unconventional superconductors are sparsely distributed in material space but clustered in families, which include copper-oxide, iron, or cerium compounds. There are also surprisingly many uranium-based unconventional superconductors, some of which display highly unusual phenomena such as multiple or even multi-component pairing states. Although these materials may not themselves be ideal for applications, their properties could be. They need to be studied and understood, to replicate their properties in more accessible materials. Here, we focus on the new superconductor UTe2, which displays several distinct, switchable superconducting states and in which superconductivity can survive in ?elds exceeding 60 T, indicating triplet (odd-parity) pairing. In addition, UTe2 has two important advantages: (i) ultra-clean single crystals with purity levels an order of magnitude better than previous best efforts are now available, facilitating probing studies of lasting relevance; (ii) its electronic structure near the Fermi energy is unusually simple, vastly simplifying any theoretical and computational description. These advantages turn UTe2 into a clean reference material in which to decode the connection between microscopic material properties and its diverse superconducting pairing states, its magnetic or charge order, and its correlated normal state properties. We will tackle this challenge by investigating the nature of the superconducting pairing states and the pair-forming interaction, the nature of the underlying strongly correlated normal state, and their interplay with nearby magnetic or charge order.

UKRI Gateway to Research · FY 2025 · 2025-02

The Outer Hebrides of Scotland are often described as remote, economically fragile and threatened by depopulation. Popular representations emphasise the preservation of 'traditional ways of life', locating the islands vaguely 'out of time'. Yet, as this project will explore, a closer look reveals not only the continuity of crofting, peat-cutting, and Gaelic speaking, but also the emergence of 'innovative' forms of social and economic organising that have been vital to navigate - and sometimes challenge - the workings of global capitalism. These approaches range from resourceful individual projects of occupational pluralism and householding practices; to collective ventures such as ground-breaking community land buyouts and community-owned renewable energy projects, alongside the creation of social enterprises, co-operatives and community development trusts. My previous research into the Outer Hebridean textile industry (Nascimento 2023) hinted at the local significance of these often overlooked strategies, and suggested the need to conduct further research to grasp the complex interplay of individual approaches and collective projects aimed to protect livelihoods, avoid depopulation and cultivate 'sustainable futures'. This project will focus on some of those resourceful approaches and outlooks, drawing on anthropological frameworks, qualitative research and participatory approaches to examine their social, moral and economic implications, and aiming to reach audiences within and beyond academia. To do so, this project will explore how ethnographic research, social reproduction theory and an expanded concept of 'work' can improve our understanding of the ways in which livelihood strategies and 'sustainable futures' are variously being imagined, negotiated, contested and 're-worked' by local actors in the present. This project will locate these strategies in relation to broader discussions on social reproduction and the emergence of 'alternative' approaches to capitalism and 'the economy', examining how they relate to societal developments that go well beyond the boundaries of this fieldwork site. This research will contribute, in unique ways, to ongoing debates in economic anthropology, highlighting the importance of more holistic and nuanced approaches to the study of social, economic and organisational life in global capitalism. Doing so, this project will also generate insights that could inform interdisciplinary discussions, and prove helpful to practitioners, policymakers and other audiences beyond academia. This is particularly vital given the recurrent complaints voiced by islanders about the striking gaps in knowledge and understanding that have continuously shaped decision-making processes in distant metropolitan centres, with significant consequences for local lives and livelihoods. The project's emphasis on livelihood strategies and visions of 'sustainable futures' is also informed by the urgent need to understand not only how island communities may be uniquely vulnerable to 'wicked problems', but also how their resourceful approaches and outlooks may inform different ways of thinking and doing, generating academic and societal impact.

UKRI Gateway to Research · FY 2025 · 2025-02

Researchers and practitioners in the field of public health are routinely faced with the task of evaluating the effect of an intervention on an outcome of interest. Often, these evaluations rely on observational time-series data from a small number of units of intervention, such as hospitals or geographical regions, of which some receive the intervention (treated units) and some do not (control units). Increasing availability of such data has led to a pressing need for statistical methodology that can be used to draw causal conclusions in this context, whilst accounting for the problem of counfounding present in observational studies. Despite recent developments, current methods cannot accommodate important facets of an intervention that are typically of interest in a public health-related context. Firstly, the strong dependence of intervention effects on the characteristics of a unit, which leads to great effect heterogeneity. Secondly, the possibility that unobserved confounders change over time and that complex interactions exist between the observed confounders. Thirdly, the presence of correlations between neighbouring units, which, while could be accounted for in models to improve statistical power,  also raise the question of how to deal with interference, i.e. the fact that the intervention will also affect the units surrounding those that have been treated. Fourthly, violation of the requirement that control units exist throughout the study, and that interventions cannot be withdrawn once delivered. I propose to develop statistical methodology that tackles these challenges, thus offering generic and much needed tools to assess public health interventions. These Bayesian methods will provide uncertainty quantification to aid policy making, and include easy-to-use software to facilitate future use. I will apply my methods to studies from the UK, arising from three key substantive areas: the evaluation of ongoing efforts to reduce Hepatitis C virus prevalence among people who inject drugs, which are part of UK's plan to eliminate the virus by 2030;  the impact that various non-pharmaceutical interventions had in containing the spread of COVID-19 during the recent pandemic; and the effects of the Soft Drinks Industry Levy on drinks containing added sugar on improving health-related outcomes such as sales of products containing added sugar.

UKRI Gateway to Research · FY 2025 · 2025-01

CONTEXT In today's rapidly urbanizing world, the need for innovative, sustainable, and efficient infrastructure solutions has never been greater. Underground construction presents a promising avenue to address this challenge, providing the means to expand vital transportation networks, utility systems, and storage facilities while minimizing surface disruption. As urban populations continue to grow, the demand for underground infrastructure will surge, requiring novel approaches that can deliver resilient, cost-effective, and environmentally conscious solutions. This fellowship seeks to harness the power of advanced digital technologies to transform underground construction, aligning with the ongoing global push for smarter, more efficient infrastructure development. CHALLENGE & APPLICATION Underground construction offers immense potential, but it also comes with significant hurdles. The complexity of soil-fluid-structure interactions (SFS) poses challenges that impact construction processes, project timelines, and costs. Traditional methods often struggle to accurately model and simulate these interactions, leading to uncertainties and suboptimal designs. This fellowship addresses this challenge by integrating cutting-edge digital tools, including Building Information Modeling (BIM), digital twins, and advanced data analytics. By doing so, it aims to revolutionize how we approach underground construction, enabling accurate prediction of SFS interactions and optimizing construction methodologies. AIMS & OBJECTIVES The primary aim of this fellowship is to reshape the landscape of underground construction by seamlessly integrating digital technologies. The project's objectives are: 1. Develop advanced digital modeling techniques that accurately predict complex SFS interactions in underground construction scenarios. 2. Create a comprehensive digital twin that integrates real-time data, enabling continuous monitoring and predictive maintenance of underground construction processes. 3. Identify and deploy optimal real-time monitoring technologies to gather data for improving the accuracy of the digital twin. 4. Apply advanced data analytics to optimize construction processes, enabling what-if scenario forecasting and predictive maintenance models. 5. Facilitate knowledge transfer and dissemination of research outcomes to industry professionals, policymakers, and stakeholders, driving the adoption of digital technologies in underground construction.

UKRI Gateway to Research · FY 2025 · 2025-01

Kidney transplantation is the best treatment for patients whose kidneys have stopped working. Patients feel better as they have better kidney function, and they have more independent lives without needing to perform regular dialysis. However, transplant patients need to take medications which have many side effects including a lower immune system. These medications (called immunosuppression) are important to stop the body 'rejecting' the transplant. The immune system recognises the part of the kidney called HLA and attacks the transplant. We all have different HLA or tissue types. The different HLA types are divided into multiple groups. However, we can now identify the exact high resolution HLA type using modern gene sequencing technology. Our lab has developed computer algorithms which compare the molecular sequence and structure of HLA to determine how different (or similar) the transplant is to the patient. We showed that the molecular mismatching scores are good at predicting rejection and antibodies against the transplant. In this study, we want to apply the molecular mismatching to children and young adults up to 35 years of age because they have high rates of infection and rejection. In the first part, we will look at how molecular mismatching can be used in the kidney allocation system. We will use modern machine learning tools to predict which transplants are more likely to stop working early. We will compare current HLA mismatching against the new molecular mismatching. We will then perform a computer simulation using information from the donors and kidney recipients that were transplanted in the last ten years. We are working on a machine learning model which can better allocate transplants to the most appropriate patient, so that each transplant lasts as long as possible for that particular patient. We want to check if the molecular scores affect waiting times. We believe that it would be easier to find a better matched kidney this way because it allows comparisons between all HLA groups. In the second part, we want to see if molecular mismatching can be used to guide what treatment children get. It would beneficial if we could reduce the medication for children with good tissue matches. We have close links with the international CERTAIN registry which contains valuable information on the treatment that children receive over time and the outcomes of their transplants. We will use machine learning again to predict how different levels and doses of immunosuppression affect rejection over time. We are conscious that machine learning methods can contain hidden biases. We will form a diverse group of doctors and include patients in this group to oversee our research. We will specifically check the impact of the algorithms on different patient groups, for example patients from ethnic minority backgrounds. We want to produce machine learning tools which are fair and transparent so that they can be used safely in day-to-day practice. In conclusion, this study combines advanced molecular tools with machine learning to improve the chances of successful kidney transplants. Better tissue matching means less risk of rejection and fewer side effects from medication.

UKRI Gateway to Research · FY 2025 · 2025-01

The EPSRC Capital Award for Core Equipment 2024/25 provides essential support for the University of Cambridge’s ambition to establish and maintain world-class laboratories that empower our researchers to conduct cutting-edge research. The University selected the equipment to include in the application via a fair and transparent internal competitive application process, which is described in Q3 Vision and Approach. Five items of equipment were selected meeting the objectives of the award and the strategic priorities of the university. The investment opportunities outlined in this proposal are in addition to planned investments in capital equipment at the institutional level; however, they align with institutional strategic initiatives, such as the West Cambridge Sharing Project (described in Q3 Vision and Approach), and strategic research priorities, such as energy and engineering biology. The equipment selected for inclusion in this award comprises: 1. a Luminex 200 multiplexed cytokine analyser; 2. an ion beam milling tool; 3. a Bruker Avance NEO 300 MHz NMR Spectrometer; 4. a Tuttnauer 85L Front loading 3Ph Autoclave; 5. a GPU server for computational research, with accompanying solid-state drives for research data storage.   This selection of equipment meets all three EPSRC call objectives: 1. benefiting multiple users, enhancing sharing, usage, and collaboration; 2. invest to save; 3. supporting early career researchers and doctoral training. The equipment will have a range of benefits. Beneficiaries will include researchers from the Departments of Materials Science and Metallurgy (MSM), Chemistry, Physics, Engineering, Chemical Engineering and Biotechnology (CEB) and Computer Science and Technology (CST) predominantly within the university, and also the wider community, through collaborative activities.  Selected items either add otherwise hitherto missing capabilities or renew/refresh existing capabilities, some of which are at end of life. The equipment will be widely accessible, benefitting researchers from a variety of disciplines and all career stages. Application areas include engineering biology research, identified as strategically important for the UK, alongside many areas essential to the energy transition: energy storage, renewable energy, batteries, carbon capture, and catalysis. The equipment will be integrated into well-established facilities and laboratories with expert support to enhance its lifespan and ensure long term sustainability. The university is committed to supporting the career development of research technical professionals and to improving the environmental sustainability of our infrastructure, and the equipment will therefore fall within this highly supportive research environment.

UKRI Gateway to Research · FY 2025 · 2025-01

The proposed project sits at the interface of combinatorics and model theory, two branches of pure mathematics that can be said to have their common origin in Ramsey's theorem dating back to the 1930s. In recent years, a powerful connection has emerged between regularity lemmas, a key tool in extremal and arithmetic combinatorics with far-reaching applications, and stability, a notion of tameness that has been central to model theory since the 1960s. The present project aims to fully explore and capitalise on the intricate relationship between higher-order generalisations of both regularity and stability, initiated in recent joint work of the applicant.

UKRI Gateway to Research · FY 2025 · 2025-01

Many mathematical models address systems with so many degrees of freedom (such as the positions and velocities of molecules in a fluid) that they are best described by continuous fields (such as the density and velocity fields governing fluid flow). Often these fields undergo noisy dynamics. The noise represents random external forcing, or the effects of unresolved microscopic motion. Even when small, noise can have huge effects, carrying the system from one state to another through a region that is uncrossable without noise. An example is the nucleation of a liquid droplet within a vapour in thermal equilibrium. Here the nucleation rate is calculable from the free energy, expressed as a function of the droplet radius. The rate is exponentially small in the maximum free energy ('barrier height') along the 'reaction pathway', which is the pathway of lowest barrier height. This type of calculation for the rare-event rate is called 'classical nucleation theory' (CNT). However, there is currently no counterpart of CNT for many other nucleation problems: those arising far from equilibrium. For these, in general, no free energy can be defined. An example is the vapour-liquid transition in 'active' systems whose particles steadily convert chemical energy into motion. These include swarming micro-organisms such as bacteria, and also synthetic systems of micron-sized self-propelled particles. Other nonequilibrium examples of nucleation type include (a) the arrival of an invading species into a new environment: if a critical population size is reached it will grow further, otherwise the new colony will die out; (b) the noise-induced transition between different flow patterns in an externally pumped fluid. A closely related class of problems arise when a rare sequence of small random disturbances (the noise) leads to the extinction of an otherwise stable population, gene, or behavioural trait. Recent progress in the mathematical field of large deviation theory (LDT) has created tools whereby nonequilibrium rare-events of both nucleation and extinction type can be studied. However, these tools are yet to be developed for systems whose degrees of freedom are best described by continuous fields. We propose to create a new LDT methodology, analagous to CNT, to address a wide range of nonequilibrium problems involving continuous fields. To achieve this, we will develop a four-fold path. Step 1 is to identify a handful of reduced coordinates, that can track the progress of the rare event. Good coordinates may emerge from mechanistic insight, but if not we can alternatively identify them using machine learning (ML). Step 2 is to calculate barrier crossing rates numerically, both in the reduced coordinate space and in a larger one found by representing accurately the fields in a brute-force basis (e.g., Fourier modes). Comparing the outcomes will reveal whether the reduced representation needs improvement, either via better mechanistic insight, or via further ML. Once a good representation is found, step 3 is to calculate the 'quasipotential landscape' (an analogue of free energy far from equilibrium), and step 4 to reconstruct the full noisy dynamics of the dimensionally-reduced model. Our work will exploit innovative numerical methods that we have recently developed, allowing rapid and efficient study of rare events in (so far, modest-dimensional) noisy systems. The new approach will then be used to explore nucleation and extinction problems in active matter physics, quantitative biology, ecology, social models, and fluid dynamics.

UKRI Gateway to Research · FY 2025 · 2025-01

This transformative research fellowship will advance electrochemical carbon dioxide capture as a greenhouse gas mitigation technology. To limit global warming to 1.5C and avoid catastrophic climate change we must greatly reduce our emissions of greenhouse gases. To this end the UK has recently committed to net zero greenhouse gas emissions by the year 2050. Carbon dioxide capture and storage (CCS) is a critical technology that must be deployed at scale if the UK is to meet this goal. CCS is a process where carbon dioxide is first captured at point sources (industrial processes, fossil fuel power) or directly from the atmosphere, before subsequently being stored underground. State of the art CCS technology uses amine molecules to absorb carbon dioxide. Subsequently a large amount of energy must be supplied in the form of heat (or a vacuum) to regenerate the amines and release pure carbon dioxide for storage, thereby increasing the cost of CCS. The amine process also suffers from (i) limited carbon dioxide capacities, (ii) amine evaporation into the atmosphere and (iii) amine degradation in the presence of oxygen and other contaminant gases. This programme explores the use of electricity to capture and release carbon dioxide as a more energy-efficient method of CCS that can overcome the limitations of amines. In electrochemical carbon dioxide capture, the charging of an energy storage device such as a battery or a supercapacitor causes the selective absorption of carbon dioxide. When the device is discharged, pure carbon dioxide is released (for subsequent storage), and much of the energy supplied during charging is recovered. Initial work suggests that this technology may be more energy-efficient than existing approaches, and there is still vast room for improvement, especially if the molecular mechanisms of capture can be understood and manipulated. We will (i) advance the understanding of electrochemical carbon dioxide capture and (ii) discover new materials and devices that capture carbon dioxide more efficiently. Specifically we will focus on electrochemical carbon dioxide capture by supercapacitors. We will measure the amount of carbon dioxide that can be captured by these devices and we will optimise the electrode and electrolyte materials to improve performance. A proper understanding of the molecular mechanism of electrochemical carbon dioxide capture may lead to breakthroughs for this technology. A key thrust of the programme is therefore mechanistic studies of the molecular-level capture mechanism. We will use a suite of experimental techniques to study the chemical structures of the electrode materials, and we will correlate these structures with their carbon capture properties. We will develop nuclear magnetic resonance studies that allow the molecular form of the bound carbon dioxide to be determined at different stages of the capture process. Our mechanistic studies will inform the design and synthesis of improved materials for electrochemical carbon dioxide capture. We will synthesise the next generation of materials with (i) larger carbon dioxide uptake capacities, (ii) lower energy requirements for regeneration and (iii) faster uptake rates. New technology generated by this work will be prototyped and developed into flow systems. The developed technology will generate clean economic growth and will help the UK meet its 2050 net-zero emissions target. The research background of ACF combined with the assembled team of partners and excellent institutional support will lead to new knowledge and technology that will make the UK world-leading in electrochemical carbon dioxide capture

UKRI Gateway to Research · FY 2025 · 2025-01

Generative artificial intelligence has made a significant leap in developing intuitive natural language based computer interfaces via large language models, and realistic image and video generation from text inputs. These have already started revolutionising creation and editing of code, text, images, videos, presentations, and many other digital media. We will extend these techniques to scene creation and processing by relying on the techniques we have been developing over the years. We will develop text-to-scene models for easy creation, intuitive control, and conversational capture of 3D objects and scenes. We will deploy these models to the new generation of extended reality devices with advanced displays, optics, sensors, and processing units to build a scene creation and editing system that uses voice and brain signals as inputs.

UKRI Gateway to Research · FY 2025 · 2025-01

The interior of mammalian cells is compartmentalized into specialized organelles with cargo being moved between these compartments by the trafficking of vesicles or tubules (little bubbles surrounded by a thin membrane made of a fatty substance called phospholipid and studded with proteins). Cargo, including trans-membrane and soluble proteins, is taken up into cells by a process called endocytosis in which vesicles formed at the cell surface deliver their cargo to the endocytic system. This consists of organelles called endosomes, endolysosomes and lysosomes. These organelles play a major role in cellular signalling, nutrition and homeostasis. Their aberrant function is linked to many pathophysiological states and they are a major site of bacterial, viral and protozoal pathogen entry into cells. Endosomes, endolysosomes and lysosomes are very dynamic organelles. They undergo constant cycles of remodelling as a result of fusion events between endosomes and lysosomes to form endolysosomes and the coupled reformation of lysosomes from endolysosomes. A key part of the re-modelling involves controlling the acidity of the lumen of these organelles. This ensures that endolysosomes, the principal site of cargo degradation, are very acidic, but terminal storage lysosomes are not acidic and therefore non-degradative. The acidity is controlled by the two-part tvacuolar ATPase (V-ATPase), a protein complex located in the membrane surrounding these organelles. The V-ATPase is a nanomachine powered by the hydrolysis of ATP and pumps hydrogen ions into the organelles to increase lumenal acidity. Its activity is mainly regulated by the state of assembly/disassembly of its two parts, The main aims and objectives of our proposal are to determine: (i) the timing of net assembly and disassembly of V-ATPase on endolysosomes and reforming lysosomes; (ii) the mechanism of regulating the net recruitment of the V1 sub-complex of V-ATPase to endolysosomes and its release from reforming lysosomes. To achieve our aims, we will exploit state of the art fluorescence and electron microscopy techniques to study cultured mammalian cells and integrate these cell biology studies with biochemical, biophysical and structural biology techniques. This will enable us to reach our goal of understanding fully the process of V-ATPase assembly/disassembly and its critical role in controlling the lumenal acidity and function of endolysosomes and lysosomes in continuously fed cells. We will then apply the resulting knowledge in a collaboration to understand the role of V-ATPase assembly/disassembly in the specialised case of secretory lysosomes required for the killing function of cytotoxic T lymphocytes (a type of white blood cell). These immune system cells destroy virally infected and cancer cells and are the cornerstone of modern cell-based immunotherapies. Abnormalities of endolysosome/lysosome acidity and function make a major contribution to many disease states including lysosome storage diseases, neurodegeneration and the response to some pathogens. In the long term our work could aid in the identification of potential targets for therapeutic interventions in these diseases. Finally, understanding the regulation of endolysosomal/lysosomal acidification is also important to the pharmaceutical industry because it affects the pharmacokinetics, drug-drug interactions and off-target toxicity of many small molecule drugs.

UKRI Gateway to Research · FY 2025 · 2025-01

This grant supports STFC IRIS Federation to deliver compute and storage to its science activities by placing hardware at the University of Cambridge.

UKRI Gateway to Research · FY 2025 · 2025-01

This project is to support the Science Data Processor (SDP) component of the SKA. The SDP is the element of the telescope responsible for processing various observed data into required data products (which consists of combined and processed raw data together with metadata), long-term preservation of these data products, and delivery of these products to SKAO and scientists working in SKA Regional Centres (SRCs). This project deals with the construction of the SDP system, its support in integration, testing and commissioning, and the development and demonstration of increasingly capable SDP pipeline performance are the key components of this project.

UKRI Gateway to Research · FY 2025 · 2025-01

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.